Semiconducting Polymer Nanoporous Thin Films as a Tool to Regulate Intracellular ROS Balance in Endothelial Cells.
The design of soft and nanometer-scale photoelectrodes able to stimulate and promote the intracellular concentration of reactive oxygen species (ROS) is searched for redox medicine applications. In this work, we show semiconducting polymer porous thin films with an enhanced photoelectrochemical generation of ROS in human umbilical vein endothelial cells (HUVECs). To achieve that aim, we synthesized graft copolymers, made of poly(3-hexylthiophene) (P3HT) and degradable poly(lactic acid) (PLA) segments, P3HT-g-PLA. In a second step, the hydrolysis of sacrificial PLA leads to nanometer-scale porous P3HT thin films. The pore sizes in the nm regime (220-1200 nm) were controlled by the copolymer composition and the structural arrangement of the copolymers during the film formation, as determined by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The porous P3HT thin films showed enhanced photofaradaic behavior, generating a higher concentration of ROS in comparison to non-porous P3HT films, as determined by scanning electrochemical microscopy (SECM) measurements. The exogenous ROS production was able to modulate the intracellular ROS concentration in HUVECs at non-toxic levels, thus affecting the physiological functions of cells. Results presented in this work provide an important step forward in the development of new tools for precise, on-demand, and non-invasive modulation of intracellular ROS species and may be potentially extended to many other physiological or pathological cell models.


Evidence for inhibition by protein kinase A of receptor/G alpha(q)/phospholipase C (PLC) coupling by a mechanism not involving PLCbeta2.
The effects of cAMP on the oxytocin-stimulated increase in phosphatidylinositide turnover and the possible pathways involved were investigated in a human myometrial cell line (PHM1-41) and in COS-M6 cells overexpressing the oxytocin receptor. Preincubation with chlorophenylthio-cAMP (CPT-cAMP), forskolin, or relaxin inhibited oxytocin-stimulated phosphatidylinositide turnover in PHM1-41 cells, and the inhibition was reversed by H-89, a relatively specific protein kinase A inhibitor. Both CPT-cAMP and transiently expressed protein kinase A catalytic subunit inhibited stimulation by oxytocin and carbachol of [3H]inositol 1,3,4-trisphosphate formation in COS-M6 cells expressing oxytocin or muscarinic M1 receptors, respectively. CPT-cAMP also inhibited phosphatidylinositide turnover stimulation by endothelin-1 in PHM1-41 cells, further demonstrating the generality of the cAMP-inhibitory mechanism. Since G betagamma activation of phospholipase Cbeta2 (PLCbeta2) is a suggested target of protein kinase A, the possibility that the oxytocin receptor couples to PLCbeta2 via G alpha(i)G betagamma activation was explored. Western blot analysis of PHM1-41 cells and COS-M6 cells detected PLCbeta1 and PLCbeta3, but not PLCbeta2. In PHM1-41 cells, pertussis toxin reduced the oxytocin-stimulated increase in [3H]inositol 1,3,4-trisphosphate by 53%, and this was reversed completely by H-89. Thus, the inhibitory effect of pertussis toxin may result from an indirect effect of cAMP elevation. These data suggest that receptor/G alpha(q)-coupled stimulation of PLCbeta1 or PLCbeta3 can be inhibited by cAMP through a phosphorylation mechanism involving protein kinase A that does not involve PLCbeta2. In smooth muscle, this mechanism could constitute potentially important cross-talk between pathways regulating contraction and relaxation.


The S100 calcium-binding protein A6 plays a crucial role in hepatic steatosis by mediating lipophagy.
S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain. In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice. Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.


Enterococcal infections: an increasing problem in hospitalized patients.
We studied 157 episodes of infection or colonization with enterococci in 122 patients over a six-month period. One hundred twelve episodes (71.3%) occurred in patients over age 60 years. The most common sites for isolation of enterococci were the urinary tract, and bone and soft tissue. Nosocomial acquisition of enterococci occurred in 74.7% of all infections, and an additional 21% of episodes occurred in patients who had been transferred from another hospital or were regularly seen in the clinic. The overall mortality was 19.6%; 71.4% of those with bacteremia died. Enterococci appear to be significant pathogens, especially in older men in veterans' acute care hospitals and nursing home care units.


Flexible ureteroscopic renal stone extraction during laparoscopic ureterolithotomy in patients with large upper ureteral stone and small renal stones.
We describe laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy. We describe its efficacy through a laparoscopic port and a ureterotomy site in patients with large upper ureteral stone and small renal stones. Between January 2009 and February 2012, we performed laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy in 11 patients who had upper ureteral and renal stones. The retroperitoneal approaches were used in all patients using 3-4 trocars. All procedures were performed successfully without significant complications. Mean operative time was 78.5 minutes (range: 52-114 minutes). The mean size of ureteral stone was 19.91 mm (range: 15-25 mm). In addition, 25 renal stones (mean size 7.48 mm, range: 2-12 mm) were removed from 11 patients. The mean length of hospital stay was 3.5 days (range: 2-6 days). Laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy can be considered one of treatment modalities for patients with large upper ureteral stones accompanied by renal stones who are indicated in laparoscopic ureterolithotomy.


[Determination of distal latency of the motor nerves of the hand].
The authors show the methodological problems connected with the determination of distal latency and the possibility of misinterpretation. They recommend the use of concentric needle electrodes together with surface electrodes for the determination of the distal latency of the hand nerves and also to always register both nerves.


THE EVOLUTION OF DIAPAUSE IN THE KILLIFISH FAMILY RIVULIDAE (ATHERINOMORPHA, CYPRINODONTIFORMES): A MOLECULAR PHYLOGENETIC AND BIOGEOGRAPHIC PERSPECTIVE.
Phylogenetic relationships within the family Rivulidae (order Cyprinodontiformes) are investigated using 1972 aligned base pairs of mitochondrial DNA (mtDNA) for samples representing 66 species. Genes analyzed include those encoding the 12S ribosomal RNA; transfer RNAs for valine, glutamine, methionine, tryptophan, alanine, asparagine, cysteine, and tyrosine; complete NADH dehydrogenase subunit II; and part of cytochrome oxidase I. Parsimony analysis of the aligned mtDNA sequences results in a single most parsimonious tree. The phylogeny reveals two independent origins of developmental diapause within the family Rivulidae. It is unlikely that diapause evolved de novo in each group, suggesting that the presence or absence of diapause is the result of developmental switches between alternative stabilized pathways. Phylogeny of the family Rivulidae shows high concordance with predictions derived from the geological history of South America and Central America. Basal lineages in the rivulid phylogeny are distributed primarily on geologically old areas, whereas more nested lineages occur in geologically younger areas. However, there is little concordance between the molecular phylogeny and currently available morphological hypotheses and existing taxonomies. Based on the mtDNA phylogeny, the genera Pterolebias, Rivulus, Pituna, and Plesiolebias are considered nonmonophyletic and warrant taxonomic reassessment.


Elevated Plasma miR-29a Levels Are Associated with Increased Carotid Intima-Media Thickness in Atherosclerosis Patients.
Atherosclerotic cardiovascular diseases, such as coronary heart disease, have become a major public health problem all over the world. MicroRNA-29a (miR-29a) modulates expression levels of collagen, inflammatory reaction and other extracellular matrix mRNAs, while adiponectin (APN), a circulating protein secreted by adipocytes, has anti-inflammatory properties. Both play multifaceted roles in angiogenesis or vascular remodelling. However, little is known about plasma miR-29a and APN levels in patients with atherosclerosis. We therefore investigated the relationship between the plasma levels of miR-29a or APN and carotid intima-media thickness (cIMT) in atherosclerosis patients (n = 85, cIMT ≥ 1.2 mm) and the controls (n = 85, cIMT < 1.2 mm). We found that the atherosclerosis group showed higher miR-29a levels (31.15 ± 3.99 vs. 26.39 ± 1.05 Ct, P < 0.001) and lower APN levels (15.93 ± 4.61 vs. 21.80 ± 7.74 ng/ml, P < 0.001), compared with control group. Thus, increased cIMT was associated with higher plasma miR-29a levels (r = 0.688, P < 0.001) and with lower plasma APN levels (r = -0.494, P < 0.001). Furthermore, multiple logistic regression analysis indicated that higher miR-29a levels (OR: 1.136, 95% CI: 1.042-1.240, P = 0.004) increased the risk for atherosclerosis, whereas higher APN levels appeared to be protective (OR: 0.122, 95% CI: 0.055-0.271, P < 0.001). The present study indicates that elevated miR-29a levels and reduced APN levels are associated with atherosclerosis.


The impact of acupuncture combined with acupoint catgut embedding on simple obesity: A systematic review and meta-analysis.
Obesity is a widespread chronic metabolic disease that significantly impairs quality of life. Studies have demonstrated the efficacy of both acupuncture and acupoint catgut embedding (ACE) in the management of obesity. However, the superiority of acupuncture combined with ACE over acupuncture alone remains a subject of controversy. This study aims to elucidate this controversy and provide robust clinical evidence. A comprehensive search of relevant literature from the initiation to July 2022 was carried out in 8 databases (PubMed, EMBASE, Cochrane database, Web of Science, CBM Database, CNKI, Wan-fang Database, and VIP Database). We included randomized controlled trials (RCTs) that investigated the treatment of simple obesity using acupuncture paired with ACE, with acupuncture alone as the control group. The pooled outcomes included body mass index (BMI), body weight (BW), %BF, waist circumference (WC), hip circumferences (HC), waist-to-hip ratio (WHR), therapeutic effective rate (TER), and adverse events. Two independent reviewers performed screening (using EndNote X9) and quality assessment (using the Cochrane Risk of Bias tool) for the included studies. with the software RevMan 5.3 was used to perform pooling of effect sizes. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 20 trials involving 15 datasets (1616 participants) were included. The findings demonstrated significant improvements in outcome measures when acupuncture was combined with ACE, compared with acupuncture alone (BMI: MD = -1.49 kg/m2, 95% confidence interval [CI] = -1.93 to -1.04, P < .01; BW: MD = -2.38, 95% CI = -3.86 to -0.89, P < .01; %BF: MD = -2.19, 95% CI = -3.23 to -1.15, P < .01; WC: MD = -2.01, 95% CI = -3.66 to -0.35, P < .05; HC: MD = -0.83, 95% CI = -1.64 to -0.02, P < .05; WHR: MD = -0.02, 95% CI = -0.03 to -0.01, P < .01; TER: OR = 2.68, 95% CI = 1.93-3.74, P < .01). Adverse effects were reported in 4 studies. The results of this meta-analysis indicate that acupuncture combined with ACE is superior to acupuncture alone in the treatment of obesity, which is supported by the subgroup analysis. The assessment of efficacy may have been influenced by variations in study quality, potentially amplifying the observed effects. RCTs with larger sample sizes and improved methodological quality are needed to enhance the validity of the findings.


Exploring the Feasibility of Calculating Expected pCO2 From Venous Blood Gas Samples Alone in Intensive Care Patients.
Introduction This study highlights the significance of assessing acid-base balance and gas exchange in intensive care patients. The research investigates the applicability of using the "expected (pCO2 = HCO3 + 15)" formula, derived from venous blood gas samples, as an alternative to Winter's formula and practical formula. The study emphasizes the importance of identifying the primary acid-base abnormality accurately and efficiently for appropriate clinical intervention in critically ill patients. Methods This study included 400 adult patients admitted to the Anesthesia Clinic in the Third Stage Anesthesia and Reanimation Intensive Care Unit at Hitit University Erol Olçok Training and Research Hospital between April 2020 and July 2023. Blood gas samples were collected simultaneously from both arterial lines and venous catheters. Patients under 18 years, pregnant women, hemodialysis patients, and those with missing data were excluded. The study aimed to calculate the expected partial pressure of carbon dioxide (pCO2) values using Winter's formula and simple formula for both arterial and venous blood gas samples and assess potential correlations between them. Results The results showed a narrow range for arterial pH values (7.12-7.72), a wider distribution for pCO2 values (17.90-81.30 mmHg), and a moderate dispersion for HCO3 values (12.80-44.33 mmol/L). Both Winter's and simple formulas were applied to estimate the expected pCO2 values, showing strong positive correlations between arterial and venous pH, pCO2, and HCO3 values. The scatterplot illustrated a very high level of association (Pearson's correlation coefficient, r = 1) between the expected pCO2 values derived from both formulas using arterial and venous blood gas samples. Conclusion The clinical study demonstrates that estimating expected pCO2 values in mixed acid-base disorders can be achieved using a simple and convenient formulation, eliminating the need for arterial blood gas sampling and its associated complications.


Cellulose production from glucose using a glucose dehydrogenase gene (gdh)-deficient mutant of Gluconacetobacter xylinus and its use for bioconversion of sweet potato pulp.
A gene fragment encoding a putative pyrroloquinoline quinone glucose dehydrogenase (PQQ GDH) was cloned from a bacterial cellulose (BC)-forming acetic acid bacterium, Gluconacetobacter xylinus (=Acetobacter xylinum) strain BPR 2001, which was isolated as a high BC producer when using fructose as the carbon source. A GDH-deficient mutant of strain BPR 2001, namely GD-I, was then generated via gene disruption using the cloned gene fragment. Strain GD-I produced no gluconic acid but produced 4.1 g.l(-1) of BC aerobically in medium containing glucose as the carbon source. The ability of strain GD-I to convert glucose to BC was approximately 1.7-fold higher than that of the wild type. Strain GD-I was also able to produce 5.0 g.l(-1) of BC from a saccharified solution, which was derived from sweet potato pulp by enzymatic saccharification. Supplementation of ethanol during aerobic cultivation further increased the concentration of BC produced by strain GD-I to 7.0 g.l(-1). The rate of conversion from glucose to BC under these cultivation conditions was equivalent to that of strain BPR 2001 cultivated with fructose as the carbon source.


Optoplasmonic Hybrid Materials for Trace Detection of Methamphetamine in Biological Fluids through SERS.
Optoplasmonic materials comprising both photonic and plasmonic elements are of particular interest for the development of substrates for surface-enhanced Raman spectroscopy (SERS). In this work, a layer of analyte-carrying dielectric nano/microspheres is placed on top of a monolayer of gold nanoparticles to enhance the intensity of the electric (E-) field localization and to enrich the analyte close to the electromagnetic hot spots. Numerical simulations of the hybrid structure confirm an increased and spatially expanded E-field enhancement at the interface. Due to a decreasing filling fraction with increasing size of the dielectric spheres, simulations predict a saturated SERS enhancement for dielectric microspheres with a diameter larger than 4 μm, which is confirmed by experimental SERS measurements. The dielectric microsphere can be functionalized with surface ligands that facilitate the binding of target molecules in solution. The deposition of the analyte-loaded microspheres on the self-assembled gold nanoparticle ensures a high local concentration of analytes in the electromagnetic "hot" surface. The performance of the optoplasmonic SERS approach for detecting methamphetamine in saliva and urine is tested, and the detection of analytes at nanomolar (nM) concentrations is demonstrated.


Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription.
Thiopurine S-methyltransferase (TPMT) activity is polymorphic, and a trimodal distribution has been demonstrated in Caucasians (low, intermediate and high methylator groups). The TPMT gene promoter contains a variable number of three GC-rich tandem repeats, namely A, B and C, ranging from three to nine in length in a A(n)B(m)C architecture. Here, we investigated the influence of number and type of TPMT gene promoter tandem repeats on human TPMT gene transcription in K562 cells transiently transfected with reporter constructs bearing various variable number of tandem repeats (VNTR) and addressed the interaction of transcription factor binding to the VNTRs by electrophoretic mobility shift assays. We found that the distribution patterns of VNTR alleles do not significantly differ among acute lymphoblastic leukemia patients, acute myeloid leukemia patients and normal individuals. We also demonstrated that the A repeat has a negative effect in TPMT gene transcription and that a positive regulatory element, identified immediately upstream to the VNTR region of the TPMT gene promoter, is indispensable for TPMT gene transcription. Our electrophoretic mobility shift assay analysis indicated that the Sp1 and Sp3 transcription factors bind to the VNTR repeats. Overall, our data underline that both the number and type of VNTRs, as well as the upstream regulatory region of the TPMT gene promoter, determine the overall level of TPMT gene transcription. It remains to be seen whether these VNTRs can be employed as pharmacogenetic markers to individualize thiopurine therapy.


Co-digestion of Laminaria digitata with cattle manure: A unimodel simulation study of both batch and continuous experiments.
This work investigated the thermophilic (55 °C) co-digestion performance both in batch and continuous mode operation. The biochemical methane potentials of L. digitata and cattle manure were 308 ± 24 and 203 ± 33 mL CH4/g VS, respectively. The optimum co-digestion feedstock ratio was found to be 80% macroalgae: 20% manure on a volatile solids basis, which produced 290 ± 19 mL CH4/g VS under long-term and stable continuous operation at an organic loading rate of 2 g VS/L/d and hydraulic retention time of 15 days. Simulations of the batch and continuous experiments were, for the first time, carried out using an integrated anaerobic bioconversion model without structural modifications. Close fits between measured and simulated data provided mutual confirmation of experimental reliability and model robustness, and provided new perspectives for the use of the software tool.


Covert bilaterality of mature ovarian teratomas.
Over a 21-year period, 213 women with mature teratoma of the ovary were operated on at Parkland Memorial Hospital. Twenty-seven had bilateral tumors. In 22 of these 27 patients, bilateral involvement was evident on clinical examination, and in 5, biopsy of an abnormal but nonteratoid appearing ovary was required to make the diagnosis. Ninety patients with a visually normal opposite ovary had no identifiable tumor in that ovary by investigative incision or incidental excision. Neither incision nor excision of the normal contralateral ovary was performed in 58 cases, and subsequently, one of these women is known to have developed a teratoma in that ovary. We conclude that synchronous covert bilaterality of mature teratomas is not common, and a visually normal contralateral ovary should not routinely be bivalved or wedge biopsied.


[Perioperative cardiovascular reactions and the noradrenaline plasma level in patients on chronic antidepressant medication].
It is still controversial whether the perioperative incidence of cardiovascular complications is increased in patients on chronic treatment with cyclic antidepressants (AD) and whether AD medication should be discontinued prior to surgery. METHODS. We measured perioperative cardiovascular variables in 31 patients on chronic treatment with tri- and tetracyclic AD and 31 patients without AD medication. Heart rate, blood pressure, and noradrenaline plasma concentrations were compared between the two groups at nine points in time. During induction of anaesthesia, the ECG was recorded continuously. After the administration of 0.01 mg/kg atropine i.v., all patients received opiate-supplemented enflurane anaesthesia. Re-uptake inhibition of noradrenaline by AD resulted in significantly higher noradrenaline plasma concentrations before and during anaesthesia in the AD-treated group. The incidence of arrhythmias, blood pressure elevations, and tachycardia was not increased in patients in AD treatment. Arrhythmias during induction of anaesthesia were seen in 6 of the AD-treated patients and 5 of the controls. Blood pressure elevations by more than 35% were seen in 10 patients on AD treatment and 8 controls. The heart rate prior to induction of anaesthesia and 2 h after the end of surgery was significantly higher in the AD-treated group. During anaesthesia the heart rate was higher at two points in time only. The incidence of tachycardia was similar in both groups. Intravenous administration of 0.01 mg/kg atropine prior to induction of anaesthesia increased the heart rate of the patients on chronic AD medication by 11.4%. This increase was significantly higher in the control group (16.2%), suggesting that patients with chronic AD treatment do not have a higher sensitivity to atropine. The elevated noradrenaline plasma levels in patients on chronic AD treatment did not result in a higher incidence of arrhythmias, blood pressure elevations, or tachycardia perioperatively. Taking these results into account, we do not consider it necessary to discontinue chronic AD medication prior to surgery in patients without cardiovascular disease.


Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment.
Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.


A first-principles analysis of hydrogen interaction in Ti-doped NaAlH4 surfaces: structure and energetics.
First principles density functional theory studies have been carried out to investigate the hydrogen interactions in Ti-doped NaAlH4 (001) and (100) surfaces. In both surfaces, Ti was found to energetically favor the interstitial sites formed by three neighboring AlH4- units and interact directly with them. The resulting local structure corresponds to a formula of TiAl3Hx with x = 12 before hydrogen desorption starts. The hydrogen desorption energies from many positions of TiAl3Hx are reduced considerably as compared with that from the corresponding clean, undoped NaAlH4 surfaces. The almost invariant local environment surrounding Ti during dehydrogenation makes the TiAl3Hx complex a precursor state for the formation of experimentally observed TiAl3. The importance of the complex has been explored by analyzing the structures and energetics accompanying hydrogen desorption from the complex and from the neighboring AlH4- units. The TiAl3Hx has extended effects beyond the locally reducing hydrogen desorption energy. It facilitates low-energy hydrogen desorption by either transferring hydrogen to the TiAl3Hx complex or reducing hydrogen desorption energy in the neighboring AlH4- by linking these AlH4- units with the complex structure. The possible mechanisms for forming octahedral AlH6(3-) were also identified in the vicinity of TiAl3Hx. Desorbing hydrogen atoms between Ti and Al atoms causes a symmetrical expansion of Ti-Al bonds and leads to the formation of octahedral AlH6(3-).


Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma.
The aim of this study was to examine the association of obesity with esophageal adenocarcinoma, and with the precursor lesions Barrett esophagus and gastroesophageal reflux disease (GERD). This case-control study included cases with GERD (n = 142), Barrett esophagus (n = 130), and esophageal adenocarcinoma (n = 57). Controls comprised 102 asymptomatic individuals. Using logistic regression methods, we compared obesity rates between cases and controls adjusting for differences in age, gender, and lifestyle risk factors. Relative to normal weight, obese individuals were at increased risk for esophageal adenocarcinoma (Odds Ratio [OR] 4.67, 95% Confidence Interval [CI] 1.27-17.9). Diets high in vitamin C were associated with a lower risk for GERD (OR 0.40, 95% CI 0.19-0.87), Barrett esophagus (OR 0.44, 95% CI 0.20-0.98), and esophageal adenocarcinoma (OR 0.21, 95% CI 0.06-0.77). For the more established risk factors, we confirmed that smoking was a significant risk factor for esophageal adenocarcinoma, and that increased liquor consumption was associated with GERD and Barrett esophagus. In light of the current obesity epidemic, esophageal adenocarcinoma incidence rates are expected to continue to increase. Successful promotion of healthy body weight and diets high in vitamin C may substantially reduce the incidence of this disease.


Storage Temperature Is More Effective Than Lactic Acid Bacteria Inoculations in Manipulating Fermentation and Bacterial Community Diversity, Co-Occurrence and Functionality of the Whole-Plant Corn Silage.
The objective of this study was to investigate effects of different lactic acid bacteria (LAB) on the fermentation process of whole-plant corn silage stored at different temperatures based on bacterial community successions, interaction networks, and predicted functions. Before ensiling, whole-plant corn was inoculated with L. plantarum (LP) or L. buchneri (LB) and the silage bags were stored at 20 or 30°C, and sampled after 0.5, 1, 3, 7, 14, and 60 d of ensiling. The higher abundances of Leuconostoc, Pedicoccus and Weissella were observed in silage stored at 30°C after 12 h of ensiling, thereby rapidly decreased pH to about 4.5. According to meta-network analysis, the bacterial communities were more sensitive to storage temperature than LAB inoculants during whole-plant corn ensiling. Species of Lactobacillus and Weissella were sensitive to 30°C, while Leuconostoc species were sensitive to 20°C in whole-plant corn silage. The storage temperature of 30°C decreased bacterial diversity and network complexity of whole-plant corn silage compared with 20°C. Additionally, LP inoculation changed the bacterial community successions during the early and middle ensiling periods, while LB inoculation affected bacterial community successions in the later stage of ensiling. The metabolic pathways of bacterial community were totally different in LB-inoculated silage from that in control and LP-inoculated silage. As the bacterial compositions became simple along with the ensiling process, the functional structure of bacterial community became simplified as well. In general, the storage temperature had a greater impact on the fermentation characteristics, bacterial community and predicted function of whole-plant corn silage compared with LAB inoculations. IMPORTANCE Increased understanding of effects of regulation measures on whole-plant corn silage is important from bacterial community succession, interaction network and predicted functions. According to alpha diversity and meta co-occurrence network, the bacterial communities were more sensitive to storage temperature than LAB inoculants during whole-plant corn ensiling. The storage temperature of 30°C decreased bacterial diversity and network complexity of whole-plant corn silage compared with 20°C. In addition, 30°C promoted the initiation of LP and LB inoculants, and 20°C was conducive to the long-term growth of LP and LB inoculants. According to the changes of bacterial community and predicated functions, it was further confirmed that the effect of LB inoculation was more obvious on whole-plant corn silage.


[Intraventricular injection of 5,7-dihydroxytryptamine alters neuronal activity of neurons in the medial prefrontal cortex of rat].
The present study is aimed to investigated the firing activity of pyramidal neurons and interneurons in the medial prefrontal cortex (mPFC) in rats with bilateral intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) by using in vivo extracellular recording. The results showed that the injection of 5,7-DHT reduced the 5-hydroxytryptamine (5-HT) levels in the mPFC and dorsal raphe nucleus in the rats. The firing rate of mPFC pyramidal neurons in rats with 5,7-DHT injection was significantly higher than that of normal rats, and the firing pattern of these neurons also changed significantly towards a more burst-firing, while the injection decreased the firing rate of mPFC interneurons and changed the firing pattern of the interneurons towards a more irregular. These results indicate that the lesions of the serotonergic neurons lead to the changes in the firing activity of mPFC pyramidal neurons and interneurons, suggesting that serotonergic system plays an important role in the regulation of the neuronal activity in the mPFC.


Consistencies between recalled panic and lactate-induced panic.
This study investigated the frequency and severity of symptoms during naturally occurring panic attacks recollected as "usual" and during sodium lactate-induced attacks. Seventy-six male and 126 female patients with panic disorder or agoraphobics with panic attack (DSM-III criteria) underwent lactate infusion studies and were serially administered the Acute Panic Inventory (API). Fifty-nine percent of the subjects were rated by an attending psychiatrist to have experienced lactate-induced panic attacks. Patients were also asked to API symptom rate their "usual" panic attacks. For panic recollected as usual, the most frequently reported symptoms (> or = 75%) at the moderate to severe levels included: afraid in general, difficulty concentrating, difficulty performing a job, desire to flee, afraid of losing control, palpitations, feeling hot or cold or both, dyspnea, dizzy-lightheaded. During lactate infusion, 25 of 29 API symptoms increased significantly from prelactate to point of panic; however, particularly robust effect sizes were exhibited for the desire to flee, dyspnea, tingling, twitching/trembling and difficulty doing a job. Comparison of panic recollected as usual and lactate-induced panic showed that more than half of the symptoms did not differ after Bonferroni correction; however, the most notable were fear in general, dyspnea, chest pain/discomfort, difficulty swallowing, feeling weak, desire to flee, and feeling hot/cold or both. These data point to a very distinctive role during both recollected and lactate-induced panic attacks for fearfulness the desire to flee (by definition), and for dyspnea, difficulty performing a job and fear of losing control. During lactate-induced panic, dyspnea exhibited the most robust effect size of all physical symptoms.


Proteome-wide identification of S-sulfenylated cysteines reveals metabolic response to freezing stress after cold acclimation in Brassica napus.
Redox regulation plays a wide role in plant growth, development, and adaptation to stresses. Sulfenylation is one of the reversible oxidative post-transcriptional modifications. Here we performed an iodoTMT-based proteomic analysis to identify the redox sensitive proteins in vivo under freezing stress after cold acclimation in Brassica napus. Totally, we obtained 1,372 sulfenylated sites in 714 proteins. The overall sulfenylation level displayed an increased trend under freezing stress after cold acclimation. We identified 171 differentially sulfenylated proteins (DSPs) under freezing stress, which were predicted to be mainly localized in chloroplast and cytoplasm. The up-regulated DSPs were mainly enriched in photosynthesis and glycolytic processes and function of catalytic activity. Enzymes involved in various pathways such as glycolysis and Calvin-Benson-Bassham (CBB) cycle were generally sulfenylated and the metabolite levels in these pathways was significantly reduced under freezing stress after cold acclimation. Furthermore, enzyme activity assay confirmed that the activity of cytosolic pyruvate kinase and malate dehydrogenase 2 was significantly reduced under H2O2 treatment. Our study provides a landscape of redox sensitive proteins in B. napus in response to freezing stress after cold acclimation, which proposes a basis for understanding the redox regulation in plant metabolic response to freezing stress after cold acclimation.


Occult lens subluxation related to laser peripheral iridotomy: A case report and literature review.
Laser peripheral iridotomy (LPI) is commonly performed as a primary treatment for acute primary angle closure glaucoma after administration of anti-glaucoma medications or for prevention of this condition. Minor complications may occur following LPI and most of them do not have deleterious consequences. We report a rare case of lens subluxation that has a possible relationship with LPI treatment. A 54-year-old female patient was initially referred for surgical treatment of medication-uncontrollable angle closure glaucoma in her left eye. The patient had undergone Neodymium:YAG LPI at an outside hospital 2 months prior to the presentation due to an episode of elevated intraocular pressure (IOP). About 5 days after the LPI, she had spontaneous blurred vision, redness, and pain in the left eye. Her IOP was found to re-rise and was not controlled well even with maximum tolerated anti-glaucoma medications during the following 2 months. On slit-lamp examination, the significant shallowing of both peripheral and central anterior chamber was noted in the left eye. Ultrasound biomicroscopy examination revealed the lens tilting towards the iris and the inferior zonular dehiscence corresponding to the iridotomy site. Lens subluxation secondary to LPI treatment in the left eye. Phacoemulsification combined with in-the-bag intraocular lens implantation was performed in the left eye. The zonular weakness corresponding to the iridotomy site was further confirmed during surgery. The patient's IOP remained stable in the first postoperative 3 months without additional anti-glaucoma medications. Laser peripheral iridotomy may cause structural zonular damage, and ophthalmologists should be aware of this potential complication and proceed with caution.


Mutually exclusive interaction of the adenovirus E4-6/7 protein and the retinoblastoma gene product with internal domains of E2F-1 and DP-1.
The binding of E2F to the adenovirus (Ad) E2a promoter is stimulated by the Ad E4-6/7 protein. E2F DNA binding activity is composed of a heterodimer of related but distinct proteins of the E2F-1 and DP-1 families. The E4-6/7 protein induces the cooperative and stable binding of E2F to an inverted repeat binding site in the E2a promoter apparently by providing a dimerization interface to two adjacent E2F heterodimers. The product of the retinoblastoma gene product (Rb) represses the transcriptional activity of E2F by direct protein-protein interaction. In this report, we have examined the regions of E2F-1 and DP-1 that are required for the induction of cooperative E2F binding to the E2a promoter by the E4-6/7 protein. Our results demonstrate that an internal segment of E2F-1, that is conserved among members of the E2F family, is required for functional interaction with the E4-6/7 product. Consistent with this observation, other members of the E2F family (E2F-2 and E2F-3) productively interact with E4-6/7. DP-1 also is necessary for stable interaction with E4-6/7 and an internal segment of DP-1 is required that is positioned in a location similar to that of the conserved E2F-1 domain. Interestingly, the binding of E4-6/7 and the binding of Rb to E2F are mutually exclusive, and our results show that the same internal segments of E2F-1 and DP-1 that are required for E4-6/7 binding are also required for stable interaction with Rb. These results suggest that the Ad E4-6/7 protein mimics Rb in part for the protein interaction requirements for E2F binding, although with different functional consequences. While Rb binding represses E2F activity, the E4-6/7 protein stimulates transactivation of the Ad E2a promoter.


Histamine release from human basophils by the insect allergen Chi t I.
Hemoglobins of the Diptera species Chironomus thummi thummi (Chi t I) are potent inhalant allergens. Chi t I-specific histamine release was measured by a new radioimmunoassay in whole human blood taken from 20 sensitized patients, 11 exposed nonsensitized probands, and 11 nonexposed controls. The sensitized patients, who all had positive skin tests and radioallergosorbent test results with Chi t I, showed a significantly higher histamine release than the two other groups. However, within the patient group, the percentage of released histamine did not correlate with the intensity of the skin test response or the concentration of Chi t I-specific IgE antibodies. Our results demonstrate that this method is a sensitive and specific in vitro test for evaluation of IgE-mediated sensitization.


Does Early versus Delayed Spanning External Fixation Impact Complication Rates for High-energy Tibial Plateau and Plafond Fractures?
High-energy tibial plateau and tibial plafond fractures have a high complication rate and are frequently treated with a staged approach of spanning external fixation followed by definitive internal fixation after resolution of soft tissue swelling. A theoretical advantage to early spanning external fixation is that earlier fracture stabilization could prevent further soft tissue damage and potentially reduce the occurrence of subsequent infection. However, the relative urgency of applying the external fixator after injury is unknown, and whether delay in this intervention is correlated to subsequent treatment complications has not been examined. Is delay of more than 12 hours to spanning external fixation of high-energy tibial plateau and plafond fractures associated with increased (1) infection risk; (2) compartment syndrome risk; and (3) time to definitive fixation, length of hospitalization, or risk of secondary surgeries? We further stratified our results based on injury site: plateau and plafond. In practical clinical terms, many of these high-energy C-type articular fractures will arrive at the regional trauma center in the evening and this investigation attempted to explore if these injuries need to be placed in temporizing fixators that evening or if they may be safely addressed in a dedicated trauma room the next morning. We performed a retrospective review of all patients at a Level I university trauma center with high-energy tibial plateau and plafond fractures who underwent staged treatment with a spanning external fixation followed by subsequent definitive internal fixation between 2006 and 2012. Patients who received a fixator within 12 hours of recorded injury time were classified as early external fixation; those who received a fixator greater than 12 hours from injury were classified as delayed external fixation. There were 80 patients (42 plateaus and 38 plafonds) in the early external fixation cohort and 79 patients (45 plateaus and 34 plafonds) in the delayed external fixation cohort. Deep infection rate was 13% in plateau fractures and 18% in plafond fractures. Rates of infection, compartment syndrome, secondary surgeries, time to definitive fixation, and length of hospitalization were recorded. Controlling for differences in open fracture severity between groups, there was no difference in infection for plafond (early fixation: 12 of 38 [32%]; delayed fixation: seven of 34 [21%]; adjusted relative risk = 1.39 [95% confidence interval {CI}, 0.45-4.31], p = 0.573) and plateau (early fixation: eight of 42 [19%]; delayed fixation: nine of 45 [20%]; adjusted relative risk: 0.93 [95% CI, 0.31-2.78], p = 0.861) groups. For compartment syndrome risk, there was no difference between early and delayed groups for plateau fractures (early fixation: six of 42 [14%]; delayed fixation: three of 45 [7%]; relative risk = 0.47 [0.12-1.75], p = 0.304) and plafond fractures (early fixation: two of 38 [5%]; delayed fixation: three of 34 [9%]; relative risk = 1.67 [0.30-9.44], p = 0.662). There was no difference for length of hospitalization for early (9 ± 7 days) versus delayed fixation (9 ± 6 days) (mean difference = 0.24 [95% CI, -2.9 to 3.4], p = 0.878) for patients with plafond fracture. Similarly, there was no difference in length of hospitalization for early (10 ± 6 days) versus delayed fixation (8 ± 4 days) (mean difference = 1.6 [95% CI, -3.9 to 0.7], p = 0.170) for patients with plateau fracture. Time to definitive fixation for plateau fractures in the early external fixation group was 8 ± 6 days compared with 11 ± 7 days for the delayed external fixation group (mean difference = 2.9 [95% CI, 0.13-5.7], p = 0.040); there was no difference in time to definitive fixation for early (12 ± 7 days) versus delayed (12 ± 6 days) for patients with plafond fractures (mean difference = 0.39 [95% CI, -2.7 to 3.4], p = 0.801). There was no difference in risk of secondary surgeries between early external fixation (21 of 38 [55%]) and delayed external fixation (13 if 34 [38%]) for plafond fractures (adjusted relative risk = 0.69 [95% CI, 0.41-1.16], p = 0.165) and no difference between early fixation (24 of 42 [57%]) and delayed fixation (26 of 45 [58%]) for plateau fractures (adjusted relative risk = 1.0 [95% CI, 0.70-1.45], p = 1.00). We were unable to detect a difference in infection, compartment syndrome, secondary procedures, or length of hospitalization for patients who undergo early versus delayed external fixation for high-energy tibial plateau or plafond fractures. This may affect decisions for resource use at trauma centers such as whether high-energy periarticular lower extremity fractures need to be spanned on the evening of presentation or whether this procedure may wait until the morning trauma room. Given the high complication rate of these injuries and clinical relevance of this question, this may also need to be examined in a prospective manner. Level IV, therapeutic study.


New observations regarding deterministic, time-reversible thermostats and Gauss's principle of least constraint.
Deterministic thermostats are frequently employed in nonequilibrium molecular dynamics simulations in order to remove the heat produced irreversibly over the course of such simulations. The simplest thermostat is the Gaussian thermostat, which satisfies Gauss's principle of least constraint and fixes the peculiar kinetic energy. There are of course infinitely many ways to thermostat systems, e.g., by fixing sigma(i)/p(i)/mu+l. In the present paper we provide, for the first time, convincing arguments as to why the conventional Gaussian isokinetic thermostat (mu = 1) is unique in this class. We show that this thermostat minimizes the phase space compression and is the only thermostat for which the conjugate pairing rule holds. Moreover, it is shown that for finite sized systems in the absence of an applied dissipative field, all other thermostats (mu not = 1) perform work on the system in the same manner as a dissipative field while simultaneously removing the dissipative heat so generated. All other thermostats (mu not = 1) are thus autodissipative. Among all mu, thermostats, only the mu = 1 Gaussian thermostat permits an equilibrium state.


[Visual function study in work with computer].
This investigation searched for the relationship between amount of nearwork, asthenopic symptoms and visual function, in a group of office workers engaged in telemarketing. Phoria, monocular accommodative facility with +/- 2 lens flippers and near point of convergence were measured in 100 office workers (mean age 21 +/- 2.6 years) whose uncorrected visual acuity was 20/30 or better. Daily hours of reading hard-copy and of computer use, and the level of asthenopic symptoms, were measured using a questionnaire. In this sample, telemarketers were involved 5.84 +/- 2.02 daily hours in computer use, and 2.87 +/- 2.13 daily hours in reading. The following asthenopic symptoms were present twice or more times in a week: headaches 16%, pain in the eyes 17%, red eyes 18%, blurred vision 10%, double vision 3%, burning eyes 19% and watery eyes 19%. An association was found between the amount of hours using computers and red eyes (chi 2 = 4.4, p = 0.0359) or blurred vision (chi 2 = 8.35, p = 0.0038). And also between deficit of convergence and headaches (chi 2 = 4.3313, p = 0.0374) or red eyes (chi 2 = 3.6416, p = 0.0564). No other associations could be found between the accommodative facility test results, the near point phoria, and the amount of nearwork or the asthenopic symptoms. In conclusion, computer use in telemarketing is associated with few asthenopic symptoms. Near point of convergence should be routinely measured, as it is associated with some asthenopic symptoms.


Recent developments in clinical acupuncture.
Recent developments in the field of clinical acupuncture in the USA and worldwide are reviewed. The discovery of beta-endorphin in support of acupuncture pain relief is discussed. Other neurotransmitters in relation to the mechanism of action of acupuncture are examined. The uses of acupuncture in treating functional disorders are listed and discussed. Supporting evidence from animal experimentation is examined. The electro-acupuncture according to Voll (EAV) system is introduced as a means to standardize the therapeutic effectiveness of acupuncture. With standardization of the therapeutic effectiveness of this procedure, the author sees acupuncture as a simple, economical and effective treatment modality.


Transfusing Wisely: Clinical Decision Support Improves Blood Transfusion Practices.
The cost and risks of red blood cell (RBC) transfusions, along with evidence of overuse, suggest that improving transfusion practices is a key opportunity for health systems to improve both the quality and value of patient care. Previous work, which included a BestPractice Advisory (BPA), was adapted in a quality improvement project designed to reduce both exposure to unnecessary blood products and costs. A prospective, pre-post study was conducted at an academic medical center with a diverse patient population. All noninfant inpatients without gastrointestinal bleeding who were not within 12 hours of surgical procedures were included. The interventions were education, a BPA, and other enhancements to the computerized provider order entry system. The percentage of multiunit (≥ 2 units) RBC transfusions decreased from 59.9% to 41.7% during the intervention period and to 19.7% postintervention (p < 0.0001). The percentage of inpatient RBC transfusion units administered for hemoglobin (Hb) ≥ 7 g/dL declined from 72.3% to 57.8% during the intervention period and to 38.0% for the postintervention period (p < 0.0001). The overall rate of inpatient RBC transfusion (units administered per 1,000 patient-days without exclusions) decreased from 89.8 to 78.1 during the intervention period and to 72.7 during the postintervention period (p <0.0001). The estimated annual cost savings was $1,050,750. The interventions reduced multiunit transfusions (by 67.1%) and transfusions for Hb ≥ 7 g/dL (by 47.4%). The improvement in the overall transfusion rate (19.0%) was less marked, limited by better baseline performance relative to other centers.


Encapsulation into carbon nanotubes and release of anticancer Cisplatin drug molecule.
Molecular dynamics simulations have been investigated to study the interactions between single-wall carbon nanotubes and an anticancer agent Pt complex (Cisplatin). The optimized diameter of the vector system has been determined to encapsulate in the best conditions the drug molecules. The simulation results show also that several drug molecules can be adsorbed inside the nanotubes, leading to an increased confinement time. Moreover, our simulations show that the release of the drug near a cell membrane model is favored, opening the way to a natural drug nanocapsule.


In Situ Analysis of the Growth and Dielectric Properties of Organic Self-Assembled Monolayers: A Way To Tailor Organic Layers for Electronic Applications.
Organic nanoscale science and technology relies on the control of phenomena occurring at the molecular level. This is of particular importance for the self-assembly of molecular monolayers (SAM) that can be used in various applications ranging from organic electronics to bioelectronic applications. However, the understanding of the elementary nanoscopic processes in molecular film growth is still in its infancy. Here, we developed a novel in situ and extremely sensitive detection method for the analysis of the electronic properties of molecular layer during molecular layer deposition. This low-frequency sensor (1 kHz) is employed to analyze the standard vapor deposition process of SAMs of molecules and, subsequently, it is used to optimize the growth process itself. By combining this method with an ex situ determination of the effective thickness of the resulting layers via ellipsometry, we observe a large difference of the permittivity (1 kHz) of the examined aminosilanes in the liquid state (εliquid = 5.5-8.8) and in SAMs (εSAM = 22-52, electric field in the plane of the layer). We ascribe this difference to either the different orientation and order of the molecules, the different density of molecules, or a combination of both effects. Our novel in situ analyses not only allows monitoring and optimizing the deposition of organic layers but also demonstrates the high potential of organic SAMs as organic high-k layers in electronic devices.


Loss-enabled sub-poissonian light generation in a bimodal nanocavity.
We propose an implementation of a source of strongly sub-poissonian light in a system consisting of a quantum dot coupled to both modes of a lossy bimodal optical cavity. When one mode of the cavity is resonantly driven with coherent light, the system will act as an efficient single photon filter, and the transmitted light will have a strongly sub-poissonian character. In addition to numerical simulations demonstrating this effect, we present a physical explanation of the underlying mechanism. In particular, we show that the effect results from an interference between the coherent light transmitted through the resonant cavity and the super-poissonian light generated by photon-induced tunneling. Peculiarly, this effect vanishes in the absence of the cavity loss.


The traditional Chinese herbal formula ASHMI inhibits allergic lung inflammation in antigen-sensitized and antigen-challenged aged mice.
Although asthma is typically characterized as a childhood disease, it can develop later in life. Older asthmatic patients may be at increased risk for corticosteroid adverse effects. We developed a novel traditional Chinese medicine to treat asthma called antiasthma simplified herbal medicine intervention (ASHMI). Herbal products may offer safer adjunctive treatment for older asthmatic patients. To investigate the effects of ASHMI on characteristics of allergic asthma in an aged mouse model of asthma. BALB/c mice (6 weeks old [young] and 6, 12, and 18 months old [aged]) received ASHMI treatment before and during intraperitoneal ovalbumin sensitization and intratracheal challenges. The control groups were untreated, age-matched, ovalbumin-sensitized and ovalbumin-challenged mice (ovalbumin mice) and naive mice. After the final antigen challenge, airway pressure (defined as the time-integrated change in peak airway pressure) after acetylcholine provocation was measured, representing airway hyperresponsiveness, and bronchoalveolar lavage fluid, sera, lung tissues for histologic analysis, messenger RNA, and collagen were collected. Mean time-integrated change in peak airway pressure values in 6-week-old and 6-, 12-, and 18-month-old ASHMI ovalbumin mice were significantly reduced compared with those of age-matched, nontreated ovalbumin mice. Bronchoalveolar lavage fluid eosinophil numbers were significantly lower in all ASHMI ovalbumin mice. Treatment with ASHMI of young and aged ovalbumin mice resulted in significantly decreased lung inflammation, detected via hematoxylin-eosin staining; airway mucous cell metaplasia, determined by means of periodic acid-Schiff staining; and messenger RNA copy numbers of the mucin gene MUC5AC. Levels of ovalbumin specific IgE and the T(H)2 cytokines interleukin 4 (IL-4), IL-5, and IL-13 in lung and splenocyte cultures were reduced. Interferon gamma secretion was increased. Treatment with ASHMI reduced collagen production. Treatment with ASHMI reduces several features of asthma in aged antigen-sensitized and antigen-challenged mice.


Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza.
Respiratory viral infections with SARS-CoV-2 and influenza viruses commonly induce a strong infiltration of immune cells into the human lung, with potential detrimental effects on the integrity of the lung tissue. Despite comprising the largest fractions of circulating lymphocytes in the lung, rather little is known about how peripheral blood natural killer (NK) cell and T cell subsets are equipped for lung-homing in COVID-19 and influenza. Here, we provide a detailed comparative analysis of NK cells and T cells in patients infected with SARS-CoV-2 or influenza virus, focusing on the protein and gene expression of chemokine receptors known to be involved in recruitment to the lung. For this, we used 28-colour flow cytometry as well as re-analysis of a publicly available single-cell RNA-seq dataset from bronchoalveolar lavage (BAL) fluid. Frequencies of NK cells and T cells expressing CXCR3, CXCR6, and CCR5 were altered in peripheral blood of COVID-19 and influenza patients, in line with increased transcript expression of CXCR3, CXCR6, and CCR5 and their respective ligands in BAL fluid. NK cells and T cells expressing lung-homing receptors displayed stronger phenotypic signs of activation compared to cells lacking lung-homing receptors, and activation was overall stronger in influenza compared to COVID-19. Together, our results indicate a role for CXCR3+, CXCR6+, and/or CCR5+ NK cells and T cells that potentially migrate to the lungs in moderate COVID-19 and influenza patients, identifying common targets for future therapeutic interventions in respiratory viral infections.


Cutaneous nocardiosis manifesting as a frontal mass in a patient with giant cell arteritis.
We report the case of a subcutaneous abscess due to Nocardia spp. mimicking a spontaneous hematoma or an aneurysm of the temporal artery branch, in a giant cell arteritis patient treated with methylprednisolone and azathioprine. Ultrasonography, incision and drainage with cultures helped in the diagnosis. This case highlights the importance of considering rare pathogens in immunosuppressed patients, besides the more frequent disease complications.


Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria.
The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.


"Why we could not eradicate polio from pakistan and how can we?"
Polio is a major health problem and a deadly infectious disease in the developing countries. It is a viral illness caused by polio virus that can lead to paralysis, limb deformities, breathing problems or even death. Polio virus resides only in humans and passes on to the environment in the faeces of someone who is infected. Polio is still endemic in three countries, i.e., Pakistan, Nigeria and Afghanistan and is eradicated from the rest of the world. Pakistan is considered as the exporter of Wild Polio Virus (WPV) with highest number of polio outbreaks among endemic countries. With the start of World Polio Eradication Initiative in 1988, the number of polio cases has been reduced up to 99% worldwide until now. In 2015, Pakistan has shown a decrease of 70-75% in number of polio cases as compare to last year which is the result of good government's initiatives. Militant organizations such as Tehreek-e-Taliban Pakistan, Al-Qaeda and Boko haram movement of northern Nigeria are a major hurdle in the eradication of polio from these countries. The misconception of people about polio vaccine, insecurity within the country and poor health system are the reasons of failure of polio eradication campaigns in these regions. Awareness campaigns about polio for locals and development of proper health system will help in the eradication of polio. Once polio is eradicated, about 40-50 billion dollars can be saved globally. With the strong commitment, seriousness and good initiatives, polio will be eradicated from Pakistan within two years more likely.


Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations.
DNA-associated proteins (DAPs) classically regulate gene expression by binding to regulatory loci such as enhancers or promoters. As expanding catalogs of genome-wide DAP binding maps reveal thousands of loci that, unlike the majority of conventional enhancers and promoters, associate with dozens of different DAPs with apparently little regard for motif preference, an understanding of DAP association and coordination at such regulatory loci is essential to deciphering how these regions contribute to normal development and disease. In this study, we aggregated publicly available ChIP-seq data from 469 human DAPs assayed in three cell lines and integrated these data with an orthogonal data set of 352 nonredundant, in vitro-derived motifs mapped to the genome within DNase I hypersensitivity footprints to characterize regions with high numbers of DAP associations. We establish a generalizable definition for high occupancy target (HOT) loci and identify putative driver DAP motifs in HepG2 cells, including HNF4A, SP1, SP5, and ETV4, that are highly prevalent and show sequence conservation at HOT loci. The number of different DAPs associated with an element is positively associated with evidence of regulatory activity, and by systematically mutating 245 HOT loci with a massively parallel mutagenesis assay, we localized regulatory activity to a central core region that depends on the motif sequences of our previously nominated driver DAPs. In sum, this work leverages the increasingly large number of DAP motif and ChIP-seq data publicly available to explore how DAP associations contribute to genome-wide transcriptional regulation.


Diffraction of acoustic-gravity waves in the presence of a turning point.
Acoustic-gravity waves (AGWs) in an inhomogeneous atmosphere often have caustics, where the ray theory predicts unphysical, divergent values of the wave amplitude and needs to be modified. Unlike acoustic waves and gravity waves in incompressible fluids, AGW fields in the vicinity of a caustic have never been systematically studied. Here, asymptotic expansions of acoustic gravity waves are derived in the presence of a turning point in a horizontally stratified, moving fluid such as the atmosphere. Sound speed and the background flow (wind) velocity are assumed to vary gradually with height, and slowness of these variations determines the large parameter of the problem. It is found that uniform asymptotic expansions of the wave field in the presence of a turning point can be expressed in terms of the Airy function and its derivative. The geometrical, or Berry, phase, which arises in the consistent Wentzel-Kramers-Brillouin approximation for AGWs, plays an important role in the caustic asymptotics. In the dominant term of the uniform asymptotic solution, the terms with the Airy function and its derivative are weighted by the cosine and sine of the Berry phase, respectively. The physical meaning and corollaries of the asymptotic solutions are discussed.


Do multiple sclerosis symptoms moderate the relationship between self-efficacy and physical activity in people with multiple sclerosis?
To investigate the bivariate correlations between objective physical activity (PA), self-efficacy, and a range of multiple sclerosis (MS) symptom measures. Also, to determine whether any MS symptom measures moderate the relationship between self-efficacy and PA. Baseline analysis from a randomized control trial exercise plus a behavior change intervention was used. Fifty-nine physically inactive people with a definite diagnosis of MS were included. Participants were asked to record 7-day objective PA with the SenseWear Armband. Additionally, measures of self-efficacy (Exercise Self-Efficacy Scale), walking endurance (6-min walk test), impact of walking (12-Item MS Walking Scale [MSWS-12]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Modified Fatigue Impact Scale) were assessed before intervention. Pearson's correlations and moderation analysis were conducted. Self-efficacy was positively associated with PA (r = .30, p < .05). HADS-Depression (r = -.25, p < .05) and MSWS-12 (r = -.31, p < .01) demonstrated statistically significant negative correlations with self-efficacy but not with PA. Moderation analysis illustrated a significant interaction between anxiety and self-efficacy (r = .39, p < .03) with an R2 value of .15. The interaction was significant at lower values of anxiety, suggesting that the relationship between self-efficacy and PA is stronger when levels of anxiety are lower. This article confirms the potential role of MS symptoms, in particular anxiety, in explaining PA behavior in an inactive sample of persons with multiple sclerosis (pwMS). Further exploration is warranted, and future PA interventions should acknowledge the potential interplay of psychosocial constructs such as self-efficacy and anxiety in changing PA behavior among pwMS. (PsycINFO Database Record


Procalcitonin in acute malaria.
Procalcitonin, the precursor of calcitonin, is elevated in patients with sepsis and infection (base-line values <0.1 ng/ml). We determined PCT in 38 hospitalised patients with suspected malaria. All of them had signs of infection and had recently returned from Africa. Plasmodium vivax was proven in 15, Plasmodium falciparum in one and an infection with both species was found in another case (n = 17). PCT was determined on admission and the days thereafter. In one patient PCT was determined every 4 hours on the first day. The maxima of the PCT concentration on day 0 and 1 were 5.3 ng/ml with proven Malaria and 0.43 ng/ml without. At the following days we found a decrease to normal values (<0.5 ng/ml) which correlated with the general condition of the patient. At a cut-off point of 2 ng/ml we found a sensitivity of 52%, positive predictive value of 74%, specificity of 86%, negative predictive value of 71%. procalcitonin, malaria


[Giant diverticulum of the transverse colon].
A complication of colonic diverticulosis, giant diverticula are seen above all in the sigmoid region. On the basis of a case involving the transverse colon, the authors stress the clinical and ultrasonographic pseudo-tumoural symptomatology as well as the degree of superinfection of the contents. Anatomical arguments would be in favour of pathogenesis by progressive increase in size of an ordinary diverticulum rather than by perforation with secondary encystment. Excision of the diverticulum required segmental colectomy.


Effects of dietary lipid sources on performance and apparent total tract digestibility of lipids and energy when fed to nursery pigs.
Acidulated fats and oils are by-products of the fat-refining industry. They contain high levels of FFA and are 10% to 20% less expensive than refined fats and oils. Two studies were designed to measure the effects of dietary lipid sources low or high in FFA on growth performance and apparent total tract digestibility (ATTD) of lipids and GE in nursery pigs. In Exp. 1, 189 pigs at 14 d postweaning (BW of 9.32 ± 0.11 kg) were used for 21 d with 9 replicate pens per treatment and 3 pigs per pen. Dietary treatments consisted of a control diet without added lipids and 6 diets with 6% inclusion of lipids. Four lipid sources were combined to create the dietary treatments with 2 levels of FFA (0.40% or 54.0%) and 3 degrees of fat saturation (iodine value [IV] = 77, 100, or 123) in a 2 × 3 factorial arrangement. Lipid sources were soybean oil (0.3% FFA and IV = 129.4), soybean-cottonseed acid oil blend (70.5% FFA and IV = 112.9), choice white grease (0.6% FFA and IV = 74.8), and choice white acid grease (56.0% FFA and IV = 79.0). Addition of lipid sources decreased ADFI (810 vs. 872 g/d; P = 0.018) and improved G:F (716 vs. 646 g/kg; P < 0.001). Diets high in FFA tended (P = 0.08) to improve final BW (21.35 vs. 21.01 kg) and ADG (576 vs. 560 g/d). Lipid-supplemented diets had greater ATTD of lipids than control diets (67.4% vs. 29.7%; P < 0.001). Apparent total tract digestibility of lipids was greater in diets with low FFA (69.9% vs. 64.9%; P < 0.001) and decreased linearly with increasing IV (73.2%, 69.1%, and 67.2%). For GE, ATTD was greater in diets with low FFA (83.1% vs. 80.9%; P = 0.001). In Exp. 2, 252 pigs at 7 d postweaning (BW of 7.0 ± 0.2 kg) were used for 28 d with 9 replicate pens per treatment and 4 pigs per pen. Diets included a control diet without added lipids and 6 treatments with 2.5%, 5.0%, or 7.5% of lipids from either poultry fat (1.9% FFA) or acidulated poultry fat (37.8% FFA) in a 2 × 3 factorial arrangement. Addition of lipids increased (P < 0.001) final BW (19.9 vs. 18.4 kg) and ADG (460 vs. 405 g/d) regardless of source. Fat increased (P < 0.001) ADFI when added at 2.5% and then decreased ADFI with each further increment (663, 740, 681, and 653 g for 0%, 2.5%, 5.0%, and 7.5% fat, respectively). Inclusion of lipids linearly (P < 0.001) improved G:F (615, 615, 688, and 692 g/kg for 0%, 2.5%, 5.0%, and 7.5% fat, respectively) and ATTD of lipids (17.8%, 50.2%, 71.0%, and 77.3% for 0, 2.5, 5.0, and 7.5% fat, respectively) and GE (76.1%, 76.4%, 83.3%, and 84.4% for 0%, 2.5%, 5.0%, and 7.5% fat, respectively). Acidulated lipids resulted in similar performance compared with refined lipids and could be economical alternatives to more expensive lipid sources.


A design and application of a multi-agent system for simulation of multi-actor spatial planning.
Multi-agent Systems (MAS) offer a conceptual approach to include multi-actor decision making into models of land use change. The main goal is to explore the use of MAS to simulate spatial scenarios based on modelling multi-actor decision-making within a spatial planning process. We demonstrate MAS that consists of agents representing organizations and interest groups involved in an urban allocation problem during a land use planning process. The multi-actor based decision-making is modelled by generating beliefs and preferences of actors about the location of and relation between spatial objects. This allows each agent to confront these beliefs and preferences with it's own desires and with that of other agents. The MAS loosely resembles belief, desire and intentions architecture. Based on a case study for a hypothetical land use planning situation in a study area in the Netherlands we discuss the potential and limitations of the MAS to build models that enable spatial planners to include the 'actor factor' in their analysis and design of spatial scenarios. In addition, our experiments revealed the need for further research on the representation of spatial objects and reasoning, learning and communication about allocation problems using MAS.


Effect of mineral salts, carbachol, and pilocarpine on nutrient digestibility and ruminal characteristics in cattle.
Fifty percent concentrate diets containing 2% sodium bicarbonate, sodium chloride, or no additional mineral salts were fed at a rate of 86 g dry matter/kg body weight X 75/d to three barren Holstein cows fitted with ruminal fistulas in a 3 X 3 Latin square design. Dietary adaptation was 14 d followed by 4 d collection. Ruminal pH, liquid volume, liquid dilution rate, and particulate rate of passage were increased with dietary mineral salts. Six Holstein cows fitted with ruminal fistulas were administered .01 mg carbachol/kg body weight/d, .10 mg pilocarpine/kg body weight/d, or saline placebo via subcutaneous, osmotically controlled pumps in a replicated 3 X 3 Latin square design. Treatments were administered for a 14-d adaptation period followed by an 8-d collection period. Both carbachol and pilocarpine increased liquid dilution rate, particulate rate of passage, and percent cellulolytic bacteria, whereas liquid volume was reduced.


Mettl14-Mediated m6A Modification Is Essential for Germinal Center B Cell Response.
The germinal center (GC) response is essential for generating memory B and long-lived Ab-secreting plasma cells during the T cell-dependent immune response. In the GC, signals via the BCR and CD40 collaboratively promote the proliferation and positive selection of GC B cells expressing BCRs with high affinities for specific Ags. Although a complex gene transcriptional regulatory network is known to control the GC response, it remains elusive how the positive selection of GC B cells is modulated posttranscriptionally. In this study, we show that methyltransferase like 14 (Mettl14)-mediated methylation of adenosines at the position N 6 of mRNA (N 6-methyladenosine [m6A]) is essential for the GC B cell response in mice. Ablation of Mettl14 in B cells leads to compromised GC B cell proliferation and a defective Ab response. Interestingly, we unravel that Mettl14-mediated m6A regulates the expression of genes critical for positive selection and cell cycle regulation of GC B cells in a Ythdf2-dependent but Myc-independent manner. Furthermore, our study reveals that Mettl14-mediated m6A modification promotes mRNA decay of negative immune regulators, such as Lax1 and Tipe2, to upregulate genes requisite for GC B cell positive selection and proliferation. Thus, our findings suggest that Mettl14-mediated m6A modification plays an essential role in the GC B cell response.


NLRC5/CITA: A Key Player in Cancer Immune Surveillance.
Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5 [nucleotide-binding domain and leucine-rich repeats containing (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5], is a key transcription coactivator of MHC class I genes. Recent genetic studies have revealed that NLRC5 is a major target for cancer immune evasion mechanisms. The reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is associated with defective MHC class I expression, impaired cytotoxic T cell activation, and poor patient prognosis. Here, we review the role of NLRC5 in cancer immune evasion and the future prospects for cancer research.


[Nobel Prize of Medicine 1997 awarded for prion theory].
The Nobel Prize 1997 for Medicine and Physiology was awarded to S.B. Prusiner, who proposed the prion hypothesis. Prions are small 'proteinaceous infectious particles' that lack nucleic acids and hence genetic information. Prions are normal host encoded proteins but with an abnormal tertiary structure, which makes them extremely resistant to chemical and physical inactivation that would modify nucleic acids. They 'replicate' by forcing their conformation upon the normal prion proteins. Recently it was demonstrated that the prion disease, bovine spongiform encephalopathy (BSE) can be transmitted to man in whom it causes a new variant of Creutzfeldt-Jakob disease.


Precise frequency transfer through a fiber network by use of 1.5-microm mode-locked sources.
We report the precise transfer of radio-frequency signals by use of the pulse repetition frequency of mode-locked laser sources at 1.5 microm transmitting through a fiber network. The passive transfer instability through a 6.9-km fiber is below 3 x 10(-14) at 1 s, which is comparable with the optical carrier-frequency transfer of a narrow-linewidth cw laser. The instability of the measurement system is below 7 x 10(-15) at 1 s. It is noted that the pulsed mode of operation offers almost an order-of-magnitude improvement in stability at 1 s over that with a sinusoidal amplitude modulation on an optical carrier.


Interaction of yeast Rab geranylgeranyl transferase with its protein and lipid substrates.
Small GTPases from the Rab/Ypt family regulate events of vesicular traffic in eukaryotic cells. For their activity, Rab proteins require a posttranslational modification that is conferred by Rab geranylgeranyltransferase (RabGGTase), which attaches geranylgeranyl moieties onto two cysteines of their C terminus. RabGGTase is present in both lower and higher eukaryotes in the form of heterodimers composed of alpha and beta subunits. However, the alpha subunits of RabGGTases from lower eukaryotes, including Saccharomyces cerevisiae (yRabGGTase), are half the size of the corresponding subunit of the mammalian enzyme. This difference is due to the presence of additional immunoglobulin (Ig)-like and leucine rich (LRR) domains in the mammalian transferase. To understand the possible evolutionary implications and functional consequences of structural differences between RabGGTases of higher and lower eukaryotes, we have investigated the interactions of yeast RabGGTase with its lipid and protein substrate. We have demonstrated that geranylgeranyl pyrophosphate binds to the enzyme with an affinity of ca. 40 nM, while binding of farnesyl pyrophosphate is much weaker, with a K(d) value of ca. 750 nM. This finding suggests that despite the structural difference, yRabGGTase selects its lipid substrate in a fashion similar to mammalian RabGGTase. However, unlike the mammalian enzyme, yRabGGTase binds prenylated and unprenylated Ypt1p:Mrs6p complexes with similar affinities (K(d) ca. 200 nM). Moreover, in contrast to the mammalian enzyme, phosphoisoprenoids do not influence the affinity of Mrs6p for yRabGGTase. Using an in vitro prenylation assay, we have demonstrated that yRabGGTase can prenylate Rab proteins in complex with mammalian REP-1, thus indicating that neither the LRR nor the Ig-like domains, nor the recently discovered alternative pathway of catalytic complex assembly, are essential for the catalytic activity of RabGGTase. Despite the ability to function in concert with yRabGGTase in vitro, expression of mammalian REP-1 could not complement deletion of MRS6 gene in S. cerevisiae in vivo. The implications of these findings are discussed.


Effects of Selenium Supplement on B Lymphocyte Activity in Experimental Autoimmune Thyroiditis Rats.
45 healthy and adult female SD rats were randomly divided into three groups: normal control group, EAT model group, and selenium yeast supplement EAT group. The EAT model rats were induced by subcutaneous injection of porcine thyroglobulin and fed with high iodine water. The concentrations of serum thyroid-stimulating hormone (TSH), TGAb, TPOAb, and B cell activating factor (BAFF) were detected in each group by enzyme-linked immunosorbent assay (ELISA), and the expression of interleukin-10 (IL-10) in thyroid tissue was detected by immunohistochemistry. B cells and regulatory B cells (Bregs) ratios in the spleen of rats were analyzed by flow cytometry. In contrast with the EAT model group, the levels of serum TSH, TGAB, TPOAb, and BAFF were decreased, while IL-10 expression was increased in thyroid tissue, and Bregs ratio was upregulated in the spleen (all p < 0.05) in the selenium yeast supplement EAT group. Selenium yeast supplement could partially attenuate immune imbalance in EAT rats, which may be related to the mechanism of modulating B lymphocyte activity.


QSP Designer: Quantitative systems pharmacology modeling with modular biological process map notation and multiple language code generation.
Typical Quantitative Systems Pharmacology (QSP) workflows involve discussion of biology, supported by graphical diagrams, followed by construction of large Ordinary Differential Equation models. QSP Designer facilitates this process by providing enhanced graphical notation, which enables hierarchical presentation with modules and handling of combinatorial complexity with diagram node arrays. Whereas the software includes a simulation engine, a major feature is full model code generation in MATLAB, R, C, and Julia to support multiple modeling communities.


Native-valve infective endocarditis caused by Enterobacteriaceae: report on 9 cases and literature review.
Although the demographic characteristics of patients who develop infective endocarditis (IE) have changed over the last few decades, Enterobacteriaceae remain rarely responsible. We report the clinical and epidemiological characteristics of 9 patients with native-valve Enterobacteriaceae IE from 6 French medical intensive care units over a 10-y period and have identified 29 additional cases in the literature. Nearly a third of the 38 patients were immunocompromised and/or had previously known valvular heart disease. Salmonella spp. and Yersinia spp. were the most frequently isolated microorganisms reported in the literature. The overall mortality rate was 24% (9/38) and was lower for operated patients (10% (1/10)) compared to those who did not undergo valve surgery (31% (8/26)). Our results confirmed the rarity of native-valve endocarditis caused by Enterobacteriaceae, pathogens frequently responsible for nosocomial and community-acquired bacteraemias. This paradox may be explained by susceptibility to the bactericidal action of serum and the inability of these bacteria to colonize the endocardium.


Nonoperative treatment of the medial malleolus in bimalleolar and trimalleolar ankle fractures: a randomized controlled trial.
To compare internal fixation with no fixation of the medial malleolus after open reduction and internal fixation of the lateral malleolus and if needed, the posterior malleolus. Randomized prospective trial. Level III trauma center in a metropolitan area. One hundred patients with bimalleolar or trimalleolar Orthopaedic Trauma Association type 44 ankle fractures and displacement of the medial malleolus less than 2 mm after open reduction and internal fixation of the lateral component. Internal fixation or nonoperative treatment of the medial malleolus. American Orthopaedic Foot and Ankle Society ankle hind foot score (AOFAS), The Olerud Molander Ankle (OMA) score, and visual analogue pain scale (VAS). Median follow-up time was 39 months (range: 24-72). There were no significant differences between the 2 groups with respect to OMA (P = 0.91), AOFAS (P = 0.85), VAS (P = 0.85), or development of osteoarthritis (P = 0.22). Reoperation and complication rates were also comparable, but 4 patients treated nonoperatively developed nonunion of the medial malleolus. These patients reported no functional disabilities and presented OMA, AOFAS, and VAS scores better than average. Our data indicate that nonoperative treatment of minimally displaced fractures of the medial malleolus after operative fixation of the fibula yields satisfactory results. However, long-term follow-up is needed due to increased risk of nonunion and uncertainty regarding the development of posttraumatic arthritis. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Dynamics of maternal morphogen gradients in Drosophila.
The first direct studies of morphogen gradients were done in the end of 1980s, in the early Drosophila embryo, which is patterned under the action of four maternally determined morphogens. Since the early studies of maternal morphogens were done with fixed embryos, they were viewed as relatively static signals. Several recent studies analyze dynamics of the anterior, dorsoventral, and terminal patterning signals. The results of these quantitative studies provide critical tests of classical models and reveal new modes of morphogen regulation and readout in one of the most extensively studied patterning systems.


Role of exercise intensity on GLUT4 content, aerobic fitness and fasting plasma glucose in type 2 diabetic mice.
Type 2 diabetes mellitus (T2D) results in several metabolic and cardiovascular dysfunctions, clinically characterized by hyperglycaemia due to lower glucose uptake and oxidation. Physical exercise is an effective intervention for glycaemic control. However, the effects of exercising at different intensities have not yet been addressed. The present study analysed the effects of 8 weeks of training performed at different exercise intensities on type 4 glucose transporters (GLUT4) content and glycaemic control of T2D (ob/ob) and non-diabetic mice (ob/OB). The animals were divided into six groups, with four groups being subjected either to low-intensity (ob/obL and ob/OBL: 3% body weight, three times/week/40 min) or high-intensity (ob/obH and ob/OBH: 6% body weight, three times per week per 20 min) swimming training. An incremental swimming test was performed to measure aerobic fitness. After the training intervention period, glycaemia and the content of GLUT4 were quantified. Although both training intensities were beneficial, the high-intensity regimen induced a more significant improvement in GLUT4 levels and glycaemic profile compared with sedentary controls (p < 0.05). Only animals in the high-intensity exercise group improved aerobic fitness. Thus, our study shows that high-intensity training was more effective for increasing GLUT4 content and glycaemia reduction in insulin-resistant mice, perhaps because of a higher metabolic demand imposed by this form of exercise.


Human head and neck squamous cell carcinoma cell lines are differentially radiosensitised by the honeybee product Propolis.
Propolis, a product of honeybees, has anti-tumoural, cytotoxic, anti-metastatic and anti-inflammatory properties. The aim of this study was the evaluation of the radiosensitising capacity of Propolis in human head and neck squamous cell carcinoma (HNSCC) cells. HNSCC cell lines (FaDu, UT-SCC15, UT-SCC45), fibroblasts (HSF2) and keratinocytes (HaCaT) were treated with Propolis (0-250 g/ml; 1, 4, 24 h) without and in combination with X-rays (0-6 Gy, single dose). Clonogenic survival, proliferation, apoptosis, expression and phosphorylation of different signalling proteins were determined. Liquid chromatography-mass spectrometry (LC-MS) was performed on Propolis. Propolis significantly (P < 0.01) reduced cell growth and clonogenic survival in a time- and concentration-dependent manner. Propolis-induced apoptosis and Caspase 3 cleavage, increased phosphorylation of Extracellular signal Regulated Kinase 1/2 (ERK1/2), protein kinase B/Akt1 (Akt1) and Focal adhesion kinase (FAK). While a 1-h Propolis pretreatment was ineffective, a 3-h pretreatment significantly (P < 0.05) radiosensitised FaDu cells. LC-MS analysis identified 14 compounds of Propolis. Our data show that Propolis exerts cytotoxicity in a concentration- and time-dependent manner. In one out of three HNSCC cell lines, Propolis also caused an enhancement of radiosensitivity. Future studies on Propolis will shed further light on its potential as an adjuvant to radiotherapy.


Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.
Gram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients. To compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days). Hospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up. Sixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84% vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively: S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88% vs. 100%; P = 0.379); and enterococci (71% vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12% vs. 32%; P = 0.058). Linezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.


HED-TIE: A wafer-scale approach for fabricating hybrid electronic devices with trench isolated electrodes.
Organic-inorganic hybrid electronic devices (HEDs) offer opportunities for functionalities that are not easily obtainable with either organic or inorganic materials individually. In the strive for down-scaling the channel length in planar geometry HEDs, the best results were achieved with electron beam lithography or nanoimprint lithography. Their application on the wafer level is, however, cost intensive and time consuming. Here, we propose trench isolated electrode (TIE) technology as a fast, cost effective, wafer-level approach for the fabrication of planar HEDs with electrode gaps in the range of 100 nm. We demonstrate that the formation of the organic channel can be realized by deposition from solution as well as by the thermal evaporation of organic molecules. To underline one key feature of planar HED-TIEs, namely full accessibility of the active area of the devices by external stimuli such as light, 6,13-bis (triisopropylsilylethynyl) (TIPS)-pentacene/Au HED-TIEs are successfully tested for possible application as hybrid photodetectors in the visible spectral range.


The regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the isolated perfused rat liver.
The effect of perfusion of an isolated rat liver on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase was studied. In liver removed during the basal period of the diurnal cycle of enzyme activity, a 227 +/- 41% increase in enzyme activity occurred after 3 h of a plasma-free perfusion. This could be prevented by the addition of cycloheximide or pure cholesterol (dispersed with lecithin) to the perfusate. In contrast, the continuous addition of taurocholate or taurochenodeoxycholate, alone or in combination, at a variety of rates did not prevent the increase in enzyme activity. The added bile salts were efficiently extracted from the perfusate and excreted in the bile. The addition of these bile salts to a cholesterol-enriched perfusate did not alter the effect obtained with cholesterol alone. If the perfusate contained whole serum, the increase induced by perfusion in the basal period was smaller (88 +/- 27%) than with plasma-free perfusate. Again, the major bile salts of the rat failed to prevent the increase in enzyme activity induced by liver perfusion. If livers were removed and perfused at the height of the diurnal cycle of enzyme activity, the enzyme activity remained high (2 +/- 10% increase) rather than decreasing, as occurs in vivo. If cholesterol was added to these perfusions, a 52 +/- 4% decrease was induced. Bile salt addition induced no decrease. From the results it is concluded that the major bile salts are not direct regulators of hepatic cholesterol synthesis, but pure cholesterol, in the absence of bile salt or lipoprotein, is able to initiate the mechanism that represses hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase.


Heart rate variability during exertional heat stress: effects of heat production and treatment.
We assessed the efficacy of different treatments (i.e., treatment with ice water immersion vs. natural recovery) and the effect of exercise intensities (i.e., low vs. high) for restoring heart rate variability (HRV) indices during recovery from exertional heat stress (EHS). Nine healthy adults (26 ± 3 years, 174.2 ± 3.8 cm, 74.6 ± 4.3 kg, 17.9 ± 2.8 % body fat, 57 ± 2 mL·kg·(-1) min(-1) peak oxygen uptake) completed four EHS sessions incorporating either walking (4.0-4.5 km·h(-1), 2 % incline) or jogging (~7.0 km·h(-1), 2 % incline) on a treadmill in a hot-dry environment (40 °C, 20-30 % relative humidity) while wearing a non-permeable rain poncho for a slow or fast rate of rectal temperature (T re) increase, respectively. Upon reaching a T re of 39.5 °C, participants recovered until T re returned to 38 °C either passively or with whole-body immersion in 2 °C water. A comprehensive panel of 93 HRV measures were computed from the time, frequency, time-frequency, scale-invariant, entropy and non-linear domains. Exertional heat stress significantly affected 60/93 HRV measures analysed. Analyses during recovery demonstrated that there were no significant differences between HRV measures that had been influenced by EHS at the end of passive recovery vs. whole-body cooling treatment (p > 0.05). Nevertheless, the cooling treatment required statistically significantly less time to reduce T re (p < 0.001). While EHS has a marked effect on autonomic nervous system modulation and whole-body immersion in 2 °C water results in faster cooling, there were no observed differences in restoration of autonomic heart rate modulation as measured by HRV indices with whole-body cold-water immersion compared to passive recovery in thermoneutral conditions.


Peer-Assisted Learning in Education of Allied Health Professional Students in the Clinical Setting: A Systematic Review.
Pressure on clinical educators to provide best practice education to growing student numbers is driving innovations in clinical education. Placing multiple students with a single clinical educator may increase capacity; however, little is known about the role and impact of peer-assisted learning (PAL) in these models. A systematic review of the literature from 1985 to 2014 was done to investigate the effectiveness of PAL amongst allied health professional students in clinical settings. Secondary aims were to investigate how PAL is defined and measured in this practice setting. Twenty-eight articles representing five allied health professions met the inclusion criteria. The risk of bias in the articles was generally high, limiting confidence in findings. Nine studies measured the effects of PAL on students, with inconsistent results across domains of satisfaction, perceived learning, and performance outcomes. Only four studies described how PAL was facilitated. Evidence supporting PAL is non-specific and lacks comparative rigour. More robust research is needed to quantify the potential benefits of PAL.


Successful management of warfarin-exacerbated diffuse alveolar hemorrhage using an extracorporeal membrane oxygenation.
Although diffuse alveolar hemorrhage complicating warfarin therapy is rare, it generally has a worsening clinical course and can be a life threatening condition. A 56-year-old male who had undergone a pulmonary lobectomy for lung cancer 2 years before had received warfarin for about 5 months due to pulmonary vein thrombosis. The patient presented with severe dyspnea and had prolonged anticoagulation values. Chest X-ray and computed tomography revealed diffuse pulmonary consolidations, and bronchoalveolar lavage demonstrated diffuse alveolar hemorrhage. The reversal of anticoagulation was initiated, and extracorporeal membrane oxygenation was performed for refractory respiratory failure that did not improve despite maximal mechanical ventilatory support. The diffuse alveolar infiltrations resolved after 5 days, and we successfully weaned off both extracorporeal membrane oxygenation and mechanical ventilation. Herein we report the detailed course of a case that was successfully treated with extracorporeal membrane oxygenation as a bridge-to-recovery for warfarin- exacerbated diffuse alveolar hemorrhage.


Functional and topological studies with Trp-containing analogs of the peptide StII(1-30) derived from the N-terminus of the pore forming toxin sticholysin II: contribution to understand its orientation in membrane.
Sticholysin II (St II) is the most potent cytolysin produced by the sea anemone Stichodactyla helianthus, exerting hemolytic activity via pore formation in membranes. The toxin's N-terminus contains an amphipathic α-helix that is very likely involved in pore formation. We have previously demonstrated that the synthetic peptide StII(1-30) encompassing the 1-30 segment of St II forms pores of similar radius to that of the protein (around 1 nm), being a good model of toxin functionality. Here we have studied the functional and conformational properties of fluorescent analogs of StII(1-30) in lipid membranes. The analogs were obtained by replacing Leu residues at positions 2, 12, 17, and 24 with the intrinsically fluorescent amino acid Trp (StII(1-30L2W), StII(1-30L12W), StII(1-30L17W), or StII(1-30L24W), respectively). The exchange by Trp did not significantly modify the activity and conformation of the parent peptide. The blue-shift and intensity enhancement of fluorescence in the presence of membrane indicated that Trp at position 2 is more deeply buried in the hydrophobic region of the bilayer. These experiments, as well as assays with water-soluble or spin-labeled lipid-soluble fluorescence quenchers suggest an orientation of StII(1-30) with its N-terminus oriented towards the hydrophobic core of the bilayer while the rest of the peptide is more exposed to the aqueous environment, as hypothesized for sticholysins.