Preliminary Research towards Acute Effects of Different Doses of Caffeine on Strength-Power Performance in Highly Trained Judo Athletes.
Although several previous studies examined the effect of pre-exercise caffeine ingestion on judo-specific performance, the optimal dose of caffeine to maximise the ergogenic effects for judoka is not clear. The main purpose of this study was to analyse the effects of oral administration of 3 and 6 mg/kg of caffeine on a battery of physical tests associated with judo performance. Ten highly trained national-level judoka (6 men and 4 women, age: 24.1 ± 4.7 years, body mass: 73.4 ± 12.9 kg, 15.1 ± 5.2 years of judo training experience, 2.6 mg/kg/day of habitual caffeine intake) participated in a randomized, crossover, placebo-controlled and double-blind experiment. Each judoka performed three identical experimental sessions after: (a) ingestion of 3 mg/kg of caffeine (CAF-3); (b) ingestion of 6 mg/kg of caffeine (CAF-6); (c) ingestion of a placebo (PLAC). After 60 min for substance absorption, participants performed the following tests: (a) bench press exercise with 50% of the load representing one-repetition maximum (1RM), including three sets of three repetitions; (b) bench pull exercise with 50% of 1RM including three sets of three repetitions; (c) countermovement jump; (d) maximal isometric handgrip strength test; (e) dynamic and isometric versions of the Judogi Grip Strength Test. In comparison with PLAC, the ingestion of CAF-3 and CAF-6 increased peak bar velocity in the bench press exercise (1.27 ± 0.11 vs. 1.34 ± 0.13 and 1.34 ± 0.15 m/s, respectively; p < 0.01) and mean bar velocity in the bench pull exercise (1.03 ± 0.15 vs. 1.13 ± 0.13 and 1.17 ± 0.15 m/s; p < 0.05). Only CAF-6 increased mean bar velocity in the bench press exercise when compared with PLAC (0.96 ± 0.09 vs. 1.02 ± 0.11 m/s; p < 0.05). Both CAF-3 and CAF-6 significantly increased the number of repetitions in the Judogi Grip Strength Test (17 ± 10 vs. 20 ± 10 and 20 ± 10 repetitions; p < 0.05). There were no differences between PLAC and caffeine doses in the remaining tests. The pre-exercise ingestion of 3 and 6 mg/kg of caffeine effectively obtained meaningful improvements in several aspects associated with judo performance. From a practical viewpoint, the selection between 3 or 6 mg/kg of caffeine may depend on previously tested individual responses during simulated competition.


Development of a Combination Fermentation Strategy to Simultaneously Increase Biomass and Enzyme Activity of D-amino Acid Oxidase Expressed in Escherichia coli.
D-amino acid oxidase (DAAO) is widely used in the industrial preparation of L-amino acids, and cultivating Escherichia coli (E. coli) expressing DAAO for the biosynthesis of L-phosphinothricin (L-PPT) is very attractive. At present, the biomass production of DAAO by fermentation is still limited in large-scale industrial applications because the expression of DAAO during the fermentation process inhibits the growth of host cells, which limits higher cell density. In this study, the factors that inhibit the growth of bacterial cells during a 5-L fed-batch fermentation process were explored, and the fermentation process was optimized by co-expressing catalase (CAT), by balancing the biomass and the enzyme activity, and by adding exogenous D-alanine (D-Ala) to relieve the limitation of DAAO on the cells and optimize fermentation. Under optimal conditions, the DO-STAT feeding mode with DO controlled at 30% ± 5% and the addition of 27.5 g/L lactose mixed with 2 g/L D-Ala during induction at 28 °C resulted in the production of 26.03 g dry cell weight (DCW)/L biomass and 390.0 U/g DCW specific activity of DAAO; an increase of 78% and 84%, respectively, compared with the initial fermentation conditions. The fermentation strategy was successfully scale-up to a 5000-L fermenter.


From mutational inactivation to aberrant gain-of-function: Unraveling the structural basis of mutant p53 oncogenic transition.
Various evidence has revealed that mutations in p53 exert activities that go beyond simply inactivation of wildtype functions but rather elicits downstream interactions that promote malignancy described as mutant p53 gain-of-function (GOF). Here we report the first account of the dynamics of mutation-induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation. Result analysis revealed that both mutants exhibited structural distortion and reduced flexibility, indicative of rigidity and kinetic stability. In addition, surface analysis revealed an increase in the accessible surface area in the p53 mutants. This suggests that the GOF transition involves protein unfolding and exposure of buried hydrophobic surface essential for interaction with HSF-1 oncogenic partner and wildtype p63, and p73 homologs. Further validation revealed binding cavities, similar in the mutants but dissimilar to the WT. Taken together, this study complements experimental findings and reveals the interplay between mutation-induced structural distortion, loss of flexibility, rigidity, enhanced stability, protein unfolding and ultimately, exposure of binding surfaces as conformational attributes that characterize mutP53 structure-GOF activities. This insight is, therefore, of great importance as it opens up a novel therapeutic approach toward the structure based targeting of mutP53 oncogenic involvement beyond wildtype inactivation. Furthermore, "exposed" binding site information obtained from this study can be explored for structure-based design of substances best described as "destabilizers" to disrupt the GOF interaction of mutp53.


MiR-204 reduces cisplatin resistance in non-small cell lung cancer through suppression of the caveolin-1/AKT/Bad pathway.
Non-small cell lung cancer (NSCLC) is the most common and lethal human malignant tumor worldwide. Platinum-based chemotherapy is still the mainstay of treatment for NSCLC. However, long-term chemotherapy usually induces serious drug resistance in NSCLC cells. Accordingly, treatment strategies that reverse the resistance of NSCLC cells against platinum-based drugs may have considerable clinical value. In the present study, we observed significant upregulation of CAV-1 expression and a significant decrease of miR-204 expression in cisplatin-resistant A549 (CR-A549) and cisplatin-resistant PC9 (CR-PC9) cells compared to their parental A549 and PC9 cells. Furthermore, we demonstrated that the downregulation of miR-204 expression was responsible for CAV-1 overexpression in these cisplatin-resistant NSCLC cells. We then found that enforced expression of miR-204 can resensitize CR-A549 and CR-PC9 cells to cisplatin-induced mitochondrial apoptosis through suppression of the caveolin-1/AKT/Bad pathway. We demonstrated that dysregulation of miR-204/caveolin-1 axis is an important mechanism for NSCLC cells to develop the chemoresistance.


Describing severe limb trauma.
Seventy-nine severe limb injuries were retrospectively reviewed to compare the AO/ASIF and the Gustillo classifications. Specifically, the suitability of these classifications with respect to prognosis and management of these cases was compared. A healed and stable wound was the ultimate outcome measure. Surrogate outcome measures used were: the time to healing; the number of anaesthetics until the wounds were healed; and the number of operations until the wounds were healed. Any change in lifestyle following the injury was also assessed. The primary healing rates of the AO/ASIF groups showed significant (P < 0.001) inter-group differences. However, when the injuries were classified using the Gustillo system, the primary healing rates did not show any differences between the groups. Also, differences in the other outcome measures were most pronounced when using the AO/ASIF system. Importantly, changes in lifestyle correlated with the injury score when using the AO/ASIF system (P < 0.05). Unlike the AO/ASIF system, the Gustillo system was not applicable in 100% of cases. A modified AO/ASIF scoring system is proposed which provides a good predictor of outcome.


[The Salernitan School of Medicine: Its History and Contribution to European Medical Education].
The Salernitan School of Medicine was founded in the late 10th century as a loose association of medical teachers. The period before the middle 13th century was divided into three phases. In the early phase, before the end of 11th century, "practica" books were written, utilizing extant ancient literature, Arabic medical treatises were translated into Latin, and the medical text "Articella" was compiled. In the high phase before the end of the 12th century, the "Articella" was commented upon and new pharmacopeia and practica books were written. In the late phase before the middle of the 13th century, physicians who graduated from Salerno were active in various countries in Europe. After the middle of the 13th century the school developed organizations and rules, became a university at the end of 16th century, and was closed in 1811. The Salernitan school produced "Articella", which pioneered in theoretical medical education, and produced "practica", which dealt with both local diseases from head to foot and systemic fever diseases, and it continued until the end of 18th century. The two major disciplines of medical education before the end of 18th century, theoretica and practica, were derived from Salerno.


Early Speech Sound Production and Its Trajectories in Very Preterm Children From 2 to 4 Years of Age.
Very preterm (VPT) children are at risk for speech and language problems throughout school age. However, little is known about early speech sound production in these children. This study aims to present a detailed description of early speech sound production and its trajectories in VPT children from 2 to 4 years of age. In addition, this study aimed to determine if early speech sound production is associated with speech production and expressive language function at 4 years of age. In 63 VPT children (< 32 weeks of gestation, 41 boys, mean gestational age = 28.8 weeks, mean birth weight = 1,135 g), speech sound production was assessed by naturalistic speech analysis at 2 years of corrected age and speech and language function by standardized tests at 4 years of age. Speech sound production was found to be abnormal in 49% of the VPT children at 2 years of age and in 19% at 4 years of age. Four different speech production trajectories from 2 to 4 years of age could be identified: a normal trajectory, an abnormal trajectory, a catch-up trajectory, and a growing-into-deficit trajectory. Early speech production, defined by the number of acquired consonants at 2 years of age, significantly predicted the word production score at 4 years of age and the sentence production score at 4 years of age. Compared to the general population, an alarmingly high proportion of VPT children showed speech production problems at 2 years of age. About half of these children showed persistent speech problems at 4 years of age. Moreover, these problems were associated with expressive language problems at the age of 4 years. https://doi.org/10.23641/asha.19310822.


Spleen and liver dendritic cells differ in their tolerogenic and cytokine induction potential.
Dendritic cells (DCs) play an important role in induction of cellular immune responses. It seems that DCs that reside in different organs may be distinct in their ability to induce immune responses. This study was done to address the differences between spleen and liver DCs in induction of immune response and/or tolerance. CD11c+ DCs were separated from the liver and spleen of C57BL/6 mice and pulsed with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. 6105 MOG35-55 pulsed spleen or liver DCs were injected in foot pad of different groups of mice. Control groups received unpulsed DCs. After 5 days, the mononuclear cells (MNCs) of the regional lymph nodes were isolated from immunized mice for cytokine assays and lymphocyte transformation test. To study the immunologic or tolerogenic effects of DCs, three weeks after immunization of mice with MOG pulsed liver or spleen DCs, experimental autoimmune encephalomyelitis (EAE) was induced in DC-immunized mice by injection of MOG along with complete Freund's adjuvant. Our results showed that spleen DCs were more potent in stimulating lymph node T cells as illustrated in lymphocyte transformation test. Moreover IL-10 production was higher in mice immunized with liver DCs compared with those immunized with splenic DCs (p=0.017). However, no significant difference in IFN-γ production was observed between two groups. We also found that liver DCs+MOG immunized mice displayed a significantly delayed disease onset compared with spleen DCs+MOG immunized mice and the control groups. The disease score was also milder in liver DCs immunized mice compared with other groups. It seems that the higher IL-10 production induced by the liver DCs may be one of the main factors in down regulation of immune responses in this organ. It can be concluded also that the liver DCs may inhibit the progress of EAE by shifting the cytokines profile.


Biologic and therapeutic determinants of bone mineral density in multiple myeloma.
The net impact of malignancy and anti-tumor therapy on bone resorption in myeloma is poorly understood because conventional skeletal radiographs are relatively insensitive for the diagnosis and monitoring of bone disease. We performed determinations of bone mineral density (BMD) at the lumbar spine, femoral neck and radial diaphysis by dual energy X ray absorptiometry (DEXA) in 168 consecutive patients with myeloma seen at our institution. Follow up studies were performed in 41 of these patients. A detailed analysis of patient and disease characteristics was performed to identify the determinants of BMD. Compared to normal age and sex matched controls, mean (+/- SE) BMD was significantly decreased at the lumbar spine (Z score -0.4 +/- 0.10) and femoral neck (Z score -1.0 +/- 0.10), but was surprisingly above normal at the radial diaphysis (Z score +0.35 +/- 0.10), a cortical bone site devoid of hematopoietic marrow, suggesting a differential bone preserving effect at this site. Lack of correlation between the BMD findings and the presence or extent of radiographically evident osteolytic lesions suggested the presence of a systemic bone disease. On multivariate analysis, duration of disease >12 months (p = 0.003) and female sex (p = 0.01) were independently associated with a lower BMD at the femoral neck/lumbar spine. On follow up DEXA (n = 41), BMD increased at > or = 1 site in 9 of 20 patients receiving bisphosphonates and in only 2 of 21 patients not receiving such therapy (p = 0.02). Similarly a decline in BMD at > or = 1 site was seen in 9 of 21 patients not receiving bisphosphonates, irrespective of the disease response status. Interval pamidronate therapy (p = 0.0007) and a low serum beta-2-microglobulin (< 2.5 mg/l) (p = 0.04) were the two most significant variables associated with an increase in BMD on multivariate analysis. These data suggest that myeloma is associated with a systemic bone disease with progressive generalized cancellous bone loss and a bone preserving effect on the radial cortical bone. The early use of bisphosphonates may improve myeloma related bone disease.


Interpeduncular Heterotopia and Brain Stem Cleft: An Isolated Finding Not Associated with Joubert Syndrome.
Interpeduncular heterotopia is a new neuroimaging finding reported in association with Joubert syndrome (JS) in a few cases in the literature. Nodular interpeduncular tissue was termed as interpeduncular heterotopia and anterior mesencephalic cap dysplasia in the literature in relation to gray and white matter content. We described the imaging findings and diffusion tensor imaging data of a case with interpeduncular heterotopia and brain stem cleft. This is the first case, in which interpeduncular heterotopia was an isolated finding not associated with JS.


Cytocompatibility studies of an in situ photopolymerized thermoresponsive hydrogel nanoparticle system using human aortic smooth muscle cells.
We have been investigating thermoresponsive hydrogel nanoparticle composite networks to develop photopolymerized hydrogels to deliver drugs for prevention of restenosis after angioplasty. These composite systems can form a gel under physiological conditions and release drugs in response to temperature changes. Our novel system, consisting of poly(N-isopropylacrylamide) thermoresponsive nanoparticles, photo cross-linker poly(ethylene glycol) diacrylate, and UV photoinitiator, 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl-1-propanone-1-one (Irgacure 2959), would be photopolymerized in situ in the presence of UV light. The focus of this study was to evaluate the effects of photoinitiator and UV exposure on human aortic smooth muscle cells (HASMCs). We found that the exposure to UV light did not significantly affect the cellular survival within doses required for photopolymerization. The photoinitiator was cytocompatible at low concentrations (< or = 0.015% w/v); however, cytotoxicity increased with increasing photoinitiator concentrations. In addition, free radicals formed in the presence of a photoinitiator and UV light caused significant levels of cell death. An antioxidant (free radical scavenger), ascorbic acid, added to the cell media, significantly improved relative cell survival but increased the hydrogel gelation time. Finally, HASMC survival when exposed to all potential cytotoxic components was also evaluated by exposing HASMCs to media incubated with our composite hydrogels. In summary, our studies show that the photoinitiator and free radicals are responsible for the cytotoxicity on HASMCs, and the addition of antioxidants can significantly reduce these harmful effects.


A new triterpene from the plant of uncaria macrophylla.
Our ongoing investigations on the stem bark of Uncaria macrophylla afforded a new ursolic triterpene, 3β,6β,19α-trihydroxy-urs-12-en-28-oic acid-24-carboxylic acid methyl ester (1), named uncariursanic acid, and three known ursolic triterpenes including 3β,6β,19α-trihydroxy-23-oxo-urs-12-en-28-oic acid (2), 3β,6β,19α-trihydroxy-urs-12-en-28-oic acid (3) and ursolic acid (4). Their structures were elucidated by extensive spectral methods, including 1D and 2D NMR and HR-ESI-MS. The cytotoxicities of the four compounds were evaluated against two cancer cell lines (MCF-7 and HepG2) by the MTT method, and only compound 4 exhibited potent activity.


On-site generation of reactive oxidative radicals from dithionite treated oxic soil slurry.
Whereas dithionite has been extensively used as a reducing agent in soil and sediment remediation, here, we demonstrate that it can be used as a potential source of oxidizing radical in oxic soils with potential application in organic pollutant remediation. Benzoic acid was used as a probe compound and the generation of its oxidative product para-hydroxybenzoic acid (p-HBA) was detected to quantify the production of oxidative radicals (ROS). By increasing the dithionite concentration from 2.5-10 Mm, the accumulated P-HBA concentration in 120 min increased from 15.0-27 µM. Whereas, above 10 mM, the p-HBA concentration decreased due to radical scavenging. Increasing soil dosage from 2.5-15 g/100 mL the accumulated p-HBA amount increased from 22.8-33.7 µM. Temperature 25-35 oC and pH 6.2-7.5 were favoured for p-HBA generation. Furthermore, we investigated the roles of different active intermediates in the reaction system and proposed the mechanism behind the ROS genearation. This study suggested that dithionite can be used as an active reagent for advanced oxidation remediation in oxic soil medium.


Dynamics of the secretory response evoked by endothelin-1 in adrenal chromaffin cells.
Recently, we have observed that endothelin-1 (ET-1) evokes the release of catecholamines (CA) from adrenal chromaffin cells. We have investigated this secretagogue action of ET-1 on cultured adrenal chromaffin cells using a real-time monitoring system. Pulsatile exposure to ET-1 evoked transient secretory responses in a dose-dependent manner, whereas repetitive stimulation produced a rapid tachyphylaxis. This secretagogue activity was dependent on extracellular Ca2+ and was blocked by 85% by 10(-5) M nifedipine. The onset of the secretory response to ET-1 was very slow, and the duration of the response was much longer than that seen with acetylcholine (ACh). These novel dynamics may well be related to the mechanism of action of ET-1 in these cells. In addition, ET-1 produced a synergistic increase in ACh-evoked release, suggesting that ET-1 may physiologically modulate ACh-evoked CA release in adrenal chromaffin cells by a mechanism involving dihydropyridine-sensitive Ca2+ channels.


Dihydroartemisinin induces ER stress-dependent apoptosis of Echinococcus protoscoleces in vitro.
In this study, we investigated the effect of dihydroartemisinin on Echinococcus protoscoleces and explored the role of endoplasmic reticulum stress in this process. Echinococcus protoscoleces were collected and cultured in RPMI 1640 medium. Changes in the expressions of glucose-regulated protein 78 (GRP-78), caspase-12, and C/EBP homologous protein (CHOP) were assessed through confocal immunofluorescence and western blot analysis. Cell viability and morphological changes were observed under a light microscope. The ultrastructure of protoscoleces was observed by scanning electron microscopy and transmission electron microscopy. Caspase-3 activity was detected using an enzyme assay kit. After dihydroartemisinin treatment, the protoscoleces showed loss of viability, and morphological changes including soma contraction, blebs formation, hooks loss, microtrichia destruction, and development of lipid droplets was observed. The levels of caspase-12 and CHOP were increased within 2 days of dihydroartemisinin treatment. However, the levels of GRP-78, caspase-12, and CHOP were decreased in 4 days. Furthermore, caspase-3 activity was increased after treatment with different concentrations of dihydroartemisinin. Dihydroartemisinin can induce apoptosis in protoscoleces via the ER stress-caspase-3 apoptotic pathway in vitro. These results indicate that dihydroartemisinin is a potentially valuable therapeutic agent against echinococcosis.


Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes.
Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.


BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine.
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.


Cervical sentinel lymph node biopsy for melanomas of the head and neck and upper thorax.
To describe a clinical experience with sentinel lymph node biopsy (SLNB) of head and neck nodal basins for clinical stage I melanomas draining to these areas. Consecutive clinical case series with a mean follow-up of 10.7 months. University tertiary care referral medical center. Seventy patients with clinical stage I cutaneous melanoma who underwent SLNB of cervical and/or parotid lymph node basins. Patients underwent same-day preoperative technetium Tc 99m lymphoscintigraphy followed by SLNB using gamma probe and blue dye (66 patients) and blue dye alone (4 patients). Patients with histological evidence of tumor (here in after "positive") according to SLNB results underwent modified cervical completion lymph node dissection, including parotidectomy, as appropriate. Patients without histological evidence of tumor (hereinafter "negative") according to SLNB results were followed up clinically without undergoing completion lymph node dissection. The rates of SLNB success, SLNB positivity, completion lymph node dissection positivity, complications, and SLNB false-negative results were determined by clinical follow-up. Locations of melanomas in the 70 patients were the face (n = 20), neck (n = 14), ear (n = 9), scalp (n = 9), and upper thorax (n = 18). Locations of basins that underwent biopsy (n = 104) were in the cervical (n = 68), parotid (n = 19), and axillary (n = 17) regions. The mean Breslow thickness was 2.1 mm (range, 0.4-12.0 mm). Sentinel lymph node biopsy was successful in 103 basins (99%). The mean number of sentinel lymph nodes per basin was 2.5 (range, 1.0-8.0). Positive sentinel lymph nodes were found in 12 patients (17%) and 15 basins (14%). Sentinel lymph node biopsy results correlated with the American Joint Committee on Cancer tumor stage (P = .05) and a Breslow thickness of 1.23 mm or greater (P = .03). Additional tumor-containing nodes were noted in 5 (42%) of the 12 patients who underwent completion lymph node dissection, and these results correlated with the presence of multiple positive sentinel lymph nodes (P = .01). There were complications in 3 patients (4%) (seromas in 2 patients and temporary spinal accessory nerve paresis in 1 patient). One nodal recurrence in a basin that was negative according to SLNB results (SLNB with blue dye only) was noted (false-negative rate, 2%). The results of SLNB were accurate in 69 patients (99%). Sentinel lymph node biopsy using lymphoscintigraphy and blue dye to manage cutaneous melanomas draining to the head and neck nodal areas is reliable and safe. Sentinel lymph node biopsy results correlated with a Breslow thickness of 1.23 mm or greater and the American Joint Committee on Cancer tumor stage. Completion lymph node dissection is recommended after determining positive SLNB results.


Electromagnetic Induction Aberration: The Possible Mechanism of Tic Douloureux.
A theory based on the principles of electromagnetic induction aberration is presented as the possible mechanism of classic trigeminal neuralgia, tic douloureux. The anatomy of the dorsal root entry zone of the trigeminal nerve at the pons in the proximity of the superior cerebellar artery presents a scenario conducive to the phenomenon of electromagnetic induction. When the action potentials traversing the axons in this zone of the compromised myelin come into juxtaposition with the vascular structure, the criteria for electromagnetic induction are satisfied. The laws of physics governing the phenomenon indicate that a new current, an aberration, would be produced. This could be responsible for the clinical symptoms of tic douloureux. Other clinical situations with similar features could share this mechanism. This proposed theory, a merger of anatomy, neurophysiology, and the physics of electromagnetic induction, extends the established concept of vascular compression as the etiology of tic douloureux.


Inhibited oxidase mimetic activity of palladium nanoplates by poisoning the active sites for thiocyanate detection.
In this work, a novel convenient colorimetric method for sensitive detection of thiocyanate (SCN-) has been developed based on its suppression of the oxidase-like activity of palladium square nanoplates on reduced graphene oxide (Pd SP@rGO). SCN- can be adsorbed onto the surface of Pd SP@rGO via binding with Pd atoms and blocks the active sites that mimic oxidase, thus inhibiting the corresponding chromogenic reaction of 3,3',5,5'-tetramethylbenzidine, which has been comprehensively revealed by the UV-vis spectra and X-ray photoelectron spectra. The color fading exhibits SCN- concentration-dependent behavior and can be easily recorded by either UV-vis spectroscopy or naked-eye observation. Therefore, both quantitative detection via measurement of the decrease in absorbance and visual detection of SCN- can be achieved. Owing to the intrinsic amplification of signals by the oxidase-like activity of Pd SP@rGO without resorting to unstable and destructive H2O2, this assay is straightforward, robust and sensitive enough for the detection of SCN- in real samples. Furthermore, an "INH" logic gate is rationally constructed based on the proposed colorimetric SCN- sensor.


New Growth Frontier: Superclean Graphene.
The last 10 years have witnessed significant progress in chemical vapor deposition (CVD) growth of graphene films. However, major hurdles remain in achieving the excellent quality and scalability of CVD graphene needed for industrial production and applications. Early efforts were mainly focused on increasing the single-crystalline domain size, large-area uniformity, growth rate, and controllability of layer thickness and on decreasing the defect concentrations. An important recent advance was the discovery of the inevitable contamination phenomenon of CVD graphene film during high-temperature growth processes and the superclean growth technique, which is closely related to the surface defects and to the peeling-off and transfer quality. Superclean graphene represents a new frontier in CVD graphene research. In this Perspective, we aim to provide comprehensive understanding of the intrinsic growth contamination and the experimental solution of making superclean graphene and to provide an outlook for future commercial production of high-quality CVD graphene films.


Synthesis and Biological Evaluation of N- Pyrazolyl Derivatives and Pyrazolopyrimidine Bearing a Biologically Active Sulfonamide Moiety as Potential Antimicrobial Agent.
A series of novel pyrazole-5-carboxylate containing N-triazole derivatives 3,4; different heterocyclic amines 7a-b and 10a-b; pyrazolo[4,3-d]pyrimidine containing sulfa drugs 14a,b; and oxypyrazolo[4,3-d]pyrimidine derivatives 17, 19, 21 has been synthesized. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. All compounds have been screened for their in vitro antimicrobial activity against three gram-positive and gram-negative bacteria as well as three fungi. The results revealed that compounds 14b and 17 had more potent antibacterial activity against all bacterial strains than reference drug Cefotaxime. Moreover compounds 4, 7b, and 12b showed excellent antifungal activities against Aspergillus niger and Candida albicans in low inhibitory concentrations but slightly less than the reference drug miconazole against Aspergillus flavus.


Motif-Raptor: a cell type-specific and transcription factor centric approach for post-GWAS prioritization of causal regulators.
Genome-wide association studies (GWASs) have identified thousands of common trait-associated genetic variants but interpretation of their function remains challenging. These genetic variants can overlap the binding sites of transcription factors (TFs) and therefore could alter gene expression. However, we currently lack a systematic understanding on how this mechanism contributes to phenotype. We present Motif-Raptor, a TF-centric computational tool that integrates sequence-based predictive models, chromatin accessibility, gene expression datasets and GWAS summary statistics to systematically investigate how TF function is affected by genetic variants. Given trait-associated non-coding variants, Motif-Raptor can recover relevant cell types and critical TFs to drive hypotheses regarding their mechanism of action. We tested Motif-Raptor on complex traits such as rheumatoid arthritis and red blood cell count and demonstrated its ability to prioritize relevant cell types, potential regulatory TFs and non-coding SNPs which have been previously characterized and validated. Motif-Raptor is freely available as a Python package at: https://github.com/pinellolab/MotifRaptor. Supplementary data are available at Bioinformatics online.


Cardiac receptor physiology and its application to clinical imaging: present and future.
Both gamma imaging and positron emission tomography (PET) imaging of cell surface receptors have become possible through the development of agonists and antagonists with high specific radioactivity and high specificity for the receptors. An understanding of the physiology of the cardiac receptor system is essential to comprehending receptor imaging. The complexity of the physiologic information developed over the past decade has been compounded by the concomitant discovery of additional receptor subtypes. The following is a review of a select group of cardiac receptors and their regulation-namely, adrenergic, muscarinic-cholinergic, adenosine, and angiotensin I and II receptors. The role of imaging regional receptor localization and function in providing new insights into cardiac pathology and therapeutic avenues is explored.


Occupational dermatoses in a Swedish aircraft plant.
A survey of occupational dermatoses, based on a questionnaire, clinical examination and patch testing, was carried out among 341 workers in an aircraft plant. The questionnaire was answered by 330 workers (96.8%). Present or previous skin disease was reported by 92 employees, who were all subjected to physical examination and patch testing. Patch testing was conducted with a standard series, as well as with a series of substances and products representing the work environment. Occupational contact allergies were established in 12 employees. In total, the figure for occupational skin diseases was 16.1% (55 workers), when calculated for all employees.


Novel placental structure in the Mexican gerrhonotine lizard, Mesaspis viridiflava (Lacertilia; Anguidae).
The evolution of viviparity alters the physical relationship between mothers and offspring and the prevalence of viviparity among squamate reptiles presents an opportunity to uncover patterns in the evolution of placental structure. Understanding the breadth of this diversity is limited because studies of placental structure and function have emphasized a limited number of lineages. We studied placental ontogeny using light microscopy for an embryological series of the Mexican gerrhonotine lizard, Mesaspis viridiflava. This species develops an elaborate yolk sac placenta, an omphaloplacenta, which receives vascular support arising in a structure known only from other gerrhonotine lizards. A prominent feature of the omphaloplacenta is a zone of uterine and embryonic epithelial cell hyperplasia located at the upper shoulder of the yolk mass, often extending above the yolk mass. The omphaloplacenta covers more than one-half of the surface area of maternal-embryonic contact. The chorioallantoic placenta has a more restricted distribution because the allantois remains in the embryonic hemisphere of the egg throughout development and lies internal to the vascular support for the omphaloplacenta in areas where they overlap. The structural profile of the chorioallantoic placenta indicates a potential for respiratory exchange and/or hemotrophic nutritive transport, while that of the omphaloplacenta suggests that nutritive transfer is primarily via histotrophy. An eggshell is present in the earliest embryonic stages examined but regresses relatively early in development. Placental specializations of this species are consistent with a pattern of matrotrophic embryonic nutrition and have evolved in a unique lineage specific developmental pattern.


Depression of synaptic efficacy in high- and low-output Drosophila neuromuscular junctions by the molting hormone (20-HE).
The molt-related steroid hormone, 20-hydroxyecdysone (20-HE), was applied to muscles 6 and 7 of third instar larval of Drosophila melanogaster neuromuscular junction preparations to examine if rapid, nongenomic responses could be observed as was shown recently to occur in crustacean neuromuscular junctions. At a dose of 10 microM, the excitatory junction potentials were reduced in amplitude within minutes. To elucidate the site of action of the hormone, focal-macropatch recordings of synaptic currents were obtained over the neuromuscular junctions. The results showed that the high-output (Is) and the low-output (Ib) motor nerve terminals, which innervate muscles 6 and 7, released fewer synaptic vesicles for each stimulation while exposed to 20-HE. Because the size and shape of synaptic currents from spontaneous releases did not change, the effects of the 20-HE are presynaptic. The rapid effects of this hormone may account in part for the quiescent behavior associated with molts among insects and crustaceans.


Sequence, organization, and transcription of the Dlx-1 and Dlx-2 locus.
There are at least five murine Dlx genes that are related to the Drosophila Distal-less homeobox gene. The Dlx genes are primarily expressed in the developing forebrain, derivatives of the cranial neural crest and restricted epidermal craniofacial and limb domains. Dlx-2 is required for differentiation of subsets of cranial neural crest and forebrain cells. Previous genomic studies have shown that Dlx-1 and Dlx-2 are linked on mouse chromosome 2, near the HoxD cluster. Here we report a detailed analysis of the nucleotide sequence (approximately 14 kb), organization, and transcription of the murine Dlx-1 and Dlx-2 locus. In addition, we show that Dlx-1 makes multiple sense transcripts and at least one antisense transcript, whereas Dlx-2 makes one major transcript. The sequence of the human Dlx-2 gene is reported and is compared to that of the murine gene. Finally, sequence analysis of the deduced protein sequences reveals several candidate functional domains.


Neural activity to a partner's facial expression predicts self-regulation after conflict.
Failure to self-regulate after an interpersonal conflict can result in persistent negative mood and maladaptive behaviors. Research indicates that lateral prefrontal cortex (LPFC) activity is related to emotion regulation in response to laboratory-based affective challenges, such as viewing emotional pictures. This suggests that compromised LPFC function may be a risk factor for mood and behavior problems after an interpersonal conflict. However, it remains unclear whether LPFC activity to a laboratory-based affective challenge predicts self-regulation in real life. We investigated whether LPFC activity to a laboratory-based affective challenge (negative facial expressions of a partner) predicts self-regulation after a real-life affective challenge (interpersonal conflict). During a functional magnetic resonance imaging scan, healthy, adult participants in committed relationships (n = 27) viewed positive, negative, and neutral facial expressions of their partners. In a three-week online daily diary, participants reported conflict occurrence, level of negative mood, rumination, and substance use. LPFC activity in response to the laboratory-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to mood or behavior the next day. However, when an interpersonal conflict did occur, ventral LPFC (VLPFC) activity predicted mood and behavior the next day, such that lower VLPFC activity was related to higher levels of negative mood, rumination, and substance use. Low LPFC function may be a vulnerability and high LPFC function may be a protective factor for the development of mood and behavior problems after an interpersonal stressor.


Pharmacokinetics of Sucralose and Acesulfame-Potassium in Breast Milk Following Ingestion of Diet Soda.
The aim of this study was to determine sucralose and acesulfame-potassium (ace-K) pharmacokinetics in breast milk following maternal ingestion of a diet soda. Thirty-four exclusively breast-feeding women (14 normal-weight, 20 obese) consumed 12 ounces of Diet Rite Cola, sweetened with 68-mg sucralose and 41-mg ace-K, before a standardized breakfast meal. Habitual non-nutritional sweeteners intake was assessed via a diet questionnaire. Breast milk was collected from the same breast before beverage ingestion and hourly for 6 hours. Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL (median peak 8.1 ng/mL) and 299.0 to 4764.2 ng/mL (median peak 945.3 ng/mL), respectively. Ace-K and sucralose transfer into breast milk following ingestion of a diet soda. Future research should measure concentrations after repeated exposure and determine whether chronic ingestion of sucralose and acesulfame-potassium via the breast milk has clinically relevant health consequences.


Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates.
Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector has been reported as a good candidate for intravascular gene delivery, but low levels of preexisting antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular delivery and cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue in nonhuman primates. Both delivery routes generated similar distribution patterns, although we observed a more robust level of transduction after CSF delivery. Consistent with previous reports administering AAV9, we found greater astrocytic than neuronal tropism via both routes, although we did find a greater magnitude of CNS transduction after CSF delivery compared with intravascular delivery. Last, we have demonstrated that delivery of AAV9 into the CSF does not shield against AAV antibodies. This has obvious implications when developing and/or implementing any clinical trial studies.


The incidence of mobility restrictions among elderly people in two Nordic localities. A five-year follow-up.
The aim of this study was to investigate the incidence of limitations in self-reported mobility as well as the decline in measured walking speed and stair-mounting ability over five years among men and women aged 75 at baseline in two Nordic localities. Another purpose was to analyze the relationship and its consistency over time between self-reports and performance-based measures in the decline of mobility. Identical Interviews and performance tests were carried out in Jyäskylä, Finland (N=244) and Glostrup, Denmark (N=275) at baseline and five years later. The subjects were asked about their ability to manage with transferring from chair or bed, walking indoors and outdoors and climbing stairs. The occurrence of new limitations in these tasks was analyzed among those who did not report limitations in the same task at baseline. Maximal walking speed and step-mounting height were measured in the laboratory. The decline in walking speed below 1.2 m/s and stair-mounting height below 30 cm was analyzed among those whose results were, initially, above these limits. Most frequently, new limitations occurred in walking outdoors and in climbing stairs (44-60%). Walking speed and stair-mounting ability deteriorated below the thresholds mentioned in 4-36% of the participants, depending on gender and locality. There were only minor differences between the two Nordic localities in the decline in mobility functions. A substantial proportion of those whose performance had declined had developed limitations in self-reported mobility as well. However, the relationship between different methods of measurement was not straightforward. This indicates that multiple approaches are needed to obtain thorough knowledge about mobility and its decline among elderly people.


Validation of the sexual interest and desire inventory-female in hypoactive sexual desire disorder.
The Sexual Interest and Desire Inventory-Female (SIDI-F) is a 13-item scale developed as a clinician-administered assessment tool to measure hypoactive sexual desire disorder (HSDD) severity in women. To estimate the reliability and validity of the SIDI-F as a measure of HSDD severity. Women, aged 18-65 years, with primary HSDD, Female Sexual Arousal Disorder (FSAD), or no Female Sexual Dysfunction (no FSD) participated in two nontreatment studies (in North America and Europe). On days 0 and 28, subjects were assessed using the SIDI-F, Female Sexual Function Index (FSFI), Changes in Sexual Functioning Questionnaire-Female (CSFQ-F), Locke-Wallace Marital Adjustment Test (MAT) and the Female Sexual Distress Scale (FSDS). Discriminant validity, convergent validity, divergent validity, test-retest validity, and internal consistency of the SIDI-F. The North American study enrolled women with HSDD (N = 113), FSAD (N = 49) and no FSD (N = 61); the European study enrolled women with HSDD (N = 130) and no FSD (N = 124). In both studies, mean SIDI-F total score for women with HSDD was lower than for those with no FSD (P < 0.001, for all) demonstrating discriminant validity. Further, mean SIDI-F total score for women with HSDD was lower than for those with FSAD in the North American study (P < 0.001). Convergent validity with the FSFI and CSFQ-F and divergent validity with MAT were demonstrated. Test-retest reliability and internal consistency were high. The SIDI-F is a valid and reliable measure of HSDD severity in women.


Plant chemiluminescence.
Light production by plants was confirmed by measuring chemiluminescence from root and stem tissue of peas (Pisum sativum), beans (Phaseolus vulgaris), and corn (Zea mays) in a modified scintillation spectrophotometer. Chemiluminescence was inhibited by treating pea roots with boiling ethanol or by placing them in a N(2) gas phase. Chemiluminescence was increased by an O(2) gas phase or by the addition of luminol. NaN(3) and NaCN blocked both in vitro and in vivo chemiluminescence.It is postulated that the source of light is the hydrogen peroxide-peroxidase enzyme system. It is known that this system is responsible for chemiluminescence in leukocytes and it seems likely that a similar system occurs in plants.


Sporotrichoid presentation of lupus vulgaris mimicking mycetoma.
Most common form of cutaneous tuberculosis (TB) is lupus vulgaris (LV). Atypical presentation of LV is rare and may lead to delay in diagnosis and hence increase in morbidity. Here, we report a case of sporotrichoid form of LV in a 38 year old male who presented as cutaneous lesions mimicking mycetoma. High index of clinical suspicion and relevant investigations play a vital role in confirmation of diagnosis wherever atypical form of cutaneous TB is suspected.


Interactions between host genetics and gut microbiome in diabetes and metabolic syndrome.
Diabetes, obesity, and the metabolic syndrome are multifactorial diseases dependent on a complex interaction of host genetics, diet, and other environmental factors. Increasing evidence places gut microbiota as important modulators of the crosstalk between diet and development of obesity and metabolic dysfunction. In addition, host genetics can have important impact on the composition and function of gut microbiota. Indeed, depending on the genetic background of the host, diet and other environmental factors may produce different changes in gut microbiota, have different impacts on host metabolism, and create different interactions between the microbiome and the host. In this review, we highlight how appropriate animal models can help dissect the complex interaction of host genetics with the gut microbiome and how diet can lead to different degrees of weight gain, levels of insulin resistance, and metabolic outcomes, such as diabetes, in different individuals. We also discuss the challenges of identifying specific disease-associated microbiota and the limitations of simple metrics, such as phylogenetic diversity or the ratio of Firmicutes to Bacteroidetes. Understanding these complex interactions will help in the development of novel treatments for microbiome-related metabolic diseases. This article is part of a special issue on microbiota.


Anatomical and functional evaluation of myocardial bridging on the left anterior descending artery by cardiovascular magnetic resonance imaging.
A myocardial muscle bridge spans a segment of a major epicardial coronary artery that is located in the myocardium. This anatomic configuration can be responsible for angina pectoris, arrhythmias or even death. The current reference standard for diagnosis is conventional x-ray coronary angiography showing systolic compression of an epicardial vessel and the typical angiographic "milking effect." We report the case of a patient with myocardial bridging on the left anterior descending artery, in whom a combination of noninvasive high resolution display of the coronary artery lumen, visualization of the myocardium and functional assessment of blood flow during dobutamine stimulation by cardiovascular magnetic resonance imaging was performed.


Computer-assisted instruction in health education: a pilot study.
This pilot study examined the effectiveness of computer-assisted instruction (CAI) in health education. Students were exposed to four PLATO (CAI mechanism) lessons and were pre- and post-tested via a cognitive examination. These results were compared to results of those students in a control group. Students in the experimental group completed evaluation questionnaires for each lesson. In addition, a cost-effectiveness study was computed for utilizing PLATO. Results indicated that (1) students enrolled in the PLATO course learned as much as the students in the Traditional course, (2) the time devoted to teaching didactic information may be reduced by a least 50 per cent, (3) students tend to prefer the use of CAI to the lecture method, and (4) departments of instruction are able to expand courses to meet the needs of those students unable to previously enroll in these classes, at no additional cost to the department of the university.


Constructing language normativity through the animation of stance in Spanish-language medical consultations.
The purpose of this study is to examine the construction of language normativity as medical providers interact with patients and animate stance within Spanish-language medical consultations. The context of the study is a clinic in which providers use Spanish to communicate with monolingual Spanish-speaking patients. This clinic is in the United States, an English-speaking macro-societal context. Findings indicate that providers who are second-language users of Spanish animate stance and interact with patients in ways such that English is constructed as normative and Spanish as marked. Implications include the need to consider how the construction of language normativity within medical consultations affects health outcomes.


The Level of Exposure-Dental Experiences Questionnaire (LOE-DEQ): a measure of severity of exposure to distressing dental events.
To understand the development of dental anxiety better and to identify those at increased risk of developing dental anxiety, the Level of Exposure-Dental Experiences Questionnaire (LOE-DEQ) was developed. The aim of the current study was to determine the psychometric properties (i.e. factor structure, reliability, and validity) of the LOE-DEQ and to determine its suitability as an additional screening instrument for dentally anxious patients. Five different samples were used: (i) highly dentally anxious patients (n = 119); (ii) general dental patients (n = 480); (iii) students (n = 186); (iv) psychiatric outpatients (n = 17); and (v) oral surgery patients (n = 34). Results of the factor analysis revealed a four-factor solution. The LOE-DEQ has sufficient internal consistency (Cronbach's alpha values ranging from 0.69 to 0.85) and satisfactory test-retest reliability (intraclass correlation coefficient = 0.78). The results further suggest that this instrument has adequate discriminant, concurrent, and predictive validity. It is concluded that the LOE-DEQ is a useful tool for assessing patients' background in terms of previous exposure to distressing dental events, which is considered a vulnerability factor in the development of dental anxiety.


Campylobacter enteritis--New Zealand, 1990.
In August-September 1990, an outbreak of Campylobacter enteritis occurred at a camp near Christchurch, New Zealand. This report provides a preliminary summary of the investigation of this outbreak by the New Zealand Communicable Disease Centre and the Canterbury Area Health Board.


Promoting stigma coping and empowerment in patients with schizophrenia and depression: results of a cluster-RCT.
There is a need for interventions supporting patients with mental health conditions in coping with stigma and discrimination. A psycho-educational group therapy module to promote stigma coping and empowerment (STEM) was developed and tested for efficacy in patients with schizophrenia or depression. 30 clinical centers participated in a cluster-randomized clinical trial, representing a broad spectrum of mental health care settings: in-patient (acute treatment, rehabilitation), out-patient, and day-hospitals. As randomized, patients in the intervention group clusters/centers received an illness-specific eight sessions standard psychoeducational group therapy plus three specific sessions on stigma coping and empowerment ('STEM'). In the control group clusters the same standard psychoeducational group therapy was extended to 11 sessions followed by one booster session in both conditions. In total, N = 462 patients were included in the analysis (N = 117 with schizophrenia spectrum disorders, ICD-10 F2x; N = 345 with depression, ICD-10 F31.3-F31.5, F32-F34, and F43.2). Clinical and stigma-related measures were assessed before and directly after treatment, as well as after 6 weeks, 6 months, and 12 months (M12). Primary outcome was improvement in quality of life (QoL) assessed with the WHO-QOL-BREF between pre-assessment and M12 analyzed by mixed models and adjusted for pre-treatment differences. Overall, QoL and secondary outcome measures (symptoms, functioning, compliance, internalized stigma, self-esteem, empowerment) improved significantly, but there was no significant difference between intervention and control group. The short STEM module has proven its practicability as an add-on in different settings in routine mental health care. The overall increase in empowerment in both, schizophrenia and depression, indicates patients' treatment benefit. However, factors contributing to improvement need to be explored.The study has been registered in the following trial registers. ClinicalTrials.gov: https://register.clinicaltrials.gov/ Registration number: NCT01655368. DRKS: https://www.drks.de/drks_web/ Registration number: DRKS00004217.


Plasmablastic Lymphoma Presenting as Extensive Peritoneal and Retroperitoneal Nodules in an HIV-Positive Patient.
Plasmablastic lymphoma (PBL) is a rare but aggressive subtype of diffuse large B-cell lymphoma (DLBCL). The diagnosis of PBL is challenging as its features overlap with lymphoma and myeloma. The most common presentation involves the oral cavity/jaw in human immunodeficiency virus (HIV)-positive patients. It has also been reported in the gastrointestinal (GI) tract, lymph nodes, and soft tissues. Usually, if PBL involves the GI tract, it presents as a gut tumor mass. In this report, we present an HIV-positive patient with PBL presenting with multiple peritoneal nodules. To our knowledge, this is the first case of PBL presenting as multiple peritoneal and retroperitoneal nodules in an HIV-positive patient. This case emphasizes the rare presentation of a rare malignancy, difficulties in establishing a diagnosis, and the importance of proper and timely management.


Attitudes toward Help-Seeking for Sexual Problems among College Women.
Prior research has indicated that 65-70% of college age women have experienced at least one sexual problem. Sexual problems are associated with higher rates of depression, anxiety, and relationship distress; however, few college age women seek professional help for sexual difficulties. The present study used the Theory of Planned Behavior to explore how adherence to traditional feminine norms and self-stigma are associated with intention to seek professional psychological help for a sexual difficulty. Results of structural equation modeling analysis demonstrated approximate fit in a sample of 259 college women. The structural model indicated that self-stigma and stronger endorsement of specific feminine gender norms (i.e., romantic relationship, sexual fidelity, sweet and nice) were found to be associated with less intention to seek help for a sexual problem. We discuss future research directions and implications for clinical services.


Thiol/Disulfide Homeostasis as an Early Biomarker to Differentiate Sepsis from Pneumonia in Intensive Care Units.
It is possible that patients with pneumonia may also have sepsis and the separation of these two clinical entities may cause some trouble to clinicians. In order to separate a patient with pneumonia and a patient with sepsis, we qualify thiol/disulfide homeostasis as a potential biomarker. This study was designed between February 2018 - February 2019 prospectively. All patients in the intensive care unit with pneumonia and sepsis were enrolled in the study. At the time of hospitalization, thiol/disulfide homeostasis was measured. Patients diagnosed with sepsis and pneumonia were compared, in regards to thiol/disulfide homeostasis. During research period, 103 patients with sepsis and 120 patients with pneumonia were enrolled into the study. When we compared native-thiol, total-thiol, and disulfide levels in both sepsis and pneumonia patients, we had similar results (p>0.05). In sepsis group, index-1 (disulfide/native thiol ratio) and index-2 (disulfide/total thiol ratio) were found to be statistically higher than the pneumonia group, and index-3 (native thiol/total thiol ratio) was statistically lower than the pneumonia group (p=0.020, p= 0.021, p=0.021, respectively). In this study, we showed that thiol/disulfide homeostasis could be used as new markers in the early period in order to separate patients with sepsis and patients with pneumonia.


A systematic review of meta-analyses comparing direct laryngoscopy with videolaryngoscopy.
In the preceding 20 years, many randomized-controlled trials and meta-analyses have compared direct Macintosh laryngoscopy with videolaryngoscopy. The videolaryngoscope blades have included both traditional Macintosh blades and hyperangulated blades. Macintosh and hyperangulated blades differ in their geometry and technique for tracheal intubation; certain patient populations may benefit from one blade type over another. The primary objective of this systematic review was to assess whether published meta-analyses comparing direct Macintosh laryngoscopy to videolaryngoscopy have accounted for the videolaryngoscope blade type. Secondary objectives evaluated heterogeneity among practitioner experience and specialty, clinical context, patient population, and original primary study outcomes. A search was performed across Ovid Medline, Ovid Embase, ClinicalKey, PubMed, TRIP, AccessAnesthesiology, Google Scholar, and ANZCA discovery. A systematic review identified meta-analyses which compared direct Macintosh laryngoscopy to videolaryngoscopy. There were no patient age or clinical specialty restrictions. Exclusion criteria included non-English language, studies comparing non-Macintosh blade to videolaryngoscopy, and studies in awake patients. Twenty-one meta-analyses were identified that were published between 1 January 2000 and 7 May 2020. Macintosh and hyperangulated videolaryngoscope blades were combined in most studies (16/21; 76%). Heterogeneity was also present among practitioner experience (20/21; 95%), clinician specialty (15/21; 71%), and clinical locations (10/21; 48%). Adult and pediatric patients were combined or not defined in 5/21 studies (24%). The primary outcomes of the meta-analyses varied, with the most common (7/21; 33%) being first-pass tracheal intubation success. Heterogeneity across important clinical variables is common in meta-analyses comparing direct Macintosh laryngoscopy to videolaryngoscopy. To better inform patient care, future videolaryngoscopy research should differentiate blade type, clinical context, and patient-related primary outcomes.


Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts.
Connexin 43 (Cx43) is the most ubiquitous connexin in various cells, and presents as hemichannels (HCs) and gap junctions (GJs) on the cell membrane. We have recently shown that Cx43 abundance was strongly reduced in fibroblasts of human gingival wounds, and blocking Cx43 function in cultured human gingival fibroblasts (GFBLs) strongly regulated the expression of wound healing-related genes. However, it is not known whether these responses involved Cx43 HCs or GJs. Here we show that Cx43 assembled into distinct GJ and HC plaques in GFBLs both in vivo and in vitro. Specific blockage of Cx43 HC function by TAT-Gap19, a Cx43 mimetic peptide, significantly upregulated the expression of several MMPs, TGF-β signaling molecules, Tenascin-C, and VEGF-A, while pro-fibrotic molecules, including several extracellular matrix proteins and myofibroblast and cell contractility-related molecules, were significantly downregulated. These changes were linked with TAT-Gap19-induced suppression of ATP signaling and activation of the ERK1/2 signaling pathway. Collectively, our data suggest that reduced Cx43 HC function could promote fast and scarless gingival wound healing. Thus, selective suppression of Cx43 HCs may provide a novel target to modulate wound healing.


Environmental Nonadditivity and Franck-Condon physics in Nonequilibrium Quantum Systems.
We show that for a quantum system coupled to both vibrational and electromagnetic environments, enforcing additivity of their combined influences results in nonequilibrium dynamics that does not respect the Franck-Condon principle. We overcome this shortcoming by employing a collective coordinate representation of the vibrational environment, which permits the derivation of a nonadditive master equation. When applied to a two-level emitter our treatment predicts decreasing photon emission rates with increasing vibrational coupling, consistent with Franck-Condon physics. In contrast, the additive approximation predicts the emission rate to be completely insensitive to vibrations. We find that nonadditivity also plays a key role in the stationary nonequilibrium model behavior, enabling two-level population inversion under incoherent electromagnetic excitation.


Effect of glycosphingolipid fatty acid chain length on behavior in unsaturated phosphatidylcholine bilayers: a 2H NMR study.
Deuterium-labeled glycosphingolipids, N-lignoceroyl[d47]galactosylceramide (24:0 fatty acid form) and N-stearoyl[d35]galactosylceramide (18:0 fatty acid form) were prepared by partial synthesis. These probe-labeled species, differing only in the lengths of their fatty acids, were compared via 2H NMR with regard to arrangement and behavior in bilayers of the monounsaturated phospholipid 1-stearoyl-2-oleoylphosphatidylcholine (SOPC). Results were used to consider the physical significance of the great range of common acyl chain lengths that is a frequent feature of cell membrane glycosphingolipids. N-lignoceroyl[d47]- and N-stearoyl[d35]galactosylceramide were incorporated at concentrations ranging from 5 to 50 mol % into unsonicated phospholipid liposomes, and their spectra were analyzed in the range +73 to -14 degrees C. For the 18:0 fatty acid derivative, first spectral moments, M1, were calculated and plotted as a function of temperature for each sample composition. Spectral inspection for regions of phase coexistence, in conjunction with consideration of M1 curves, permitted derivation of phase diagram boundaries which were then refined using spectral subtraction techniques. The phase diagram for galactosylceramide with short fatty acid in SOPC was compared to the corresponding phase diagram for its long-chain analogue, derived previously in the same fashion [Morrow, M. R., Singh, D., Lu, D., & Grant, C. W. M. (1992) Biochim. Biophys. Acta 1106, 85-93]. The binary phase diagrams referred to above, which reflect the behavior of short- and long-chain glycolipids in a common phospholipid host matrix, displayed important similarities and differences. In fluid membranes, the behavior appeared to be remarkably alike, as reflected in superimposable fluidus curves over the concentration range studied.(ABSTRACT TRUNCATED AT 250 WORDS)


Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome.
Adenosine to inosine (A-to-I) RNA editing has been shown to be an essential event that plays a significant role in neuronal function, as well as innate immunity, in mammals. It requires a structure that is largely double-stranded for catalysis but little is known about what determines editing efficiency and specificity in vivo. We have previously shown that some editing sites require adjacent long stem loop structures acting as editing inducer elements (EIEs) for efficient editing. The glutamate receptor subunit A2 is edited at the Q/R site in almost 100% of all transcripts. We show that efficient editing at the Q/R site requires an EIE in the downstream intron, separated by an internal loop. Also, other efficiently edited sites are flanked by conserved, highly structured EIEs and we propose that this is a general requisite for efficient editing, while sites with low levels of editing lack EIEs. This phenomenon is not limited to mRNA, as non-coding primary miRNAs also use EIEs to recruit ADAR to specific sites. We propose a model where two regions of dsRNA are required for efficient editing: first, an RNA stem that recruits ADAR and increases the local concentration of the enzyme, then a shorter, less stable duplex that is ideal for efficient and specific catalysis. This discovery changes the way we define and determine a substrate for A-to-I editing. This will be important in the discovery of novel editing sites, as well as explaining cases of altered editing in relation to disease.


Longitudinal trends in serum ferritin levels and associated factors in a national incident hemodialysis cohort.
The rise in serum ferritin levels among US maintenance hemodialysis patients has been attributed to higher intravenous iron administration and other changes in practice. We examined ferritin trends over time in hemodialysis patients and whether iron utilization patterns and other factors [erythropoietin-stimulating agent (ESA) prescribing patterns, inflammatory markers] were associated with ferritin trajectory. In a 5-year (January 2007–December 2011) cohort of 81 864 incident US hemodialysis patients, we examined changes in ferritin averaged over 3-month intervals using linear mixed effects models adjusted for intravenous iron dose, malnutrition and inflammatory markers. We then examined ferritin trends across strata of baseline ferritin level, dialysis initiation year, cumulative iron and ESA use in the first dialysis year and baseline hemoglobin level. In models adjusted for iron dose, malnutrition and inflammation, mean ferritin levels increased over time in the overall cohort and across the three lower baseline ferritin strata. Among patients initiating dialysis in 2007, mean ferritin levels increased sharply in the first versus second year of dialysis and again abruptly increased in the fifth year independent of iron dose, malnutrition and inflammatory markers; similar trends were observed among patients who initiated dialysis in 2008 and 2009. In analyses stratified by cumulative iron use, mean ferritin increased among groups receiving iron, but decreased in the no iron group. In analyses stratified by cumulative ESA dose and baseline hemoglobin, mean ferritin increased over time. While ferritin trends correlated with patterns of iron use, increases in ferritin over time persisted independent of intravenous iron and ESA exposure, malnutrition and inflammation.


Traffic Signal Control With Adaptive Online-Learning Scheme Using Multiple-Model Neural Networks.
This article proposes a new traffic signal control algorithm to deal with unknown-traffic-system uncertainties and reduce delays in vehicle travel time. Unknown-traffic-system dynamics are approximated using a recurrent neural network (NN). To accurately identify the traffic system model, an online-learning scheme is developed to switch among a set of candidate NNs (i.e., multiple-model NNs) based on their estimation errors. Then, a bank of optimal signal-timing controllers is designed based on the online identification of the traffic system. Simulation studies have been carried out for the obtained control strategies using multiple-model NNs, and the desired results have been obtained. Moreover, compared with the widely used actuated traffic signal control schemes, it is shown that the proposed method can reduce vehicle travel delays and improve traffic system robustness.


A mixed-methods evaluation of complementary therapy services in palliative care: yoga and dance therapy.
To inform service provision and future research, we evaluated two complementary therapy services: yoga classes and dance therapy [The Lebed Method (TLM)]. Both were run as 6-week group courses. Patients completed the Measure Yourself Concerns and Wellbeing questionnaire pre- and post-course. Mean change over time was calculated for patient-nominated concern and well-being scores. Qualitative data regarding factors affecting health other than the therapy and benefits of the service were analysed using content analysis. Eighteen patients participated (mean age 63.8 years; 16 female; 14 cancer diagnoses); 10 were doing yoga, five TLM, and three both yoga and TLM; 14 completed more than one assessed course. Patients' most prevalent concerns were: mobility/fitness (n= 20), breathing problems (n= 20), arm, shoulder and neck problems (n= 18), difficulty relaxing (n= 8), back/postural problems (n= 8), fear/anxiety (n= 5). Factors affecting patients' health other than the therapy were prevalent and predominantly negative (e.g. treatment side effects). Patients reported psycho-spiritual, physical and social benefits. Concern scores improved significantly (P < 0.001) for both therapies; improved well-being was clinically significant for yoga. Evaluations of group complementary therapy services are feasible, can be conducted effectively and have implications for future research. Yoga and TLM may be of benefit in this population.


Chromoplast morphology and beta-carotene accumulation during postharvest ripening of Mango Cv. 'Tommy Atkins'.
Accumulation of beta-carotene and trans-cis isomerization of ripening mango mesocarp were investigated as to concomitant ultrastructural changes. Proceeding postharvest ripening was shown by relevant starch degradation, tissue softening, and a rising sugar/acid ratio, resulting in a linear decrease (R (2) = 0.89) of a ripening index (RPI(KS)) with increasing ripening time. A modest accumulation of all-trans-beta-carotene and its cis isomers resulted in a slight pigmentation of the mango chromoplasts, because ambient temperatures of 18.2-19.5 degrees C provided suboptimal ripening conditions, affecting color development and beta-carotene biosynthesis. The ultrastructures of chromoplasts from mango mesocarp and carrot roots were comparatively studied by means of light and transmission electron microscopy. Irrespective of the ripening stage, mango chromoplasts showed numerous plastoglobuli varying in size and electron density. They comprised the main part of carotenoids, thus supporting the partial solubilization of the pigments in lipid droplets. However, because different pigment-carrying tubular membrane structures were also observed, mango chromoplasts were assigned to the globular and reticulotubular types, whereas the crystalline type was confirmed for carrot chromoplasts. The large portions of naturally occurring cis-beta-carotene in mango fruits contrasted with the predominance of the all-trans isomer characteristic of carrots, indicating that the nature of the structure where carotenoids are deposited and the physical state of the pigments are crucial for the stability of the all-trans configuration.


Misconceptions in Van den Broeck's representation of misconceptions about learning disability research.
The methods and conclusions of Van den Broeck (in this issue) are evaluated from two perspectives: (a) statistical considerations and (b) theoretical models of IQ and achievement, specifically reading achievement. We consider the statistical model proposed by Van den Broeck for the regression-based discrepancy model (RDM) to be either irrelevant or conceptually inconsistent with current models of IQ and achievement. The resulting simulation produced exemplar cases that are not realistic in terms of practice. The theoretical representations of IQ and achievement were, in our understanding, inconsistent with contemporary models of either. We suggest that acceptable models support the use of the RDM as it has been proposed by us and by others as one component of the determination of the presence or absence of a learning disability.


Exploring the meaning of spirituality with aging adults in Appalachia.
This phenomenological study explored the meaning of spirituality in the lives of aging adults in Appalachia. Forty adult volunteers in varying states of health ranging in age from 59 to 94 years participated in focus groups. Through open-ended questions, respondents described their perceptions of spirituality, spirituality, and health, and the role of spirituality in helping them cope. Themes that emerged from the data were a conviction that God exists and acts in the lives of persons, calls them to action, and is a source of connection in times of loss. Spirituality positively affects attitude, particularly as health declines. Respondents expected respectful and empathic health care providers who would meet their physical needs and be concerned about their spiritual needs. Spirituality was of paramount importance in the lives of these elders; thus, health care providers must consciously include spirituality in assessments and interventions. Nursing curricula must prepare students to provide spiritual care.


Interrelated family-building behaviors: cohabitation, marriage, and nonmarital conception.
Data from the National Longitudinal Study of the High School Class of 1972 are used to estimate a series of models of entry into marriage, entry into cohabitation, and nonmarital pregnancy. Our models account explicitly for the endogeneity of one outcome as a predictor of another by taking into account both heterogeneity across individuals due to unmeasured factors that may affect all these outcomes and the correlation in the unmeasured factors across processes. We find that these heterogeneity components are strongly and positively related across the outcomes. Women who are more likely to cohabit, marry, or become pregnant while unmarried are also more likely to do each of the others. Although black and white women differ in the likelihood of these behaviors, the interrelations of the behaviors are quite similar across groups.


Suberin production by isolated tomato fruit protoplasts.
The multilamellar wall secreted by protoplasts isolated from locule tissue of tomato (Lycopersicon esculentum L.) fruit was purified, and an extract was obtained after depolymerization with BF(3)-methanol. Analysis of this extract using thin layer chromatography demonstrated the presence of fatty acid methyl esters, fatty alcohols, dicarboxylic acid dimethyl esters, and omega-hydroxy acid methyl esters. These components were quantified using an Iatroscan thin layer chromatography-flame ionization detection system. The different chain lengths in each group were identified and quantified using gas chromatography. The results clearly indicated the presence of suberin.


Giant electric field effect on the second hyperpolarizability of symmetric singlet diradical molecules.
This contribution reveals the effects of a static electric field on the static second hyperpolarizability γ of symmetric singlet diradical molecules using the valence configuration interaction scheme. It is found that under the effect of a field, the component of γ along the axis joining the two radical sites can be gigantically (approximately two to three orders) enhanced for symmetric diradicals having intermediate diradical characters with respect to those of closed-shell and pure diradical molecules in the absence of a field. Moreover, this electric field enhancement of γ increases as a function of the diradical character. These results and their analysis propose therefore a new strategy to design materials with exceptional nonlinear optical responses.


Association between detrusor overactivity and postoperative outcomes in patients undergoing male bone anchored perineal sling.
In this study we determined if there was an association between the presence of preoperative detrusor overactivity and patient outcomes after bone anchored perineal sling. A total of 85 men underwent a male perineal sling procedure for urodynamically proven stress urinary incontinence. Preoperative history and physical examination were performed, and patients completed self-assessment questionnaires. Based on urodynamics patients were divided into 2 groups of those with and those without detrusor overactivity. Questionnaires including the Patient Global Impression of Improvement Scale were readministered postoperatively. Success was defined by the Patient Global Impression of Improvement as very much better or much better. Failure was defined by the responses of a little better, no change, a little worse or much worse. Successes and failures were compared to the presence of detrusor overactivity. Preoperative parameters, preoperative and postoperative questionnaire scores, and postoperative pad and anticholinergic use were compared between the 2 groups. A total of 72 patients were included in the analysis, and of these 22 (30.6%) had detrusor overactivity and 50 (69.4%) did not. All patients completed the Patient Global Impression of Improvement. There was no statistical difference in the number of cases classified as successes or failures in the 2 groups (p = 0.4213). A significantly higher percentage of patients with detrusor overactivity required postoperative anticholinergics. There was no statistical difference in the number of patients using pads postoperatively. Preoperative detrusor overactivity was not associated with worse postoperative outcomes. Men with urodynamic stress urinary incontinence and detrusor overactivity may be considered for a male sling procedure. However, they may require postoperative anticholinergics and should be counseled accordingly.


Mutation of aspartic acid 262 on estrogen receptor abrogates estradiol signaling pathway.
ERα (estrogen receptor alpha) exerts nuclear genomic actions and membrane-initiated non-genomic effects. The mutation of aspartic acid into alanine in vitro revealed the critical role of aspartic acid 258 (corresponding to mouse amino acid site 262) of ERα for non-nuclear function. Our previous in vitro study revealed that this mutation blocked estrogen's non-genomic effects on vascular endothelial H2S release. Here, we studied the in vivo role of the aspartic acid 262 of ERα in the reproductive system and in the vascular tissue. We generated a mouse model harboring a point mutation of the murine counterpart of this aspartic acid into alanine (ERαD262A). Our results showed that the ERαD262A females are fertile with standard hormonal serum levels, but the uterine development and responded with estrogen and follicular development are disrupted. In line with our previous study, we found that the rapid dilation of the aorta was abrogated in ERαD262A mice. In contrast to the previously reported R264-ERα mice, the classical estrogen genomic effector SP1/NOS3/AP1 and the nongenomic effectors p-eNOs, p-AKT, and p-ERK were disturbed in the ERαD262A aorta. Besides, the serum H2S concentration was decreased in ERαD262A mice. Together, ERαD262A mice showed compromised both genomic and non-genomic actions in response to E2. These data showed that aspartic acid 262 of ERα are important for both genomic and non-genomic effects of E2. Our data provide a theoretical basis for further selecting an effective non-genomic mouse model and provide a new direction for developing estrogen non-genomic effect inhibitors.


Stimulation of adherent cells by addition of purified proteins of viral hemorrhagic septicemia virus to trout kidney cell cultures.
Purified proteins of the virus causing viral hemorrhagic septicemia in the trout were added to cultures on semisolid medium of leukocytes obtained from either healthy or immunized rainbow trout. Adherent cells were specifically stimulated by the glycoprotein of the viral spikes and, to a lesser extent, by the nucleoproteins. In contrast, a specific memory response was associated more with the nucleoproteins than with the glycoprotein when leukocytes from trout immunized with the virus were employed. These results suggest the necessity of employing both proteins in subunit vaccination trials and the possibility of using this assay to select the proper epitopes for genetically engineered proteins during subunit vaccine development.


Analysis of dark spots growing in organic EL devices by time-of-flight secondary ion mass spectrometry.
Chemical structural analysis of tape-stripped surfaces at dark spots growing in organic electroluminescent (EL) devices during exposure to the atmosphere was done by time-of-flight secondary ion mass spectrometry (OF-SIMS). The EL devices consist of indium-tin-oxide, triphenylamine-tetramer, tris(8-hydroxyquinoline)aluminum (Alq3), and a Mg-Ag cathode deposited in order under vacuum on a glass substrate. It was found that the interface between the Alq3 layer and the Mg-Ag cathode was exposed as a result of tape-stripping, where a large number of dark spots were observed on both sides. Secondary ion images of O-, Mg+, and Alq2+ were observed from the dark spots on the cathode side. On the other hand, Mg+ and O- images with a nucleus in the center were observed from the Alq3 side. It is concluded from the results that the constituent element Mg of the cathode was oxidized at the interface adjacent to the Alq3 layer during exposure to the atmosphere, forming a dark spot with a nucleus in the center. Finally, it was confirmed that the TOF-SIMS analysis of the tape-stripped surface is useful for the analysis of the mechanism of dark spot formation.


A descriptive study of the work of community psychiatric nurses with elderly demented people.
This study examines the work of community psychiatric nurses (CPNs) with elderly demented people. A total of 14 cases, taken from the caseloads of four CPNs, were examined by direct observation of CPNs' practice and in-depth interviews. The data were analysed using a method suggested by Dey (1993). The validity of the findings was checked internally by means of respondent validation and externally by CPNs from other teams working with elderly demented people. It was found that the CPNs operated two strategies: one directed towards the client and the other towards the family. The process underlying these strategies consisted of five overlapping phases: assessment, planning, intervention, evaluation, and termination. The CPNs' working process was set within a framework containing their understanding of what they understood as 'community', the management style within the team and the quality and availability of clinical supervision. This process is integrated with existing literature on community psychiatric nursing and suggestions are made regarding possible developments within the speciality.


Identification of attentional and hyperactivity problems in primary care: a report from pediatric research in office settings and the ambulatory sentinel practice network.
To 1) determine the frequency of identification of attentional and hyperactivity problems (AHPs) by clinicians, and 2) examine whether minority children or children from less well-educated, lower-income, or lower-functioning families would be more likely to be identified as having AHPs. Prospective cohort study of 22 059 consecutive children 4 to 15 years of age being seen for acute, chronic, and health supervision visits. Practices of 401 pediatric and family practice clinicians in 44 states, Puerto Rico, and 4 Canadian provinces. Parent questionnaires included demographic information and the Pediatric Symptom Checklist. Clinician questionnaires categorized psychosocial problems and addressed how assessment of problems was made. Analyses compared children with newly identified AHPs with those with other newly identified psychosocial problems. Clinicians identified behavior problems in 18.7% of children, with 9.2% of the entire sample identified as having AHPs. Among those with newly assessed AHPs, clinicians identified minority children and those from low-income or poorly functioning families as having AHPs at the same rate as other children. However, even after controlling for symptoms, males were more likely than females (odds ratio, 2.81) to be identified as having AHPs. Older clinicians were significantly more likely to identify children as having AHPs (odds ratio, 2.09). In assessing AHPs, clinicians used standardized tools such as behavioral questionnaires for only 36.9% of children, and Diagnostic and Statistical Manual criteria for 38.3% of children. AHPs are highly prevalent in primary care practice. Clinicians do not appear predisposed to label children from disadvantaged backgrounds as having AHPs. Primary care assessment of AHPs lacks standardization.


Tropism of Extracellular Vesicles and Cell-Derived Nanovesicles to Normal and Cancer Cells: New Perspectives in Tumor-Targeted Nucleic Acid Delivery.
The main advantage of extracellular vesicles (EVs) as a drug carrier system is their low immunogenicity and internalization by mammalian cells. EVs are often considered a cell-specific delivery system, but the production of preparative amounts of EVs for therapeutic applications is challenging due to their laborious isolation and purification procedures. Alternatively, mimetic vesicles prepared from the cellular plasma membrane can be used in the same way as natural EVs. For example, a cytoskeleton-destabilizing agent, such as cytochalasin B, allows the preparation of membrane vesicles by a series of centrifugations. Here, we prepared cytochalasin-B-inducible nanovesicles (CINVs) of various cellular origins and studied their tropism in different mammalian cells. We observed that CINVs derived from human endometrial mesenchymal stem cells exhibited an enhanced affinity to epithelial cancer cells compared to myeloid, lymphoid or neuroblastoma cancer cells. The dendritic cell-derived CINVs were taken up by all studied cell lines with a similar efficiency that differed from the behavior of DC-derived EVs. The ability of cancer cells to internalize CINVs was mainly determined by the properties of recipient cells, and the cellular origin of CINVs was less important. In addition, receptor-mediated interactions were shown to be necessary for the efficient uptake of CINVs. We found that CINVs, derived from late apoptotic/necrotic cells (aCINVs) are internalized by in myelogenous (K562) 10-fold more efficiently than CINVs, and interact much less efficiently with melanocytic (B16) or epithelial (KB-3-1) cancer cells. Finally, we found that CINVs caused a temporal and reversible drop of the rate of cell division, which restored to the level of control cells with a 24 h delay.


Comparison of five bilevel pressure ventilators in patients with chronic ventilatory failure: a physiologic study.
To compare patient-ventilator interaction and comfort in patients with chronic ventilatory failure (CVF) who are undergoing noninvasive positive-pressure ventilation with five different commercial bilevel pressure home ventilators. Also, we wanted to evaluate the short-term effects of the five ventilators on physiologic variables, namely, breathing patterns and inspiratory muscles. Randomized, controlled physiologic study. Pulmonary division of a rehabilitation institution. Twenty-eight patients with CVF due to COPD (17 patients) and restrictive chest wall diseases (11 patients). Sensation of comfort, breathing patterns and minute ventilation (E), respiratory muscles and mechanics, and patient-ventilator interaction during both unassisted and assisted ventilation with the five ventilators applied randomly. The five ventilators showed different flow and pressure waveforms. The level of comfort was somehow different among the studied ventilators. When compared to unassisted ventilation, all ventilators induced a significant increase in E (p < 0.01) without any significant difference among ventilators. Use of the five ventilators resulted in significant differences in peak airway opening pressure (Pao,peak) but not in mean airway opening pressure computed over a period of 1 min (PTPao,min), and in a duty cycle. Ineffective efforts (IEs) were similar among the studied ventilators. In comparison with unassisted ventilation, all ventilators induced significant reductions in inspiratory muscle effort (p < 0.001). No significant relationship was found between level of comfort and PTPao,min, Pao,peak, or the number of IEs. In stable, awake patients with CVF, all of the studied ventilators were well-tolerated, although with a great intersubject variability in comfort, and performed well in terms of improvement in E and inspiratory muscle unloading, thus fulfilling the aims of mechanical ventilation. This effect was obtained with similar levels of PTPao,min, despite the fact that Pao,peak was different among some ventilators. The number of IEs was similar among the studied ventilators.


Achromatic approach to phase-based multi-modal imaging with conventional X-ray sources.
Compatibility with polychromatic radiation is an important requirement for an imaging system using conventional rotating anode X-ray sources. With a commercially available energy-resolving single-photon-counting detector we investigated how broadband radiation affects the performance of a multi-modal edge-illumination phase-contrast imaging system. The effect of X-ray energy on phase retrieval is presented, and the achromaticity of the method is experimentally demonstrated. Comparison with simulated measurements integrating over the energy spectrum shows that there is no significant loss of image quality due to the use of polychromatic radiation. This means that, to a good approximation, the imaging system exploits radiation in the same way at all energies typically used in hard-X-ray imaging.


Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion.
Cdc42 cycling through GTP/GDP states is critical for its function in the second/granule mobilization phase of insulin granule exocytosis in pancreatic islet beta cells, although the identities of the Cdc42 cycling proteins involved remain incomplete. Using a tandem affinity purification-based mass spectrometry screen for Cdc42 cycling factors in beta cells, RhoGDI was identified. RNA interference-mediated depletion of RhoGDI from isolated islets selectively amplified the second phase of insulin release, consistent with the role of RhoGDI as a Cdc42 cycling factor. Replenishment of RhoGDI to RNA interference-depleted cells normalized secretion, confirming the action of RhoGDI to be that of a negative regulator of Cdc42 activation. Given that RhoGDI also regulates Rac1 activation in beta cells, and that Rac1 activation occurs in a Cdc42-dependent manner, the question as to how the beta cell utilized RhoGDI for differential Cdc42 and Rac1 cycling was explored. Co-immunoprecipitation was used to determine that RhoGDI-Cdc42 complexes dissociated upon stimulation of beta cells with glucose for 3 min, correlating with the timing of glucose-induced Cdc42 activation and the onset of RhoGDI tyrosine phosphorylation. Glucose-induced disruption of RhoGDI-Rac1 complexes occurred subsequent to this, coincident with Rac1 activation, which followed the onset of RhoGDI serine phosphorylation. RhoGDI-Cdc42 complex dissociation was blocked by mutation of RhoGDI residue Tyr-156, whereas RhoGDI-Rac1 dissociation was blocked by RhoGDI mutations Y156F and S101A/S174A. Finally, expression of a triple Y156F/S101A/S174A-RhoGDI mutant specifically inhibited only the second/granule mobilization phase of glucose-stimulated insulin secretion, overall supporting the integration of RhoGDI into the activation cycling mechanism of glucose-responsive small GTPases.


Immunomodulation of encephalomyocarditis virus-induced disease in A/J mice.
The E variant of encephalomyocarditis (EMC) virus causes an encephalomyelitis and coagulative necrosis of the pancreas and parotid glands in some but not all strains of inbred and outbred mice. In other models of disease caused by picornaviruses, depletion of specific lymphocyte subsets abrogates the development of tissue lesions. In this study, severe encephalomyelitis and acinar pancreatitis and parotitis developed in adult male A/J mice infected with 100 PFU of EMC virus. Depletion of the CD4+ subset of T lymphocytes in vivo with a monoclonal antibody (MAb) prior to EMC virus inoculation protects mice from developing encephalomyelitis, pancreatitis, and parotitis. This effect is also seen when animals are treated with anti-CD4 and anti-CD8 in combination, but the anti-CD8 MAb alone does not ameliorate the disease. Overall, concentrations of virus in tissues from anti-CD4-treated animals are lower than in immunologically intact control mice. Small-plaque variants of virus were also recovered from the tissues in some animals in this group. CD4+ lymphocytes are involved in the expression of EMC virus-induced pancreatitis and parotitis in A/J mice. This specific subset of T cells would appear to influence EMC viral tropism or replication in various organs.


The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL/6 Mice.
The toxicity of many "inert" ingredients of pesticide formulations, such as safeners, is poorly characterized, despite evidence that humans may be exposed to these chemicals. Analysis of ToxCast data for dichloroacetamide safeners with the ToxPi tool identified benoxacor as the safener with the highest potential for toxicity, especially liver toxicity. Benoxacor was subsequently administered to mice via oral gavage for 3 days at concentrations of 0, 0.5, 5, and 50 mg/kg bodyweight (b.w.). Bodyweight-adjusted liver and testes weights were significantly increased in the 50 mg/kg b.w. group. There were no overt pathologies in either the liver or the intestine. 16S rRNA analysis of the cecal microbiome revealed no effects of benoxacor on α- or β-diversity; however, changes were observed in the abundance of certain bacteria. RNAseq analysis identified 163 hepatic genes affected by benoxacor exposure. Benoxacor exposure expressed a gene regulation profile similar to dichloroacetic acid and the fungicide sedaxane. Metabolomic analysis identified 9 serum and 15 liver metabolites that were affected by benoxacor exposure, changes that were not significant after correcting for multiple comparisons. The activity of antioxidant enzymes was not altered by benoxacor exposure. In vitro metabolism studies with liver microsomes and cytosol from male mice demonstrated that benoxacor is enantioselectively metabolized by cytochrome P450 enzymes, carboxylesterases, and glutathione S-transferases. These findings suggest that the minor toxic effects of benoxacor may be due to its rapid metabolism to toxic metabolites, such as dichloroacetic acid. This result challenges the assumption that inert ingredients of pesticide formulations are safe.