Nursing procedures and alterations in transcutaneous oxygen tension in premature infants.
This study evaluated the effects of three routine nursing procedures--suctioning, repositioning, and performing a heelstick--on blood oxygen levels in premature infants, using a transcutaneous oxygen (Tcp02) monitor. Twenty-five infants with respiratory distress syndrome were monitored for three hours during which all three procedures were performed. Continuous Tcp02 records were used for measurement of baseline Tcp02 degree and duration of Tcp02 changes, length of procedural time, and rest time prior to procedures. Data were analyzed to determine if Tcp02 was altered during routine procedures, and if the degree of change was affected by length of procedure or length of rest prior to a procedure. Degree of Tcp02 change was analyzed in relation to length of time taken to recover from procedures. Tcp02 was decreased significantly during suctioning and repositioning but not during heelstick. The three procedures resulted in different degrees of change in Tcp02. Suctioning elicited the greatest decrease, followed by respositioning then heelstick. Recovery time was related to the degree of change in Tcp02 only after the repositioning procedure. Length of procedure and rest time did not relate to the degree of change in Tcp02, suggesting that it was the type of procedure that determined infant response.


Monitoring VHA Optometric Eye Exam Services, Nation-Wide, 2014-2016.
It is important to monitor the use of optometric services by Veterans and consider the implications for other optometric and vision rehabilitation services. We did not find public health reports documenting the recent utilization of Veterans Health Administration (VHA) optometric eye exam services. A cross-sectional study design was used in this secondary data analysis report. We were interested in reporting on the number of Veterans using the VHA system with at least one VHA optometric eye exam service in 2014, 2015, or 2016 within a VHA optometry clinic. The data from Veterans were derived from the VHA Corporate Data Warehouse. The number of unique Veteran patients who had at least one indication of VHA optometric eye exam service, nation-wide, increased from 1.4 million Veteran patients in 2014 to 1.6 million patients in 2016. The percentage of Veterans using VHA optometric eye exam services out of all unique VHA patients receiving care in the VHA system in 2014, 2015, and 2016 was 25.4%, 25.8%, and 26.8%, respectively. During each year of this time period, about 94% of the Veteran patients were male using optometric eye exam services. Florida, California, Texas, Ohio, and New York had the largest number of Veterans using optometric eye exam services, at least once, in 2014, 2015, or 2016. Veteran patients who made at least one VHA optometric eye exam service visit, nation-wide, increased from 2014 to 2016. Data showed that Veteran patients in the older age groups (age 55 and greater) used optometric eye exam services differently when compared with Veterans in the younger age groups. This difference may invite consideration of the differing optometric needs of these two, broad groups of eligible Veterans in order to expand access to VHA optometric clinical services.


Palladium-catalyzed para-selective arylation of phenols with aryl iodides in water.
Highly para-selective palladium-catalyzed direct arylation of phenols with aryl iodides was demonstrated by taking advantage of the formal inverse direct arylation strategy. A series of 4-aryl phenols were synthesised by employing water as a "green" solvent under mild reaction conditions.


Through thick and thin: cryptic sympatric speciation in the submersed genus Najas (Hydrocharitaceae).
Cryptic sympatric species arise when reproductive isolation is established in sympatry, leading to genetically divergent lineages that are highly similar morphologically or virtually indistinguishable. Although cryptic sympatric species have been reported in various animals, fungi, and protists, there are few compelling examples for plants. This investigation presents a case for cryptic sympatric speciation in Najas flexilis, a widespread aquatic plant, which extends throughout northern North America and Eurasia. The taxon is noted for its variable seed morphology, which earlier research associated with cytotypes; i.e., diploids were characterized by thicker seeds and tetraploids by thinner seeds. However, cytotypes are not patterned geographically with diploid and tetraploid plants often found in close proximity within the same lake. Using digital image and DNA sequence analyses, we found that diploids and tetraploids are well-isolated and remain genetically distinct throughout their sympatric range, where sterile hybrids occur frequently. Incorporation of sequence data from the single-copy nuclear phytoene desaturase locus revealed further that the tetraploids are allopolyploid derivatives of N. flexilis and N. guadalupensis, the latter a closely related species with an overlapping distribution. We conclude that the taxon widely known as N. flexilis actually comprises two cryptic, sibling species, which diverged in sympatry by interspecific hybridization and subsequent chromosomal isolation. By comparing seed morphology of type specimens, we associated the names N. flexilis and N. canadensis to the diploids and tetraploids respectively. Additionally, the narrowly restricted taxon known formerly as N. muenscheri is shown via morphological and genetic evidence to be synonymous with N. canadensis.


[Comparative evaluation of Iterative and FORE-Iterative reconstruction algorithms for PET/CT].
In this study, the properties of the reconstruction algorithm Iterative in comparison with the FORE-Iterative using 18F-FDG PET/CT data were evaluated. The study was conducted in the Department of Nuclear Medicine of Evangelismos Athens General Hospital, in which data from 9 patients were collected and reconstructed with both algorithms, Iterative and FORE-Iterative. For each patient, the image quality was assessed using parameters such as SUVmax, SUVpeak, SUVmean, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Regions of interest were defined based on medical expertise focusing on the tumor areas. Based on the results of this study, images reconstructed with Iterative algorithm have better image quality compared to the images reconstructed with FORE-Iterative algorithm, considering that this particular method improves SNR and CNR. Using the Iterative algorithm, the image becomes sharper due to reduced noise resulting in safer clinical observations, and as a result a more accurate diagnosis.


Preparation and characterization of nickel nanoparticles for binding to his-tag proteins and antigens.
The purpose of these studies was to prepare nanoparticles (NPs) with a small amount of surface-chelated nickel for obtaining enhanced binding of histidine-tagged (his-tag) proteins compared to non-histidine-tagged protein binding to charged nanoparticles. NPs were prepared from oil-in-water microemulsion precursors using emulsifying wax, 3 mM Brij 78 and 0.1 mM DOGS-NTA-Ni lipid (referred to as Ni-NPs). The amount of lipid entrapped in the NPs was quantitated by atomic emission spectroscopy (AES). The Ni-NPs were investigated for binding to two his-tag proteins, green fluorescent protein (GFP) and his-tag HIV-1 Gag p24. In vivo studies in mice were carried out to evaluate the immune responses obtained to his-tag Gag p24 bound to Ni-NPs. AES studies demonstrated that approximately 5% of the DOGS-NTA-Ni lipid used was entrapped in the NPs. The optimal binding ratio his-tag GFP and his-tag Gag p24 to Ni-NPs was found to be 1:33.7 and 1:35.4 w/w, respectively. This interaction was stable at 37 degrees C in PBS, pH 7.4 over 4 h and the interaction of his-tag GFP with the Ni-NPs was enhanced compared to control NPs prepared with no Ni on the surface (NTA-NPs). The in vivo studies demonstrated enhanced serum IgG and IgG2a responses to his-tag Gag p24 bound to Ni-NPs compared to protein adjuvanted with Alum or adsorbed on the surface of control NTA-NPs. Ni-NPs can be used to bind strongly to his-tag proteins. This system was demonstrated to have potential applications in vaccine delivery for enhancing immune responses to protein-based vaccines.


Impact of steam treatment on shelf-life stability of a xanthone-rich green herbal tea (Cyclopia maculata Andrews Kies) - identifying quality changes during storage.
Steam treatment of shredded, fresh C. maculata (honeybush) plant material improves the aroma of this green herbal tea with a slight impact on color and phenolic content, but the effect on storage stability is not known. Steam-treated (60 s before drying) and untreated (control) dried plant material was stored under normal storage conditions in semi-permeable sachets at 25 °C and 60% relative humidity. Reference samples of treated (steamed) and untreated (control) material were stored at 0 °C in impermeable pouches for maximum retention of quality. The stability of the herbal tea was assessed in terms of sensory profile, phenolic composition and color over a storage period of 6 months. Normal storage conditions resulted in a significant (P < 0.05) decrease in green color, especially in steamed samples. Intensities of fruity and sweet-associated aroma attributes increased progressively during storage, while the opposite was observed for vegetal and cereal-like attributes. These changes in the aroma profile were more pronounced in untreated (control) samples. Individual phenolic content remained stable during storage. Storage of 3 to 6 months may result in a more appealing aroma profile and enhanced product quality, despite loss of green color. © 2018 Society of Chemical Industry.


Apatinib promotes apoptosis of the SMMC-7721 hepatocellular carcinoma cell line via the PI3K/Akt pathway.
The present study investigated the inhibitory effects of apatinib on the proliferation of the SMMC-7721 hepatocellular carcinoma cell line to explore the possible mechanism. The MTT assay was used to detect the inhibitory effects of the different concentrations of apatinib on the proliferation of SMMC-7721 cells. Annexin V/PI double staining was performed to investigate the effects of apatinib on the apoptosis of SMMC-7721 cells. Expression of the apoptosis-related genes Bcl-2, Bax and caspase-9 after apatinib treatment was detected by reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. Expression of the PI3K, p-PI3K, Akt and p-Akt proteins after apatinib treatment was detected using western blot analysis. The MTT results showed that apatinib inhibited the in vitro proliferation of SMMC-7721 cells. Annexin V/PI double staining showed that apatinib induced the apoptosis of SMMC-7721 cells in a concentration-dependent manner. Results of RT-qPCR and western blot analysis showed that apatinib was able to induce the expression of pro-apoptotic genes Bax and caspase-9 and inhibited the expression of anti-apoptotic gene Bcl-2. In addition, the western blot analysis revealed that p-PI3K and p-Akt was significantly decreased following apatinib treatment, while no significant differences were found in the total protein levels of PI3K and Akt. The results of the present show that apatinib is capable of promoting the apoptosis of SMMC-7721 cells by inhibiting the PI3K/Akt signal transduction pathway, upregulating the expression of pro-apoptotic genes Bax and caspase-9, and downregulating the expression level of the anti-apoptotic gene Bcl-2.


[Exploration of extra-cephalic pain induced in essential headaches].
The deep pain threshold and migrainous patient's tolerance were investigated by different methods such as: the post-ischemic stasis, muscular exercise in an ischemic condition, sural pressure, comparing them with the cold pain test employed to assess the superficial pain threshold. The tests were carried out simultaneously and symmetrically to both extremities in order to check the possible asymmetry of the pain threshold. Migrainous patients showed a reduced threshold and a lower tolerance to deep pain, while this is not evident when testing the superficial threshold. The simultaneous measurement of both extremities showed higher differences in migrainous patients than in control patients. The meaning of the change of systemic pain is discussed, with special reference to the possible correlation with the hypothesis of a central origin of pain in essential headaches.


Impute the missing data using retrieved dropouts.
In the past few decades various methods have been proposed to handle missing data of clinical studies, so as to assess the robustness of primary results. Some of the methods are based on the assumption of missing at random (MAR) which assumes subjects who discontinue the treatment will maintain the treatment effect after discontinuation. The agency, however, has expressed concern over methods based on this overly optimistic assumption, because it hardly holds for subjects discontinuing the investigational drug. Although in recent years a good number of sensitivity analyses based on missing not at random (MNAR) assumptions have been proposed, some use very conservative assumption on which it might be hard for sponsors and regulators to reach common ground. Here we propose a multiple imputation method targeting at "treatment policy" estimand based on the MNAR assumption. This method can be used as the primary analysis, in addition to serving as a sensitivity analysis. It imputes missing data using information from retrieved dropouts defined as subjects who remain in the study despite occurrence of intercurrent events. Then imputed data long with completers and retrieved dropouts are analyzed altogether and finally multiple results are summarized into a single estimate. According to definition in ICH E9 (R1), this proposed approach fully aligns with the treatment policy estimand but its assumption is much more realistic and reasonable. Our approach has well controlled type I error rate with no loss of power. As expected, the effect size estimates take into account any dilution effect contributed by retrieved dropouts, conforming to the MNAR assumption. Although multiple imputation approaches are always used as sensitivity analyses, this multiple imputation approach can be used as primary analysis for trials with sufficient retrieved dropouts or trials designed to collect retrieved dropouts.


[Suppression of cell proliferation by inhibitors to redox signaling in human lens epithelial cells].
Physiological level of reactive oxygen species (ROS) has been shown to play an important role in mitogen-stimulated cell signaling in many cell types. Both EGF and bFGF can induce ROS generation in human lens epithelial cells. But the role of ROS and Redox signaling on EGF and bFGF-stimulated cell proliferation is not clear. This study was to investigate the control of EGF and bFGF-induced cell proliferation by Redox signaling in human lens epithelial cells (SRA 01/04), using specific inhibitors to Redox signaling. EGF and bFGF-induced cell proliferation was measured by [methyl-3H] thymidine incorporation assay. In some experiments, cell proliferation was also measured by trypan blue negative cell counting parallel with 3H-thymidine incorporation assay. The inhibitors used in this study include: catalase (specific enzyme to detoxify hydrogen peroxide), N-acetyl-L-cysteine (free radical scavenger), DPI (inhibitor for NADPH oxidase) and AACOCF3 (specific inhibitor for cytosolic phospholipase A2, which had been shown to play important role in ROS generation in our previous study). Serum starved SRA 01/04 cells were pretreated with these inhibitors for 30 minutes before exposure to EGF or bFGF (20 microg/L). In short term study, all these inhibitors were removed before adding growth factor, while in long term study, inhibitors were maintained in the medium along with growth factor. Cells were kept growing in the medium with 20 microg/L EGF or 20 microg/L bFGF for 48 hours. Then cell proliferation was quantified by [methyl-3H] thymidine incorporation assay or by cell counting. We found that catalase, NAC, DPI and AACOCF3 were able to suppress EGF and bFGF-induced cell proliferation in both short term and long term study. In EGF study, 20 microg/L EGF produced about 26% (t = 7.093, P <0.01) increase in DNA synthesis after 48 hours. Pretreatment of the cells for 30 minutes with 1 x 10(5) U/L catalase, 0.5 mmol/L NAC, 0.1 micromol/L DPI or 0.5 micromol/L AACOCF3 inhibited EGF-stimulated DNA synthesis by 18.0% (t=6.132, P<0.01), 24.6% (t=6.188, P<0.01), 28.5% (t=6.386, P<0.01) and 16.4% (t =3.705, P =0.001) respectively. The inhibition was dose-dependent and was proved by trypan-blue negative cell counting. If the cells were treated with inhibitors for 48.5 hours (long term study), the lowest concentrations to inhibit cell proliferation were much lower than those used in short term study. Treatment of the cells with 0.5 x 10(5) U/L catalase, 0.2 mmol/L NAC, 0.01 micromol/L DPI and 0.1 micromol/L AACOCF3 led to suppression on DNA synthesis significantly. Similar results were detected in bFGF study. 48 hours treatment with 20 microg/L bFGF induced about 28.8% (t =9.523, P <0.01) increase in cell proliferation. If the cells were pretreated with 1 x 10(5) U/L catalase, 0.5 mmol/L NAC, 0.1 micromol/L DPI or 0.5 micromol/L AACOCF3 for 30 minutes, bFGF-stimulated cell proliferation was suppressed by 24.5% (t = 6.697, P < 0.01), 22.2% (t = 6.693, P<0.01), 23.9% (t =6.661, P<0.01) and 30.5% (t =8.959, P <0.01) respectively. If cells were treated with inhibitors for 48.5 hours, the lowest concentration of catalase, NAC, DPI and AACOCF3 to inhibit cell proliferation significantly was 0.5 x 10(5) U/L( t =21.641, P <0.01), 0.2 mmol/L (t =11.218, P < 0.01), 0.01 micromol/L (t = 4.570, P <0.01) and 0.1 micromol/L (t = 5.426, P < 0.01) respectively, lower than those used in short term study. We conclude that mitogenic stimulus function of EGF and bFGF in human lens epithelial cells appears to be mediated via ROS to activate cell proliferation. Inhibition of Redox signaling, either by removal of ROS (the role of catalase and NAC) or blocking ROS generation (the role of DPI and AACOCF3), eradicate EGF and bFGF-stimulated cell proliferation. It is proposed that Redox signaling may play an important role in cell proliferation in human lens epithelial cells.


Parameterization and conformational sampling effects in pharmacophore multiplet searching.
Pharmacophore patterns in ligands can be effectively characterized in terms of their constituent pharmacophore multiplets. Bitsets (fingerprints) encoding which particular multiplets are found in a given ligand have been and continue to be used as molecular descriptors in a range of molecular modeling applications, from ligand alignment and diversity analysis to pharmacophore-based flexible searching. Being able to create, store, and manipulate multiplets in compressed form - as bitmaps - has made it possible to integrate them into high-throughput technologies. A number of key parameters affect how well multiplets perform, including the granularity of edge length binning; how different multiplets are weighted in creating hypotheses from multiple ligands; and the number of bits that should be included in a pharmacophore hypothesis. The similarity metric employed for bitmap comparisons also affects search performance, as does the conformational sampling regime used for characterizing flexible molecules. In this report we explore the effect of parameter variation on within- and between-class similarity across seven different pharmacological classes and introduce a new measure of molecular similarity - the asymmetric stochastic cosine - uniquely suited to searching a database for matches to query hypotheses deduced from multiple ligands. Surprisingly, it turns out that the most discriminating bitmaps are obtained using relatively few conformers. The extreme discrimination power seen for single conformers, however, seems to reflect consistent effects of 2D connectivity on the 3D structure obtained. Conformational sampling by systematic search reinforces such circumstantial discrimination and should be avoided. The potential for systematic bias becomes clear when the behavior of otherwise similar conformational ensembles created by local energy minimization or by random sampling is considered. Consolidating information from multiple known actives or establishing single "bioactive" conformations a priori are safer ways to improve discrimination in pharmacophoric multiplet searching.


Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner.
Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S-CMC), a mucolytic agent, in cellular and animal models of oxidative stress-mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress-induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases.


Prevlaence of chronic kidney disease markers in Kumbotso rural Northern Nigeria.
Data- on the epidemiology of Chronic Kidney Disease (CKD) from sub-SaharanAfrica are sparse. We investigated the prevalence of CKD and its early markers in Kumbotso, a rural community in northern Nigeria. A total of 480 individuals were randomly selected from the general population using multistage stratified random sampling. Relevant- demographic and clinical data were obtained using a structured questionnaire. Biological samples (urine and blood) were drawn for relevant investigations. CKD (estimated glomerular filtration rate [eGFR <60 mls/min) was found in 117 participants (26%). Proteinuria was present in 106 persons (23.6%) and haematuria in 7 individuals (1.6%). The most common CKD stage was stage 1 (20%). CKD was associated with hypertension (P=0.002), diabetes (P=0.001), high cholesterol (P=0.030), smoking (P=0.015), increasing BMI (P=0.020), and increasing age (P=0.003). After adjusting for potential confounding with logistic regression modeling we found BMI, family history of hypertension, history of diabetes mellitus and family history of renal disease to be independent predictors of CKD. Early markers of CKD are common among rural inhabitants of northern Nigeria and this call for concerted efforts towards institution of preventive measures.


Precision of fit between implant impression coping and implant replica pairs for three implant systems.
The fabrication of an accurately fitting implant-supported fixed prosthesis requires multiple steps, the first of which is assembling the impression coping on the implant. An imprecise fit of the impression coping on the implant will cause errors that will be magnified in subsequent steps of prosthesis fabrication. The purpose of this study was to characterize the 3-dimensional (3D) precision of fit between impression coping and implant replica pairs for 3 implant systems. The selected implant systems represent the 3 main joint types used in implant dentistry: external hexagonal, internal trilobe, and internal conical. Ten impression copings and 10 implant replicas from each of the 3 systems, B (Brånemark System), R (NobelReplace Select), and A (NobelActive) were paired. A standardized aluminum test body was luted to each impression coping, and the corresponding implant replica was embedded in a stone base. A coordinate measuring machine was used to quantify the maximum range of displacement in a vertical direction as a function of the tightening force applied to the guide pin. Maximum angular displacement in a horizontal plane was measured as a function of manual clockwise or counterclockwise rotation. Vertical and rotational positioning was analyzed by using 1-way analysis of variance (ANOVA). The Fisher protected least significant difference (PLSD) multiple comparisons test of the means was applied when the F-test in the ANOVA was significant (α=.05). The mean and standard deviation for change in the vertical positioning of impression copings was 4.3 ±2.1 μm for implant system B, 2.8 ±4.2 μm for implant system R, and 20.6 ±8.8 μm for implant system A. The mean and standard deviation for rotational positioning was 3.21 ±0.98 degrees for system B, 2.58 ±1.03 degrees for system R, and 5.30 ±0.79 degrees for system A. The P-value for vertical positioning between groups A and B and between groups A and R was <.001. No significant differences were found for vertical positioning between groups B and R. The P-value for rotational positioning between groups A and B and between groups A and R was <.001. No significant differences were found for rotational positioning between groups B and R. The results of the study confirmed that implant systems differ in precision of fit. Vertical precision between paired implant components is a function of joint type and the tightening force applied to the guide pin. The magnitude of vertical displacement with applied torque is greater for conical connections than for butt joint connections. The rotational freedom between paired components is unique to the implant system and is presumably related to the machining tolerances specified by the manufacturer.


Reduced Graphene Oxide Quantum Dot Light Emitting Diodes Fabricated Using an Ultraviolet Light Emitting Diode Photolithography Technique.
Graphene quantum dots usually suffer from serious fluorescence quenching in aggregates and the solid state due to easy agglomeration and aggregation-induced quenching, which seriously restrict their practical applications. An ingenious strategy to kill three birds with one stone, the ultraviolet (UV) photolithography technique, was studied, and blue-emitting reduced graphene oxide quantum dot (rGOQD)-based light emitting diodes (LEDs) with efficient solid state emission were first fabricated using UV photolithography. First, rGOQDs were prepared by the in situ photoreduction of GOQDs by using the photoinitiator phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide with 395 nm UV LED exposure. Furthermore, rGOQD/photoresist patterns were prepared under the same conditions. Meanwhile, the in situ photoreduction of GO in the aforementioned photoresist to rGO was realized by UV photolithography to improve the conductivity of the rGOQD/photoresist films. Additionally, the in situ photoreduction of GOQDs in different surroundings was studied, with the results showing that GOQDs are more easily photoreduced in ionic liquids and that the photoluminescence spectrum obtained for rGOQDs exhibits a 70 nm blueshift with a narrow full-width at half-maximum compared to GOQDs.


Quantification of casein phosphorylation with conformational interpretation using Raman spectroscopy.
Raman spectroscopy is emerging as a powerful method for obtaining both quantitative and qualitative information from biological samples. One very interesting area of research, for which the technique has rarely been used, is the detection, quantification and structural analysis of post-translational modifications (PTMs) on proteins. Since Raman spectra can be used to address both of these questions simultaneously, we have developed near infrared Raman spectroscopy with appropriate chemometric approaches (partial least squares regression) to quantify low concentration (4 microM) mixtures of phosphorylated and dephosphorylated bovine alpha(s)-casein. In addition, we have used these data in conjunction with Raman optical activity (ROA) spectra and NMR to assess the structural changes that occur upon phosphorylation.


Advances in image-guided intratumoral drug delivery techniques.
Image-guided drug delivery provides a means for treating a variety of diseases with minimal systemic involvement while concurrently monitoring treatment efficacy. These therapies are particularly useful to the field of interventional oncology, where elevation of tumor drug levels, reduction of systemic side effects and post-therapy assessment are essential. This review highlights three such image-guided procedures: transarterial chemoembolization, drug-eluting implants and convection-enhanced delivery. Advancements in medical imaging technology have resulted in a growing number of new applications, including image-guided drug delivery. This minimally invasive approach provides a comprehensive answer to many challenges with local drug delivery. Future evolution of imaging devices, image-acquisition techniques and multifunctional delivery agents will lead to a paradigm shift in patient care.


Maximum entropy production and plant optimization theories.
Plant ecologists have proposed a variety of optimization theories to explain the adaptive behaviour and evolution of plants from the perspective of natural selection ('survival of the fittest'). Optimization theories identify some objective function--such as shoot or canopy photosynthesis, or growth rate--which is maximized with respect to one or more plant functional traits. However, the link between these objective functions and individual plant fitness is seldom quantified and there remains some uncertainty about the most appropriate choice of objective function to use. Here, plants are viewed from an alternative thermodynamic perspective, as members of a wider class of non-equilibrium systems for which maximum entropy production (MEP) has been proposed as a common theoretical principle. I show how MEP unifies different plant optimization theories that have been proposed previously on the basis of ad hoc measures of individual fitness--the different objective functions of these theories emerge as examples of entropy production on different spatio-temporal scales. The proposed statistical explanation of MEP, that states of MEP are by far the most probable ones, suggests a new and extended paradigm for biological evolution--'survival of the likeliest'--which applies from biomacromolecules to ecosystems, not just to individuals.


ER stress is not elevated in the 5XFAD mouse model of Alzheimer's disease.
Alzheimer's disease mouse models that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1) form β-amyloid (Aβ) plaques, a hallmark Alzheimer's disease lesion. It has been assumed that the neuroinflammation, synaptic dysfunction, neurodegeneration, and cognitive impairment observed in these mice are caused by cerebral Aβ accumulation. However, it is also possible that accumulation of the overexpressed transmembrane proteins APP and PS1 in the endoplasmic reticulum (ER) triggers chronic ER stress and activation of the unfolded protein response (UPR). The 5XFAD mouse, a widely used amyloid pathology model, overexpresses APP and PS1, displays aggressive amyloid pathology, and has been reported to exhibit ER stress. To systematically evaluate whether 5XFAD mice have increased ER stress, here we used biochemical approaches to assess a comprehensive panel of UPR markers. We report that APP and PS1 levels are 1.8- and 1.5-fold, respectively, of those in 5XFAD compared with nontransgenic brains, indicating that transgenes are not massively overexpressed in 5XFAD mice. Using immunoblotting, we quantified UPR protein levels in nontransgenic, 5XFAD, and 5XFAD;BACE1-/- mice at 4, 6, and 9 months of age. Importantly, we did not observe elevation of the ER stress markers p-eIF2α, ATF4, CHOP, p-IRE1α, or BiP at any age in 5XFAD or 5XFAD;BACE1-/- compared with nontransgenic mice. Despite lacking Aβ generation, 5XFAD;BACE1-/- mice still expressed APP and PS1 transgenes, indicating that their overexpression does not cause ER stress. These results reveal the absence of ER stress in 5XFAD mice, suggesting that artifactual phenotypes associated with overexpression-induced ER stress are not a concern in this model.


Atherosclerosis severity but not undiagnosed diabetes predicts new cardiovascular events of subjects in secondary cardiovascular prevention.
Undiagnosed diabetes (DM2), especially in individuals that have experienced a major atherosclerotic vascular event, could increase the risk of a second major cardiovascular (CV) event. The aim of this study was to evaluate the impact of type 2 diabetes (DM2), diagnosed after a major cardiovascular event, on subsequent CV disease in high risk individuals. 411 subjects without known DM2 and with a history of a prior major CV event were followed for a second major CV event (fatal and nonfatal MI, fatal and nonfatal stroke or any arterial revascularization procedure). At baseline, each individual underwent a physical, biochemical examination, an OGTT and dosed A1c. In addition, patients were classified as having monovascular or polyvascular disease. The average follow-up duration was 31 months. The incidence of second CV events was 10.70 per 100 person-years (114 events/1066 person-years). The diagnosis of occult DM2 was not associated with major CV events, either using A1c values ≥6.5%, fasting glucose ≥126 mg/dL or 2 h post-load glucose ≥200 mg/dL. Polyvascular disease was the only significant predictor of a second major CV event (HR 2.60, 95% CI 1.72-3.95) after adjustment for age, BMI, smoking status, systolic blood pressure, high-density and low-density lipoprotein cholesterol and high sensitivity C-reactive protein. DM2 that was newly diagnosed after established vascular atherosclerotic disease did not increase the risk of new major CV events. In our population only the polyvascular disease was able to identify the subjects at high risk for a second major cardiovascular event.


Inspiratory muscle training in chronic airflow limitation: comparison of two different training loads with a threshold device.
The usefulness of inspiratory muscle training (IMT) in chronic airflow limitation (CAL) patients is a controversial issue, mainly due to differences in the training load. To further evaluate this aspect, we studied the effect of the magnitude of the load using a threshold pressure trainer. Ten CAL patients (5 males, 5 females) 67 +/- 2 yrs (mean +/- SEM) and forced expiratory volume in one second (FEV1) 36 +/- 2% pred, were trained for 30 min a day using a load of 30% of their maximal inspiratory mouth pressure (PImax) (Group 1). Another 10 CAL patients (5 males, 5 females), 73 +/- 2 yrs and FEV1 37 +/- 2% pred), were trained using only 12% of their PImax (Group 2). Training was assessed by PImax, inspiratory muscle power output (IMPO), sustainable inspiratory pressure (SIP), maximal inspiratory flow rate (VImax), pattern of breathing during loaded breathing, Mahler's dyspnoea score, and the 6 min walking distance (6MWD). After 5 weeks of training, Group 1 exhibited significant increments in: PImax (34 +/- 11%); IMPO (92 +/- 16%); SIP (36 +/- 9%); and VImax (34 +/- 13%). Dyspnoea was also reduced, and the 6MWD increased by 48 +/- 22 m. We observed no significant changes in Group 2. During loaded breathing, Group 1 showed a significant increment in tidal volume (VT) and mean inspiratory flow (VT/TI), and a reduction in inspiratory time (TI). In Group 2, VT and VT/TI also increased significantly, but the breathing frequency increased with a reduction of expiratory time.(ABSTRACT TRUNCATED AT 250 WORDS)


Connective-tissue macromolecules in Golgi chicken tendon organs and at their interface with muscle fibers and adjoining tendinous structures.
Tendon organs from leg and forearm muscles of white leghorn chickens were examined with a library of monoclonal antibodies to determine the composition of their connective-tissue framework and the types of connective-tissue macromolecules that occur at the sites where muscle fibers attach to the receptors. The capsules of the tendon organs were positive for connective-tissue macromolecules typical of basal lamina (collagen type IV, laminin, and heparin sulfate proteoglycan) and for tenascin, collagen types III and VI, and fibronectin. Connective-tissue bundles in the lumen of a receptor reacted primarily with antibodies against collagen type I and 4-chondroitin sulfate. The narrow partitions that divide each lumen into compartments stained for collagen type III. Toward its tendinous end, a receptor made few contacts with muscle fibers. Instead, the capsule and the collagenous bundles blended gradually with the intermuscular portions of tendons. At the muscular end, the connections were more complex. Muscle fibers that attached in series to tendon organs split to produce basal lamina-covered, finger-like extensions, which were separated from each other by fissures. Tongues of connective tissue containing tenascin, collagen types I and VI, and fibronectin extended into the fissures. Distally the tongues were continuous with the tenascin in the capsule and just internal to the capsule, fibronectin and basal lamina macromolecules in the capsule, and collagen type I in the collagenous bundles. The uninterrupted presence of these macromolecules around terminating muscle fibers and in the capsule and/or the intraluminal collagen bundles suggests that muscle fibers that attach in series at the muscular end exert a force during muscular contraction on the intraluminal collagen bundles and on the receptor capsule.


Anatomical Single-Bundle Anterior Cruciate Ligament Reconstruction Using a Calcium Phosphate-Hybridized Tendon Graft with More than an Average of 5 Years of Follow-Up: A Follow-Up Study of a Randomized Controlled Trial.
Calcium phosphate (CaP)-hybridized tendon grafting using an alternate soaking process improves tendon-to-bone healing in anterior cruciate ligament (ACL) reconstructions. This study aimed to compare bone tunnel enlargement, knee osteoarthritis, and clinical results between CaP-hybridized tendon grafting and conventional grafting in anatomical single-bundle ACL reconstruction. This study was a follow-up of a randomized controlled trial. Between July 2011 and December 2015, 90 patients underwent unilateral anatomical single-bundle ACL reconstructions and were randomly assigned to the CaP-hybridized tendon grafting (CaP group, n = 45; age, 27.1 [14-54] years; sex, 21 males and 24 females) or conventional grafting (control group, n = 45; age, 22.9 [13-58] years; sex, 26 males and 19 females). The randomization was performed according to the days of the week when the patients first visited the outpatient. The CaP-hybridized tendon grafting was created intraoperatively. The tendon grafts were soaked in a calcium solution for 30 s. After that, the tendon grafts were soaked in a NaHPO4 solution for 30 s. This soaking cycle between the calcium solution and the NaHPO4 solution was repeated 10 times. The bone tunnel enlargement, osteoarthritis grade, clinical score, and sports level were evaluated in patients who could be followed up for >3 years (CaP group, n = 20, average follow-up period 6.0 [5.1-6.9] years; control group, n = 15, average follow-up period 5.6 [4.3-6.9] years). Clinical scores, sports levels, and osteoarthritis grades were analyzed using a generalized linear mixed model (GLMM) based on repeated measurement data from preoperative and final observations, with time, group, sex, age, and BMI as fixed effects and the effect of individual differences as variable effects. In addition, bone-tunnel enlargements were analyzed using generalized linear models (GLM) with group, sex, age, and BMI as the main effects. Compared with the control group, the CaP group exhibited significantly reduced bone-tunnel enlargement on the femoral side (anteroposterior diameter; CaP group, 7.9% [-1.1-16.8] vs. control group, 29.2% [17.9-40.5], p = 0.004, MCID 16.05, proximal-distal diameter; CaP group, 7.9% [-1.9-17.8] vs. control group, 22.8% [10.9-34.7], p = 0.062, MCID 15.00). The osteoarthritis grades progressed in both groups (p < 0.001). The clinical scores and sports levels were not significantly different between the groups. This study suggests that the calcium phosphate-hybridized tendon graft reduces femoral bone-tunnel enlargement after anatomical single-bundle anterior cruciate ligament reconstruction in an average >5-year follow-up period. A longer follow-up period is necessary to reveal the clinical effects of the calcium phosphate-hybridized tendon grafts in anterior cruciate ligament reconstruction.


Interpretation of magnetic resonance images making use of in vitro examinations of spinal tissue.
T1 and T2 relaxation times were determined in vitro at 21 MHz (0.5 T) for a variety of spinal and paraspinal tissues. Intensity formulas for spin echo and inversion recovery sequences were derived and used to calculate the intensities of these tissues as they would appear in magnetic resonance images. The intensity was calculated as a function of various repetition, echo, and inversion times. It is shown that the combination of acquiring in vitro relaxation time values and calculating intensity as a function of pulse timings is useful to predict the parameter setting for optimal contrast between certain tissues without applying series of magnetic resonance images.


Polymerase chain reaction-based diagnostic assay to detect cattle chronically infected with Babesia bovis.
From a B. bovis gene sequence coding for a 60 kDa merozoite surface protein previously published, two sets of primers were designed for the Polymerase Chain Reaction (PCR) assay. Primer set BoF/BoR was used to prime Taq Polymerase DNA amplification of a 350 bp fragment of the target B. bovis DNA. Primer set BoFN/BoRN was used to prepare a PCR-synthesized, Digoxigenin-dUTP-labeled probe (291 bp) which would hybridize to a sequence within the PCR-amplified parasite target DNA. PCR amplification of target DNA obtained from in vitro-cultured B. bovis and nucleic acid hybridization of amplified product with the nonradioactive DNA probe showed that a 350 bp fragment could be detected when as little as 10 pg of genomic parasite DNA was utilized in the assay. A fragment of similar size was amplified from genomic DNA from four other B. bovis isolates but not from B. bigemina, Anaplasma marginale, or bovine leukocyte DNA. The PCR product was detected in blood samples containing approximately 3 B. bovis-infected erythrocytes (20 microliters of packed cells with a parasitemia of 0.000001%). By using the PCR/DNA probe assay, 16 out of 20 animals experimentally inoculated with B. bovis were detected positive, whereas no PCR product was observed in bovine blood samples collected from 20 B. bigemina-infected, and 20 uninfected cattle tested. The PCR-DNA probe assay was shown to be sensitive in detecting some cattle with B. bovis-chronic infection. The specificity and high analytical sensitivity of the test provides a valuable tool to apply in conducting epidemiological studies.


Effect of Shading on Development, Yield and Quality of Bastard Balm Herb (Melittis melissophyllum L.).
The aim of the study was to assess the effects of Melittis melissophyllum shading on its development and accumulation of phenolics. Their content (verbascoside, apiin, luteolin-7-O-glucoside, coumarin, 3,4-dihydroxycoumarin, o-coumaric acid 2-O-glucoside as well as o-coumaric, p-coumaric, chlorogenic, caffeic, ferulic and cichoric acid) was determined in the herb using HPLC-DAD. The results showed that the content of abovementioned flavonoids and phenolic acids was highest in plants grown under full sunlight. On the other hand, a higher content of coumarin was observed in shaded plants, especially after the seed-setting stage. A similar tendency was noted for the amount of chlorophyll a and b. The content of hydrogen peroxide and malondialdehyde, the activity of polyphenol oxidase and catalase and the antioxidant capacity of plant extracts (measured using DPPH, ABTS and FRAP assays) were found to be the highest in the plants grown in full sunlight. However, the plants grown in moderate (30%) shade were found to thrive best.


Urban-rural differences in food consumption and environment and anthropometric parameters of older adults: results from ELSI-Brazil.
This study aimed to identify dietary and anthropometric differences in older Brazilian adults (≥ 50 years old) living in urban-rural areas. This is a cross-sectional study with data from the second wave (9,949 participants) of the Brazilian Longitudinal Study of Aging (ELSI-Brazil) from 2019-2021. Weekly dietary intake of fruit/vegetables, beans, and fish; self-perception of salt consumption; food environment (availability of fruit/vegetables in the neighborhood and self-production of food); and objective anthropometric parameters (body mass index [BMI] and waist circumference [WC]) were evaluated. Analyses were adjusted for schooling level. Compared to urban areas, rural areas show lower consumption of fruit/vegetables five days or more per week (74.6% vs. 86.4%) and greater adequate salt intake (96.8% vs. 92.1%) - differences we observed for men and women. Rural areas showed lower high WC (61.9% vs. 68%), significant only for men. Considering food environment, rural areas had lower fruit and vegetable availability in the neighborhood (41.2% vs. 88.3%) and higher self-production of food (38.2% vs. 13.2%). We observed a lower consumption of fruit/vegetables five days or more per week in rural areas with fruit/vegetable availability in the neighborhood and no self-production of food. Urban and rural areas show food and nutritional diversity. Incentives for fruit or vegetable consumption among residents in urban areas should consider the greater availability of these foods in their neighborhood, whereas, in rural areas, self-production of food should be encouraged. Adequate salt intake and ideal WC maintenance should be reinforced in urban areas.


[Nursing practice in home care: social-demographic profile and professional practice].
To characterise the Andalusian nurses providing home care (HC), to describe the activities developed, to define the components of nursing practice and to identify differences between the care of terminal cancer, of AIDS patients, of elderly people with dementia and of patients who had undergone more serious out-patient surgery. Cross-sectional descriptive study using a postal questionnaire. Primary care centres in Andalusia. 348 PC nurses working in home care. Multi-stage sampling, proportional by provinces. Social-demographic and work characteristics, nursing activity in the home, type and frequency of activities performed in the care of each kind of patient and use of protocols. 61.14% reply rate. 65.5% were women, with mean age of 39.7 and averaging 10 years of PC experience. Mean number of patients attended was 10.5 per week, and mean time was 20.7 minutes. 90.1% had attended cancer patients, 16.7% AIDS patients, 83.3% elderly people with dementia, and 87.2% patients discharged early. In all cases the most commonly developed item was the technical one, followed by preventive/health promotion and psycho-social. Except in the case of evaluation of physiological needs, in all the other activities the frequency of the item was in function of the pathology of the patient (P<.05). Nursing practice in the home of terminal cancer patients and of elderly people with dementia only differs in the handling of emotional problems in both patient and carer, and in the preventive item (P<.05). 60% of the sample said they used no protocol in home care. The most common activities in care of home care patients are giving treatment, dressings, bandages, and monitoring of the vital constants, followed by assessment of physiological needs. Nursing practice does not seem to be fully conditioned by the pathology, but rather in function of groups of patients with similar needs and problems. Most Andalusian home-care nurses use no protocol in caring for these four classes of patient.


Transformation of an alpha-helix peptide into a beta-hairpin induced by addition of a fragment results in creation of a coexisting state.
Intrinsic rules of determining the tertiary structure of a protein have been unknown partly because physicochemical factors that contribute to stabilization of a protein structure cannot be represented as a linear combination of local interactions. To clarify the rules on the nonlinear term caused by nonlocal interaction in a protein, we tried to transform a peptide that has a fully helical structure (Target Peptide or TP) into a peptide that has a beta-hairpin structure (Designed Peptide or DP) by adding seven residues to the C terminus of TP. According to analyses of nuclear magnetic resonance measurements, while the beta-hairpin structure is stabilized in some DPs, it is evident that the helical structure observed in TP is also persistent and even extended throughout the length of the molecule. As a result, we have produced a peptide molecule that contains both the alpha-helix and beta-hairpin conformation at an almost equally populated level. The helical structures contained in these DPs were more stable than the helix in TP, suggesting that stabilizing one conformation does not result in destabilizing the other conformation. These DPs can thus be regarded as an isolated peptide version of the chameleon sequence, which has the capability of changing the secondary structure depending on the context of the surrounding environment in a protein structure. The fact that the transformation of one secondary structure caused stabilization of both the original and the induced structure would shed light on the mechanism of protein folding.


The electronic cigarette: the new cigarette of the 21st century?
The electronic nicotine delivery system, also known as the electronic cigarette, is generating considerable controversy, not only in the general population but also among health professionals. Smokers the world over have been increasingly using electronic cigarettes as an aid to smoking cessation and as a substitute for conventional cigarettes. There are few available data regarding the safety of electronic cigarettes. There is as yet no evidence that electronic cigarettes are effective in treating nicotine addiction. Some smokers have reported using electronic cigarettes for over a year, often combined with conventional cigarettes, thus prolonging nicotine addiction. In addition, the increasing use of electronic cigarettes by adolescents is a cause for concern. The objective of this study was to describe electronic cigarettes and their components, as well as to review the literature regarding their safety; their impact on smoking initiation and smoking cessation; and regulatory issues related to their use.


Influence of Intragastric Administration of Traditional Japanese Medicine, Ninjin'Yoeito, on Cerebral Blood Flow via Muscarinic Acetylcholine Receptors.
Ninjin'yoeito (NYT) is a traditional medicine that has been used for mitigating physical frailty, such as fatigue and anorexia, as well as for cognitive dysfunction. Maintenance of adequate cerebral blood flow (CBF) is important for preventing cognitive dysfunction. The present study aimed to examine the effect of NYT on CBF. Male C57BL/6 J mice were anesthetized with urethane and were artificially ventilated. We measured CBF in the neocortex with laser-speckle contrast imaging for 10 min before administration and 60 min after administration. We administered NYT solution (0.25, 0.5, 1, and 2 g/kg) or vehicle (distilled water; DW) over 5 min via an intragastric catheter. We surgically transected the vagus nerve to investigate its contribution as a neural pathway and intraperitoneally injected atropine to block muscarinic acetylcholine receptors. Finally, we tested the CBF response to cutaneous brushing stimulation applied to the left hind paw (30 sec). CBF decreased after DW administration, starting from 30 min onward, whereas CBF did not change after NYT. The averaged CBF change following DW administration differed from that following NYT (1 g/kg) but not from those following the other doses of NYT. Arterial pressure was not affected by either solution. CBF after NYT (1 g/kg) was not affected by vagotomy but was lower following additional atropine. In response to brushing stimulation, CBF in the right (contralateral) parietal cortex increased. The magnitude of CBF increase following NYT was greater than that following DW. These results suggest that NYT prevents CBF decrease via cholinergic activation independent of vagal activity and enhances the CBF response to somatosensory stimulation.


The effect of microwaves on dimensions and nucleic-acid concentration in snail neurons.
Effects of microwaves (continuous wave, frequency 2450 MHz, rate of energy absorption 15.5 mW/g, irradiation time 60 min) on isolated subesophageal ganglia of Helix lucorum snail were studied. During exposure a constant temperature of the solution in which the ganglia were bathed was maintained. It was found that such an exposure led to a decrease in the concentration of nucleic acids in snail neurons as well as to an increase of nuclear area and to dimunition of cytoplasmic area.


[Pituitary adenomas invading the cavernous sinus. Transcranial transcavernous approach].
Pituitary adenomas represent a significant proportion (+o-13%) of all intracranial tumors. Surgical treatment is as rule performed by transsphenoidal approach. However, a small but not insignificant subgroup of pituitary adenomas (5 to 7%) invade the lateral parasellar structures and the cavernous sinus in particular, and poses obvious problems to the therapeutic strategy, since transsphenoidal removal of these adenomas is usually incomplete. To evaluate the results of transcranial removal of a consecutive series of pituitary adenomas invading the cavernous sinus. A retrospective study of 9 patients harbouring pituitary adenomas invading the cavernous sinus who had been submitted to transcranial surgery was conducted. These patients were operated on in the time span June 1999 - December 2003, in the Nuova Clinica Latina (now NCL- Neurological Centere of Latium), Rome Italy, and the Hospital "Hermanos Ameijeiras", La Habana, Cuba, using a fronto-orbitozigomatic (FOZ) craniotomy, anterior clinoidectomy and a limited dissection of the cavernous sinus through the antero-medial triangle. Total macroscopical removal was achieved in 8 cases, partial in 1, who showed improvement or normalization of the hormonal levels and of the preoperative symptoms. Transitory complications occurred in 6 patients, one of them showed a permanet neurological deficit (paresis of the III cranail nerve). Transcranial transcavernous approach is an effective technique for attempting total removal of intracavernous pituitary adenomas. It allows to achieve remission of symptoms and hormonal control in the medium-long term. However complications are relatively frequent, and permanent sequelae are not negligible.


Fabrication of wound dressings: Herbal extract-loaded nanoliposomes embedded in fungal chitosan/polycaprolactone electrospun nanofibers for tissue regeneration.
Wound healing is a complex process and one of the major therapeutic and economic subjects in the pharmaceutical area. In recent years, the fabrication of nano-sized wound dressing models has attracted great attention for tissue regeneration. Plant extracts loaded nanoparticles are environmentally friendly and non-toxic and the release of the bioactive substance will be controlled to the wound area. This study aims to fabricate wound dressing models that contain bioactive components for tissue regeneration. Fungal chitosan/polycaprolactone nanofiber was fabricated by electrospinning and it has been characterized. Plant extracts loaded nanoliposomes were prepared, characterized, and embedded in nanofiber structures. The effectiveness of wound dressing models for tissue regeneration was evaluated by in vitro and in vivo studies. It was observed that all wound dressing models positively affect the cell viability of human dermal fibroblast cells. It was determined that plant extracts loaded nanoparticles embedded in nanofibers increased in cell viability than nanoparticles that were non-embedded in nanofiber structures. Histological analysis showed that plant extract-loaded nanoliposomes embedded in chitosan/PCL nanofibers were used for tissue regeneration. The most effective nanofibers were determined as Wd-ClNL nanofibers. RESEARCH HIGHLIGHTS: Hypericum perforatum L. and Cistus laurifolius L. were prepared by modified ultrasonic extraction method. Fungal chitosan/polycaprolactone nanofiber was fabricated by electrospinning and it has been characterized. Plant extract-loaded nanoliposomes were prepared, and characterized. They were embedded in chitosan/polycaprolactone nanofiber. Effects of the wound dressing model were analyzed by in vitro and in vivo assays for tissue regeneration.


Minerals as ergogenic aids.
Chromium, magnesium, zinc, and selenium are essential minerals for humans. They all are involved in a number of metabolic reactions in the body; many of these reactions are involved in energy metabolism, and hence it is thought that they may exert an ergogenic effect. However, the data on their effects as ergogenic aids have been equivocal. Longitudinal research is required (including supplementation studies) to follow athletes over time and properly evaluate effects of these minerals upon performance. The purpose of this review is to evaluate the ergogenic effects of chromium, magnesium, zinc, and selenium.


Solubilizing carbon nanotubes through noncovalent functionalization. Insight from the reversible wrapping of alginic acid around a single-walled carbon nanotube.
Carbon nanotubes coated with alginic acid (AA) through noncovalent functionalization have been shown to be soluble and dispersed in water. In the present contribution, all-atom molecular dynamics simulations have been performed to probe the self-assembly mechanism that underlies the formation of complexes by AA and a single-walled carbon nanotube (SWCNT), both in the gas phase and in an aqueous solution. Results of these simulations reveal that AA can wrap around SWCNT by virtue of van der Waals attractions and organize into a compact helical structure, a process induced in the gas phase by hydrogen-bonding interactions. In contrast, in an alginate aqueous solution, a loose helical wrapping mode is found to be favored by virtue of electrostatic repulsions in conjunction with the weakening of hydrogen-bonding interactions. Documented experimentally (Liu, Y.; et al. Small 2006, 2, 874-878) and coined "Great Wall of China" motif, the typical arrangement of AA residues around the tubular structure, conducive to dissolve nanotubes, is observed in the present simulations. Investigation of metal cations binding to AA suggests that calcium ions can mediate aggregation of AA chains by interacting strongly with the carboxylate groups, thereby leading to reverse unwrapping. The results reported in this work shed meaningful light on the potential of noncovalent functionalization for solubilizing carbon nanotubes, and open exciting perspectives for the design of new wrapping agents that are envisioned to form the basis of innovative nanomaterials targeted at chemical and biomedical applications.


Acromegaly is associated with increased cancer risk: a survey in Italy.
It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18-1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07-2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55-5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32-6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.


Inhibitory effect of histone on the peroxidase activity of the Hp/Hb complex.
The human leukocyte nuclear histones can bind to haptoglobin (Hp), and thus interfere with subsequent binding of Hb. The Hp/Hb complex possesses peroxidase activity, but a Hp/histone complex does not. The inhibitory effect of histone molecules depends directly on the Hp and Hb, as well as the histone concentrations. The biological significance of the complex Hp/Hb as a measure of intravascular hemolysis and the interference of histones in this assay is briefly discussed.


Mixed methods research in mental health nursing.
Mixed methods research is becoming more widely used in order to answer research questions and to investigate research problems in mental health and psychiatric nursing. However, two separate literature searches, one in Scotland and one in the USA, revealed that few mental health nursing studies identified mixed methods research in their titles. Many studies used the term 'embedded' but few studies identified in the literature were mixed methods embedded studies. The history, philosophical underpinnings, definition, types of mixed methods research and associated pragmatism are discussed, as well as the need for mixed methods research. Examples of mental health nursing mixed methods research are used to illustrate the different types of mixed methods: convergent parallel, embedded, explanatory and exploratory in their sequential and concurrent combinations. Implementing mixed methods research is also discussed briefly and the problem of identifying mixed methods research in mental and psychiatric nursing are discussed with some possible solutions to the problem proposed.


Optimising graphene visibility in van der Waals heterostructures.
Graphene constitutes one of the key elements in many functional van der Waals heterostructures. However, it has negligible optical visibility due to its monolayer nature. Here we study the visibility of graphene in various van der Waals heterostructures and include the effects of the source spectrum, oblique incidence and the spectral sensitivity of the detector to obtain a realistic model. A visibility experiment is performed at different wavelengths, resulting in a very good agreement with our calculations. This allows us to reliably predict the conditions for better visibility of graphene in van der Waals heterostructures. The framework and the codes provided in this work can be extended to study the visibility of any 2D material within an arbitrary van der Waals heterostructure.


Microwave and ultrasound pre-treatments to enhance anthocyanins extraction from different wine lees.
Wine lees are rich in anthocyanins (AC), natural colorants with health promoting properties. The extraction kinetics of AC from different wine lees in conventional solid-liquid extraction were studied for the first time. The influence of parameters such as temperature, solid-liquid ratio (RS-L) and type of solvent (hydro-alcoholic mixtures) was also studied. Furthermore, microwaves (MW) and ultrasounds (US) were used as pre-treatments (a prior step to the conventional extraction) in order to increase AC yield. Maximum extraction yield (2.78 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) was achieved after 15 min at 25 °C, with a RS-L of 1/10 (g/mL) and with a 50%vol. ethanol mixture. When MW were used AC extraction yield was doubled (6.20 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) and the required time to achieve a constant yield was reduced (from 15 min to 90 s). Meanwhile, US only shortened extraction time in less proportion (from 15 to 5 min). Putative identification of main extract compounds was performed by LC/MS-MS.


Novel enzyme from rat liver that cleaves an ADP-ribosyl histone linkage.
A novel enzyme that splits a bond between ADP-ribose and histone was discovered and partially purified from rat liver cytosol. The 105,000 X g supernatant of rat liver homogenate was precipitated by 45% saturated ammonium sulfate and then chromatographed on a DEAE-cellulose column. The enzyme activity was eluted in a single peak at about 0.2 M NaCl and clearly separated from poly(ADP-ribose) glycohydrolase which came out at 0.13 M NaCl. In contrast to the latter enzyme, this new enzyme catalyzed the spliting of a linkage between ADP-ribose and a protein portion in mono ADP-ribosylated histone H2B but little, if any, of the glycosidic ribosyl(1"-2') ribose bonds within poly(ADP-ribose). Analysis of the reaction product by paper chromatography and Dowex 1 column chromatography indicated that the split product contained the ADP-ribose moiety but was not exactly identical with ADP-ribose. Available evidence suggested that it was either an altered ADP-ribose molecule produced by a structural rearrangement or ADP-ribose itself linked to an unidentified compound. The enzyme had a pH optimum of about 6.0 and was inhibited by 80-90% in the presence of 5 mM ADP-ribose.


Nomograms for prediction of disease recurrence in patients with primary Ta, T1 transitional cell carcinoma of the bladder.
We developed nomograms to predict disease recurrence in patients with Ta, T1 transitional cell carcinoma of the bladder. Thirty-eight training hospitals participated in this retrospective multicenter study. Between 1998 and 2002, a total of 1,587 patients with newly diagnosed non-muscle invasive bladder cancer were enrolled in this study. Patients with prior histories of bladder cancer, non-transitional cell carcinoma, or a follow-up duration of less than 12 months were excluded. With univariate and multivariate logistic regression analyses, we constructed nomograms to predict disease recurrence, and internal validation was performed using statistical techniques. Three-year and five-year recurrence-free rates were 64.3% and 55.3%, respectively. Multivariate analysis revealed that age (hazard ratio [HR]=1.437, p<0.001), tumor size (HR=1.328, p=0.001), multiplicity (HR=1.505, p<0.001), tumor grade (HR=1.347, p=0.007), concomitant carcinoma in situ (HR=1.611, p=0.007), and intravesical therapy (HR=0.681, p<0.001) were independent predictors for disease recurrence. Based on these prognostic factors, nomograms for the prediction of disease recurrence were developed. These nomograms can be used to predict the probability of disease recurrence in patients with newly diagnosed Ta, T1 transitional cell carcinoma of the bladder. They may be useful for patient counseling, clinical trial design, and patient follow-up planning.


Meta-analysis of auditory P50 sensory gating in schizophrenia and bipolar disorder.
The ability of the brain to reduce the amount of trivial or redundant sensory inputs is called gating function. Dysfunction of sensory gating may lead to cognitive fragmentation and poor real-world functioning. The auditory dual-click paradigm is a pertinent neurophysiological measure of sensory gating function. This meta-analysis aimed to examine the subcomponents of abnormal P50 waveforms in bipolar disorder and schizophrenia to assess P50 sensory gating deficits and examine effects of diagnoses, illness states (first-episode psychosis vs. schizophrenia, remission vs. episodes in bipolar disorder), and treatment status (medication-free vs. medicated). Literature search of PubMed between Jan 1st 1980 and March 31st 2019 identified 2091 records for schizophrenia, 362 for bipolar disorder. 115 studies in schizophrenia (4932 patients), 16 in bipolar disorder (975 patients) and 10 in first-degree relatives (848 subjects) met the inclusion criteria. P50 sensory gating ratio (S2/S1) and S1-S2 difference were significantly altered in schizophrenia, bipolar disorder and their first-degree relatives. First-episode psychosis did not differ from schizophrenia, however episodes altered P50 sensory gating in bipolar disorder. Medications improve P50 sensory gating alterations in schizophrenia significantly and at trend level in bipolar disorder. Future studies should examine longitudinal course of P50 sensory gating in schizophrenia and bipolar disorder.


Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway.
Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.


Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.
Counseling patients with chronic hepatitis B virus (HBV) on their individual risk of liver disease progression is challenging. This study aimed to develop nomograms for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B. Two thirds of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study cohort was allocated for model derivation (n = 2,435), and the remaining third was allocated for model validation (n = 1,218). Previously confirmed independent risk predictors included in three Cox proportional hazards regression models were sex, age, family history of hepatocellular carcinoma, alcohol consumption habit, serum ALT level, hepatitis B envelope antigen (HBeAg) serostatus, serum HBV DNA level, and HBV genotype. Regression coefficients were rounded into integer risk scores, and predicted risk over 5- and 10-year periods for each risk score was calculated and depicted in nomograms. The predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC) and the correlation between predicted and observed hepatocellular carcinoma risk. All selected risk predictors were statistically significant in all models. In each model, either HBeAg seropositivity or HBeAg seronegativity with high viral load (HBV DNA level >or= 100,000 copies/mL) and genotype C infection had the highest risk scores. All AUROCs for risk prediction nomogram were >or= 0.82 in both model derivation and validation sets. The correlation coefficients between the observed hepatocellular carcinoma risk and the nomogram-predicted risk were greater than 0.90 in all model derivation and validation sets. These easy-to-use nomograms based on noninvasive clinical characteristics can accurately predict the risk of hepatocellular carcinoma in patients with chronic hepatitis B. They may facilitate risk communication between patients and clinicians.


Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.


Treatment of panic disorder: focus on paroxetine.
Panic disorder is a chronic and disabling condition associated with significant morbidity. Treatment of panic disorder has evolved significantly in the past 20 years with the availability of serotonergic antidepressants, including the selective serotonin reuptake inhibitors (SSRIs). Of these, paroxetine was the first to receive an indication for treatment of panic disorder and has been extensively studied in this area. A series of randomized, double-blind, placebo-controlled studies have demonstrated the efficacy and safety of paroxetine treatment of panic disorder, with a majority of patients achieving panic-free status during 12-week studies. Continued treatment with paroxetine results in sustained rates of remission compared with placebo. The combination of paroxetine and cognitive behavioral therapy appears to offer benefits of efficacy and sustained therapeutic response.


Carcinoid tumors of the rectum. Silver reactions, fluorescence, and serotonin content of the cytoplasmic granules.
The argyrophil and argentaffin staining reactions of the intracytoplasmic granules of 23 carcinoid tumors of the rectum were studied. The granules were evaluated for the presence of amines by means of formalin-induced fluorescence and an immunoperoxidase method for serotonin. The results indicate that most rectal carcinoids are argyrophil when the more sensitive Grimelius method is employed. Only occasionally are rectal carcinoids argentaffin, a feature that correlates with positive fluorescent reactions and suggests amine content. Of three argentaffin tumors, one stained positively for serotonin, and a second contained clusters of pleomorphic electron-dense granules of the type more typically seen in known amine-containing carcinoid tumors. For practical purposes, the Grimelius argyrophil stain is most useful in confirming a light-microscopic diagnosis of a rectal carcinoid.


Sevoflurane-Remifentanil Versus Propofol-Remifentanil Anesthesia During Noncardiac Surgery for Patients with Coronary Artery Disease - A Prospective Study Between 2016 and 2017 at a Single Center.
BACKGROUND Volatile anesthesia possesses cardioprotective properties, and it is widely used in patients undergoing coronary artery bypass surgery, but no randomized controlled trials (RCTs) are available on the use of sevoflurane-remifentanil versus propofol-remifentanil anesthesia for patients with coronary artery disease (CAD) during noncardiac surgery. This study was designed to compare the 2 different types of general anesthesia in patients with CAD undergoing noncardiac surgery at a single center. MATERIAL AND METHODS Patients with CAD undergoing noncardiac surgery were enrolled in an RCT conducted between March 2016 and December 2017. The participants were randomized to receive either sevoflurane-remifentanil or propofol-remifentanil anesthesia. The primary endpoint was occurrence of in-hospital cardiovascular events. The secondary endpoints included delirium, postoperative nausea and vomiting (PONV), Intensive Care Unit (ICU) length of stay (LOS), in-hospital morbidity and mortality, and hospital LOS. RESULTS A total of 164 participants completed the study (sevoflurane: 81; propofol: 83). The occurrence of in-hospital cardiovascular events did not differ between the 2 groups (42.6% vs 39.4%, P=0.86). The occurrence of delirium did not differ between the 2 groups after the operation. PONV had a higher frequency after sevoflurane anesthesia at 48 h compared with propofol. In-hospital morbidity and mortality, ICU LOS, and hospital LOS were similar between the 2 groups (all P>0.05). At 30 days after surgery, no between-group differences in cardiac morbidity and mortality were observed. CONCLUSIONS In this study, anesthesia using sevoflurane-remifentanil did not provide additional postoperative cardioprotection in comparison with propofol-remifentanil in patients with CAD undergoing noncardiac surgery.


Adenosine, adenosine receptors and their role in glucose homeostasis and lipid metabolism.
Adenosine is an endogenous metabolite that is released from all tissues and cells including liver, pancreas, muscle and fat, particularly under stress, intense exercise, or during cell damage. The role of adenosine in glucose homeostasis has been attributed to its ability to regulate, through its membrane receptors, processes such as insulin secretion, glucose release and clearance, glycogenolysis, and glycogenesis. Additionally, adenosine and its multiple receptors have been connected to lipid metabolism by augmenting insulin-mediated inhibition of lipolysis, and the subsequent increase in free fatty acids and glycerol levels. Furthermore, adenosine was reported to control liver cholesterol synthesis, consequently affecting plasma levels of cholesterol and triglycerides, and the amount of fat tissue. Alterations in the balance of glucose and lipid homeostasis have implications in both cardiovascular disease and diabetes. The ability of different adenosine receptors to activate and inhibit the same signaling cascades has made it challenging to study the influence of adenosine, adenosine analogs and their receptors in health and disease. This review focuses on the role and significance of different adenosine receptors in mediating the effect of adenosine on glucose and lipid homeostasis. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.


Ultrastructural study of poly- -hydroxybutyrate granules from Bacillus cereus.
The freeze-etching technique was used to examine the effects of fracturing and etching on the appearance of poly-beta-hydroxybutyrate granules from Bacillus cereus. These granules were examined in extracts isolated by hypochlorite or by sonic treatment, and also in fixed and unfixed intact cells; in the latter case they were compared with granules in thin sections of intact cells. After freeze-fracturing, the diameter of the granules in intact cells was between 240 and 720 nm. The granules consisted of a central core, of diameter between 140 and 370 nm, which occupied less than 50% of the volume of the granule and which was either stretched or removed on fracturing; the core was surrounded by an outer coat which may be bounded by a membrane.


[Not Available].
This paper is concerned with an important and original chapter in the history of experimental psychology in Italy, at the end of the nineteenth century. The first growth of the new science was connected with the possibility of using the methods of experimental psychology to study insanity problems. The limits of anatomical investigations were overcome by neurophysiological researches, but also by studies on reaction time. The measurement of time taken by a given mental operation showed the importance of attention in every mental act. These experiments, carried out on lunatics, showed considerable fluctuations of reaction time, an indication of the diminished power of attention. Great variations were due to different forms of mental disease, which could be better known thanks to this study. The first laboratory of experimental psychology in Italy was established in the Psychiatric Institute of Reggio Emilia, and Gabriele Buccola, a young psychiatrist, was the first to make use of lunatics to study the problems of normal psychology. An exact description of his psychometric researches, which used recent scientific instruments like Hipp's chronoscope, made it possible to verify the validity of the most important psychological laws and to go deep into the study of mental disease. In this way many problems-like the distinction between illusions and hallucinations, the existence of fixed ideas or particular maniacal forms-could be considered from a different point of view. Through the description of the Buccola's work, this paper aims to assess the relationship between experimental psychology and psychiatry: if the study of mental pathology has given rise to the growth of psychological researches, a new explanatory model has made it possible to overcome the conflicts between medico-organic and psychic approach in insanity studies.


Ataluren in cystic fibrosis: development, clinical studies and where are we now?
Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC). Areas covered: We discuss the discovery of the small-molecule drug ataluren, which in vitro has been shown to allow read-through of PTCs and facilitate synthesis of full-length protein. We review clinical studies that have been performed involving ataluren in CF. Early-phase short-term cross-over studies showed improvement in nasal potential difference. A follow-up phase III randomised controlled trial did not show a significant difference for the primary outcome of lung function, however a post-hoc analysis suggested possible benefit in patients not receiving tobramycin. A further randomised controlled trial in patients not receiving tobramycin has been reported as showing no benefit but has not yet been published in full peer-reviewed form. Expert opinion: A small-molecule approach to facilitate read-through of PTCs in nonsense mutations makes intuitive sense. However, at present there is no high-quality evidence of clinical efficacy for ataluren in people with CF.


Clinical applications of flow cytometry.
By providing multiple analyses on single cells, flow cytometry allows the description of cellular heterogeneity, establishing the biologic counterpart of clinical heterogeneity common to most tumors. Analysis of DNA content, a reflection of cell ploidy, is useful in establishing the prognosis of many solid tumors, while analysis of other markers has been crucial in increasing our knowledge of lymphoid differentiation, classifying hematologic malignancies, and detecting minimal residual disease.


Bacterial expression of a mitochondrial cytochrome c. Trimethylation of lys72 in yeast iso-1-cytochrome c and the alkaline conformational transition.
Saccharomyces cerevisiae iso-1-cytochrome c has been expressed in Escherichia coli by coexpression of the genes encoding the cytochrome (CYC1) and yeast cytochrome c heme lyase (CYC3). Construction of this expression system involved cloning the two genes in parallel into the vector pUC18 to give the plasmid pBPCYC1(wt)/3. Transcription was directed by two promoters, Lac and Trc, that were located upstream from CYC1. Both proteins were expressed in the cytoplasm of E. coli cells harboring the plasmid. Semianaerobic cultures grown in a fermentor produced 15 mg of recombinant iso-1-cytochrome c per liter of culture. Attempts to increase production by addition of IPTG suppressed the number of copies of the CYC1 gene within the population. Wild-type iso-1-cytochrome c expressed with pBPCYC1(wt)/3 in E. coli was compared to the same protein expressed in yeast. At neutral pH, the two proteins exhibit indistinguishable spectroscopic and physical (Tm, Em') characteristics. However, electrospray mass spectrometry revealed that the lysyl residue at position 72 is not trimethylated by E. coli as it is by S. cerevisiae. Interestingly, the pKa of the alkaline transition of the protein expressed in E. coli is approximately 0.6 pKa unit lower than that observed for the cytochrome expressed in yeast (8.5-8.7). 1H NMR spectroscopy of the bacterially expressed cytochrome collected at high pH revealed the presence of a third alkaline conformer that is not observed in the corresponding spectrum of the cytochrome expressed in yeast. These observations suggest that Lys72 can serve as an axial ligand to the heme iron of alkaline iso-1-ferricytochrome c if it is not modified posttranscriptionally to trimethyllysine.


IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.
Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1β was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1β and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-β expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.


Synaptically activated Cl- accumulation responsible for depolarizing GABAergic responses in mature hippocampal neurons.
It is known that GABA, a major inhibitory transmitter in the CNS, acts as an excitatory (or depolarizing) transmitter transiently after intense GABAA receptor activation in adult brains. The depolarizing effect is considered to be dependent on two GABAA receptor-permeable anions, chloride (Cl-) and bicarbonate (HCO3-). However, little is known about their spatial and temporal profiles during the GABAergic depolarization in postsynaptic neurons. In the present study, we show that the amplitude of synaptically induced depolarizing response was correlated with intracellular Cl- accumulation in the soma of mature hippocampal CA1 pyramidal cells, by using whole cell patch-clamp recording and Cl- imaging technique with a Cl- indicator 6-methoxy-N-ethylquinolinium iodide (MEQ). The synaptically activated Cl- accumulation was mediated dominantly through GABAA receptors. Basket cells, a subclass of fast-spiking interneurons innervating the somatic portion of the pyramidal cells, actually fired at high frequency during the Cl- accumulation accompanying the depolarizing responses. These results suggest synaptically activated GABAA-mediated Cl- accumulation may play a critical role in generation of an excitatory GABAergic response in the mature pyramidal cells receiving intense synaptic inputs. This may be the first demonstration of microscopic visualization of intracellular Cl- accumulation during synaptic activation.


Tall cell and diffuse sclerosing variants of papillary thyroid cancer: outcome and predicting value of risk stratification methods.
Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification. A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification). Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both. In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.


Relationships between physical activity and motor skills in middle school children.
The purpose of this study was to examine the relationships between physical activity measured as pedometer steps and performance on three motor skill tests. A secondary purpose was to determine if middle school children are meeting the recommendation for the number of daily steps. A sample (n =217) of 6th, 7th and 8th grade students participated. Each subject wore a Digi-Walker pedometer for three consecutive days. Subjects additionally recorded their pedometer steps in two 45 min.-physical education classes. There were strong significant correlations between daily steps taken by boys and girls, pedometer steps during physical education class and the AAHPERD Passing Test and the Bass Stick Balance. Similar correlations were weaker for the Side-Step Agility Test. Multivariate analysis of variance was utilized to examine variability of the three skills test by sex and year in school. Differences between students in Grades 7 and 8 on the AAHPERD Passing Test were significant. In addition, significant differences between daily pedometer steps and steps during physical education between Grades 6 and 7 were observed. Boys and girls had similar means on the AAHPERD Passing Test and Bass Stick Balance Test, but not on the Side-Step Agility Test. Scores on the three movement skills tested in this study were not strongly related to physical activity of the entire sample. Steps taken by middle school children appear not to be related to these measures of motor skills.


Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.
Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca2+-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher's exact test (P < 0.05 and P < 0.01, respectively). Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.


[The evaluation of prognostic value of cyclin B1 expression in patients with resected non-small-cell lung cancer stage I-IIIA--preliminary report].
Lung cancer is a leading cause of cancer death in the majority of developed countries and in Poland. THE AIM of this study was to evaluate the prognostic significance of cyclin B1 expression in primary, resected stage I-IIIA non-small cell lung cancer. The expression of cyclin BI was investigated in the paraffin-embedded tumor tissues of 71 patients (53 male and 18 female, aged 59.27 + 8.50 years), using a mouse monoclonal antibody to cyclin B1. In all patients the 24 month survival was determined. Thirty eight (54%) patients survived and 33 (46%) died. Positive expression of cyclin B1 was documented in 6 (8.5%) tumor tissue specimens. Only cytoplasmatic staining was revealed. The prognostic values of cyclin B1 expression were presented in all examined patients and in patients with squamous cell lung cancer, adenocarcinoma and separately in every stage of disease. Any correlations between cyclin B1 expression and survival of patients were not confirmed in all examined groups. In examined groups we did not reveal neither the prognostic value of cyclin B1 expression in patients with resected nonsmall cell lung cancer nor the correlations between cyclin B1 expression and neoadjuvant chemotherapy. More studies are expected in the future.


Progress of Nonmetallic Electrocatalysts for Oxygen Reduction Reactions.
As a key role in hindering the large-scale application of fuel cells, oxygen reduction reaction has always been a hot issue and nodus. Aiming to explore state-of-art electrocatalysts, this paper reviews the latest development of nonmetallic catalysts in oxygen reduction reactions, including single atoms doped with carbon materials such as N, B, P or S and multi-doped carbon materials. Afterward, the remaining challenges and research directions of carbon-based nonmetallic catalysts are prospected.