Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on GxE interactions and pathogenic pathways.
Preterm delivery (PTD, <37 weeks of gestation) is a significant clinical and public health problem. Previously, we reported that maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 synergistically increase the risk of low birth weight. This study investigates the relationship between maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 with preterm delivery (PTD) as a whole and preterm subgroups. This case-control study included 1,749 multi-ethnic mothers (571 with PTD and 1,178 controls) enrolled at Boston Medical Center. After adjusting covariates, regression analyses were performed to identify individual and joint associations of maternal smoking, two functional variants of CYP1A1 and GSTT1 with PTD. We observed a moderate effect of maternal smoking on PTD (OR = 1.6; 95% CI: 1.1-2.2). We found that compared to non-smoking mothers with low-risk genotypes, there was a significant joint association of maternal smoking, CYP1A1 (Aa/aa) and GSTT1 (absent) genotypes with gestational age (beta = -3.37; SE = 0.86; P = 9 x 10(-5)) and with PTD (OR = 5.8; 95% CI: 2.0-21.1), respectively. Such joint association was particularly strong in certain preterm subgroups, including spontaneous PTD (OR = 8.3; 95% CI: 2.7-30.6), PTD < 32 weeks (OR = 11.1; 95% CI: 2.9-47.7), and PTD accompanied by histologic chorioamnionitis (OR = 15.6; 95% CI: 4.1-76.7). Similar patterns were observed across ethnic groups. Taken together, maternal smoking significantly increased the risk of PTD among women with high-risk CYP1A1 and GSTT1 genotypes. Such joint associations were strongest among PTD accompanied by histologic chorioamnionitis.


Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy.
The presence of lymph node metastasis (LNM) at radical prostatectomy (RP) is associated with poor outcome, and optimal treatment remains undefined. An understanding of the natural history of node-positive prostate cancer (PCa) and identifying prognostic factors is needed. To assess outcomes for patients with LNM treated with RP and lymph node dissection (LND) alone. We analyzed data from a consecutive cohort of 369 men with LNM treated at a single institution from 1988 to 2010. RP and extended LND. Our primary aim was to model overall survival, PCa-specific survival, metastasis-free progression, and freedom from biochemical recurrence (BCR). We used univariate Cox proportional hazard regression models for survival outcomes. Multivariable Cox proportional hazard regression models were used for freedom from metastasis and freedom from BCR, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesical invasion, surgical margin status, and number of positive nodes as predictors. Sixty-four patients with LNM died, 37 from disease. Seventy patients developed metastasis, and 201 experienced BCR. The predicted 10-yr overall survival and cancer-specific survival were 60% (95% confidence interval [CI], 49-69) and 72% (95% CI, 61-80), respectively. The 10-yr probability of freedom from distant metastasis and freedom from BCR were 65% (95% CI, 56-73) and 28% (95% CI, 21-36), respectively. Higher pathologic Gleason score (>7 compared with ≤ 7; hazard ratio [HR]: 2.23; 95% CI, 1.64-3.04; p < 0.0001) and three or more positive lymph nodes (HR: 2.61; 95% CI, 1.81-3.76; p < 0.0001) were significantly associated with increased risk of BCR on multivariable analysis. The retrospective nature and single-center source of data are study limitations. A considerable subset of men with LNM remained free of disease 10 yr after RP and extended LND alone. Patients with pathologic Gleason score <8 and low nodal metastatic burden represent a favorable group. Our data confirm prior findings and support a plea for risk subclassification for patients with LNM.


Metabolism and toxicological detection of the new designer drug 4'-methoxy-alpha-pyrrolidinopropiophenone studied in rat urine using gas chromatography-mass spectrometry.
R,S-4'-Methoxy-alpha-pyrrolidinopropiophenone (MOPPP) is a new designer drug with assumed amphetamine-like effects, which has appeared on the illicit drug market. The aim of this study was to identify the MOPPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and GC-MS. Analysis of urine samples of rats treated with MOPPP revealed that MOPPP [limit of detection (S/N 3) was 100 ng/ml] was completely metabolized by demethylation of the methoxy group, hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam and/or oxidative desamination to the corresponding diketo compounds. To some extent, the demethylated MOPPP metabolites were hydroxylated with partial subsequent methylation in position 3'. The hydroxy groups were found to be partly conjugated. Based on these data, MOPPP could be detected in urine via its metabolites by full-scan GC-MS using MS for screening and library search for identification by comparison of the spectra with reference spectra.


In silico prediction suggests inhibitory effect of halogenated boroxine on human catalase and carbonic anhydrase.
This research work included bioinformatics modeling of the dipotassium-trioxohydroxytetrafluorotriborate-halogenated boroxine molecule, as well as simulation and prediction of structural interactions between the halogenated boroxine molecule, human carbonic anhydrase, and human catalase structures. Using computational methods, we tried to confirm the inhibitory effect of halogenated boroxine on the active sites of these previously mentioned enzymes. The three-dimensional crystal structures of human catalase (PDB ID: 1DGB) and human carbonic anhydrase (PDB ID: 6FE2) were retrieved from RCSB Protein Data Bank and the protein preparation was performed using AutoDock Tools. ACD/ChemSketch and ChemDoodle were used for creating the three-dimensional structure of halogenated boroxine. Molecular docking was performed using AutoDock Vina, while the results were visualized using PyMOL. Results obtained in this research are showing evidence that there are interactions between the halogenated boroxine molecule and both previously mentioned proteins (human carbonic anhydrase and human catalase) in their active sites, which led us to the conclusion that the inhibitory function of halogenated boroxine has been confirmed. These findings could be an important step in determining the exact mechanisms of inhibitory activity and will hopefully serve in further research purposes of complex pharmacogenomics studies.


Pitfalls and problems in studies on the methylation of phosphatidylethanolamine.
Recent articles have confused the steady state concentration of radioactivity in N-methylphosphatidylethanolamine (PME) and N,N-dimethylphosphatidylethanolamine (PDE) with the amount of these products formed during the conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC). This paper clarifies this problem and reports the apparent Km values for AdoMet and pH optima for the conversion of PE to PME, PDE, and PC by rat liver microsomes. We purified AdoMet and [methyl-3H]AdoMet and measured the transfer of tritium to PME, PDE, and PC as a function of time. There was an initial lag in the formation of [3H]PC followed by linear incorporation of isotope. In contrast, labeled PME and PDE reached and maintained steady state levels within 1 to 2 min. Hence, calculations of the rate of formation of PME, PDE, and PC must take into account the subsequent conversion of PME and PDE to PC. The PE N-methyltransferase was assayed at pH 6.6, 9.2, and 10.25 and the apparent Km for AdoMet for the three methylation reactions was calculated. The formation of PME was best estimated by the dpm in PME + 1/2 dpm in PDE + 1/3 dpm in PC. The synthesis of PDE from PME was estimated from 1/2 dpm in PDE and 1/3 dpm in PC, and the formation of PC from PDE estimated by 1/3 dpm in PC. The apparent Km for AdoMet at pH 10.25 for the conversion of PE to PME was 58 microM, PME to PDE was 65 microM, and PDE to PC was 96 microM. The pH optimum for each of these methylation reactions was 10.25. This high value was not due to alkaline degradation of AdoMet or denaturation of the enzyme. The apparent Km for AdoMet was also estimated for the conversion of exogenous PME to PDE (50 microM) and exogenous PDE to PC (45 microM). Since recent studies on the methylation of PE have not taken into account the conversion of newly formed PME and PDE to PC, the results and conclusions about apparent Km values for AdoMet, pH optima, and the number of enzymes involved must be re-evaluated.


Bikeshare and subway ridership changes during the COVID-19 pandemic in New York City.
The COVID-19 pandemic has been unprecedented in its scale and speed, impacting the entire world, and having an impact on metropolitan transportation systems. New York City (NYC) was especially hard hit in March and April 2020. A mandatory stay-at-home order was instituted, with all but essential businesses ordered closed. In this paper we examine the impact on the Citi Bike system and the NYC subway. Usage patterns during the lockdown are compared to corresponding days in 2019. Controlling for weather patterns we examine the effect of the lockdown and subsequent reopening of economic activity up through the end of September 2020. The results show that both subway ridership and bikeshare usage plummeted initially; bikeshare usage has nearly returned to normal while subway ridership remains substantially below pre-COVID levels. Implications for policy suggest that the bikeshare system provides resilience to the overall transportation system during disasters when public transit is considered dangerous or is disrupted.


Magnetic coil stimulation of the human lumbosacral vertebral column: site of stimulation and clinical application.
We describe the technique of magnetic coil (MC) stimulation of the lumbosacral roots and the possible site of stimulation in 22 control subjects, and the clinical usefulness of MC stimulation in 5 patients with low back pain. We observed 2 components in the compound muscle action potential of the soleus muscle following MC stimulation over the lumbosacral region. The second component had the physiological properties of the H reflex. The conduction time from the anterior horn cells of the lumbosacral spinal cord to the site of nerve root stimulation over the lumbosacral vertebral column was indirectly calculated as between 3.9 and 4.1 msec. Assuming a conduction velocity of 50 m/sec this would represent a distance of approximately 20 cm from the spinal motor neurons. Based on our control and patient data we conclude that the MC stimulation may be an useful technique for the diagnosis of lumbosacral radiculoplexopathy.


Deep or partial caries removal: which is best?
Searches for studies were made using the databases: Medline, Evidence-based Medicine Reviews, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and OVID's Database of Abstracts of Reviews of Effects. Only studies reported in English with human participants were included. Randomised controlled trials (RCT) and relevant observational studies were included. No other inclusion or exclusion criteria are described. A formal data extraction process is not described and a qualitative description of the included studies is provided. Ten articles reporting six studies were included. The results of three RCT, one with a followup period of 10 years, provide evidence supporting the practice of leaving behind infected dentine, the removal of which would risk pulp exposure. A number of other studies show that cariogenic bacteria, once isolated from their source of nutrition by a restoration of sufficient integrity, either remain dormant or die and thus pose no risk to the health of the dentition. There is substantial evidence that, for caries management, it is not necessary to remove all vestiges of infected dentin from lesions approaching the pulp.


Brain isoenzyme of creatine kinase. II. Species specificity of enzyme and presence of inactive form in striated muscle of rabbit and man.
Antibodies specific for the brain isoenzymes (BB) of creatine kinase were prepared by the injection of the highly purified rabbit enzyme into roosters. The antibodies were found to cross-react only partially with BB of rat, guinea pig, sheep, monkey, and man, demonstrating that these proteins are not entirely identical with respect to their antigenic sites. A greater degree of species specificity seems to exist for BB than for the muscle isoenzyme (MM) suggesting that BB may have undergone considerable evolutionary modification. Developmentally mature rabbit cardiac and skeletal muscles contained large quantites of an enzymatically inactive BB which can be detected immunochemically. It is antigenically identical with active rabbit BB but the two proteins can be separated by DEAE-cellulose chromatography. Enzymatically inactive BB is also present in human skeletal muscle. The presence of MM in muscle provides sufficient catalytic function and may have permitted the evolution of inactive BB in an additional (noncatalytic) metabolic role.


Glucuronic acid metabolites of phenolic acids target AKT-PH domain to improve glucose metabolism.
Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism. It is not clear whether phenolic acids or their metabolites play a major role in vivo. In this study, caffeic acid (CA) and ferulic acid (FA), the two most ingested phenolic acids, and their glucuronic acid metabolites, caffeic-4'-O-glucuronide (CA4G) and ferulic-4'-O-glucuronide (FA4G), were investigated. Three insulin resistance models in vitro were established by using TNF-α, insulin and palmitic acid (PA) in HepG2 cells, respectively. We compared the effects of FA, FA4G, CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels. The potential targets and related pathways were predicted by network pharmacology. Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target. To investigate the binding mode, molecular docking was performed. Then, we performed membrane recruitment assays of the AKT pleckstrin homology (PH) domain with the help of the PH-GFP plasmid. AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds. Finally, the downstream signaling pathway of AKT was investigated by Western blot analysis. The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption. AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis. The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds. The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site. CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane, while increasing the activity of AKT. Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3β in the AKT signaling pathway to increase glucose consumption. In conclusion, our results suggested that the metabolites of phenolic acids, which contain glucuronic acid, are the key active substances and that they activate AKT by targeting the PH domain, thus improving glucose metabolism.


Targeting gene expression to cones with human cone opsin promoters in recombinant AAV.
Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long- and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.


Dissociation of intracellular Ca2+ release and Ca2+ entry response to 5-hydroxytryptamine in cultured canine tracheal smooth muscle cells.
The relationship between the agonist-sensitive Ca2+ pool and those discharged by the Ca2+ -ATPase inhibitor thapsigargin (TG) were investigated in canine tracheal smooth muscle cells (TSMCs). In fura-2-loaded TSMCs, 5-hydroxytryptamine (5-HT) stimulated a rapid increase in intracellular Ca2+ ([Ca2+]i), followed by a sustained plateau phase that was dependent on extracellular Ca2+. In such cells, TG produced a concentration-dependent increase in [Ca2+]i, which remained elevated over basal level for several minutes and was substantially attenuated in the absence of extracellular Ca2+. Application of 5-HT after TG demonstrated that the TG-sensitive compartment partly overlapped the 5-HT-sensitive stores. Pre-treatment of TSMCs with TG significantly inhibited the increase in [Ca2+]i induced by 5-HT in a time-dependent manner. Similar results were obtained with two other Ca2+ -ATPase inhibitors, cyclopiazonic acid and 2,5-di-t-butylhydroquinone. Although these inhibitors had no effect on phosphoinositide hydrolysis, Ca2+ -influx was stimulated by these agents. These results suggest that depletion of the agonist-sensitive Ca2+ stores is sufficient for activation of Ca2+ influx. Some characteristics of the Ca2+ -influx activated by depletion of internal Ca2+ stores were compared with those of the agonist-activated pathway. 5-HT-stimulated Ca2+ influx was inhibited by La3+, membrane depolarisation, and the novel Ca2+ -influx blocker 1-¿beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl¿-1H-imidazole hydrochloride (SKF96365). Likewise, activation of Ca2+ influx by TG also was blocked by La3+, membrane depolarisation, and SKF96365. These results suggest that (1) in the absence of PI hydrolysis, depletion of the agonist-sensitive internal Ca2+ stores in TSMCs is sufficient for activation of Ca2+ influx, and (2) the agonist-activated Ca2+ influx pathway and the influx pathway activated by depletion of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool are indistinguishable.


Ceriopsin E, a new epoxy ent-kaurene diterpenoid from Ceriops decandra.
A new epoxy ent-kaurene diterpenoid, ceriopsin E (1), has been isolated from the mangrove plant Ceriops decandra and its structure elucidated by spectral data and single-crystal X-ray analysis.


Population structure and seasonal intra-burrow movement of Ornithodoros turicata (Acari: Argasidae) in gopher tortoise burrows.
Burrows of the gopher tortoise, Gopherus polyphemus Daudin, were sampled for Ornithodoros turicata (Dugès) infestation using carbon dioxide baits and vacuum extraction. Ticks were captured, marked, released, and recaptured, and population estimates were made using the Lincoln index. Estimated population ranged from 47 to 1,338 ticks per burrow. The tick population consisted predominantly of nymphs, with a significant increase in the larval population during the months of June and July. Adult sex ratio was slightly male-biased, but numbers of adults collected were consistently low. Ticks exhibited a low interburrow movement, but depth preferences fluctuated with season; more ticks occurred in the upper strata of the burrows during the hot, humid months.


The adsorption of antifreeze glycoprotein fraction 8 on dry and wet mica.
The adsorption of AFGP 8 on mica was studied by atomic force microscopy. The results shown in this paper emphasize the strong adsorption affinity of these proteins to hydrophilic surfaces, in this case mica. The dependence of the surface morphology while drying a droplet of protein solution, and the tendency to form 3-D aggregates at high concentration was observed. The behavior indicates that single-molecule-high aggregates (8.1 Å) are formed at low concentration; as the concentration increases, a double layer seems to appear in equilibrium with large aggregates; and as the concentration is increased further, the equilibrium is shifted toward larger aggregates leaving behind residual single-molecule-high aggregates. The hydrophilicity of the protein was demonstrated by the spontaneous adsorption of the protein directly from solution, as monitored by in situ imaging.


The significance of creatine kinase (CKBB) in metastatic cancer of the prostate.
Alterations of serum creatine kinase isoenzymes were observed in five cases of prostatic carcinoma. Creatine kinase isoenzyme BB was found in the serum of two of three cases with metastases. Its presence in serum does not seem to be related to acid phosphatase activity but seems associated with extension of the tumor to other tissues. Preliminary studies on effusions from patients with malignant and non-malignant prostates showed that CK-BB was detectable only in cytology positive effusions. This finding suggests that CK-BB may be a tumor product rather than a result of a host response. The observation of CK-BB in a significant percentage of patients (two of three) with metastatic carcinoma of the prostate is of interest and suggests that CK-BB isoenzymes may have some predictive value in following patients with malignant disease.


L-asparaginase of Tetrahymena pyriformis is associated with a kinase activity.
Most of L-asparaginase activity of Tetrahymena pyriformis was found to be present in microsomal membranes from which it has been purified to homogeneity (Tsirka, S.A.E. and Kyriakidis, D.A. Mol. Cell. Biochem. 83: 147-155, 1988). The native enzyme has a relative molecular weight of approximately 200 kDa, while under denaturing conditions the enzyme exhibits a subunit size of 39 kDa. Aminoacid analysis and an oligopeptide from N-terminal sequence have been determined. Dephosphorylation of L-asparaginase by alkaline phosphatase results in an activation of its catalytic activity. This enzyme also exhibits intrinsic phosphorylation activity with a Km value for ATP of 0.5 mM. Autophosphorylation with [gamma-32P] ATP of purified L-asparaginase results in the phosphorylation of tyrosine residues as well as in loss of its activity. Mg2+ and Ca2+ added together act synergistically to stimulate the kinase activity by more than 160%. The polyamines putrescine, spermidine and spermine activate the kinase approximately 100%, while neither cAMP or cGMP have any effect. These results indicate that this membrane protein with dual L-asparaginase/kinase activity must play an important role in regulating the intracellular levels of L-asparagine in Tetrahymena pyriformis.


Comparative Evaluation of Chest Tube Insertion Site Dressings: A Randomized Controlled Trial.
Little empirical evidence is available to guide decisions on what type of dressing to use and how often to change the dressing after placement of a thoracostomy tube. This prospective randomized controlled study was conducted to compare various dressing types and procedures after placement of thoracic and mediastinal chest tubes. Outcome measures included length of time between dressing changes, skin integrity, air leak presence, and patient-reported pain. The study involved a convenience sample of 127 patients with 236 chest tubes from 3 intensive care units at a midwestern regional medical center. The patients were randomized to 1 of 3 groups: (1) gauze and tape dressing changed once daily, (2) gauze and tape dressing changed every 3 days, and (3) silicone foam dressing changed every 3 days. Patients with silicone foam dressings reported less pain at the insertion site than did patients with standard gauze and tape dressings, and patients with daily dressing changes reported significantly more pain with dressing removal than did patients with dressing changes every 3 days. The silicone foam dressing was associated with better skin integrity than the gauze and tape dressing. Dressing intactness, number of days with a chest tube inserted, and patient demographic characteristics did not differ significantly among the 3 groups. Overall, the best type of dressing for promoting skin integrity and patient comfort was the silicone foam dressing. The results of this study may help identify best practices for dressing type and procedures among patients with chest tubes.


Numbers and ratios of X-chromosomal-linked opsin genes.
Quantitative Southern blotting and PCR/RFLP analysis were used to determine the number and ratio of long-wave-sensitive (L-) and mid-wave-sensitive (M-) opsin genes in 25 colour-normal caucasian males. The average observed ratio was 1:2.8 +/- 1.2 for Southern blot analysis and 1:3.0 +/- 1.7 for PCR/RFLP analysis. Thus, the two techniques yielded similar results for the ratio of L- to M-opsin genes (Wilcoxon t-test, P < 0.01). PCR/RFLP analysis of a Sma I polymorphism specific for the most proximal opsin gene suggested an average gene number of 6.0 +/- 2.1, with a range from 4 to 12 in individual subjects. In contrast, Southern blot analysis suggested an average number of 3.8 +/- 1.2, with a range from 2 to 7 (on the assumption that only one L-opsin gene is ever present). Differences between the L- to M-opsin gene ratio and the total gene number in some subjects may result from the presence of multiple L-opsin genes and/or hybrid opsin genes in colour-normal males. An exact determination of the total gene number will require employing other molecular techniques.


A stress-related transcription factor belonging to the YL-1 family is differently regulated in durum wheat cultivars differing in drought sensitivity.
The Mediterranean area is characterised by unfavorable environmental conditions such as heat stress and drought responsible for yield loss of crops like durum wheat, widely cultivated in this area. The response of plants to stressing environments is mediated by activation of a complex gene network, strictly related to the genetic background. Among the genes induced by drought, those coding for proteins acting as key regulators of signal transduction are of great interest. Characterization of these genes is a crucial point to understand their potential roles in plant stress response, also in view of their possible use in molecular breeding. In this work we have characterised a Triticum durum gene, named TdDRG1, in two commercial cultivars, Primadur and Svevo, differing for drought stress resistance. TdDRG1 codes for a putative transcription factor belonging to the VPS72/YL-1 family, highly conserved in plants and animals. The expression analysis indicates that this gene is expressed at higher level in roots of the resistant cultivar Svevo, than in the susceptible Primadur. The gene structure was determined in both cultivars and the regulatory activity of 5' upstream regions was analyzed by transient expression analysis using tobacco protoplasts. Dissimilar expression level of TdDRG1 in the two cultivars can be explained by the differences observed in gene structure. In particular, differences in 5' upstream regions could account for contrasting ability to cope with drought of the two cultivars. The data obtained in this study provide indications for further insight into the molecular basis of differences in drought stress response.


[Risk factors of ischemic heart disease, data of exercise tests, 24-hour ECG monitoring and coronary angiography in young women with history of myocardial infarction].
Most frequent risk factors in a group of 40 premenopausal women with history of myocardial infarction were smoking (70%) and hypertension (62.5%). Reaction to bicycle exercise tests was negative in 42% and ischemic (mainly pain combined with ST-segment changes) in 50% of these women. Ischemic ECG changes were found during both exercise test and 24-hour ECG monitoring in 30% and were not found at all in 40% of women. Angiography revealed coronary artery stenoses in 58% of women.


Concurrent multiple left atrial focal activations with fibrillatory conduction and right atrial focal or reentrant activation as the mechanism in atrial fibrillation.
We examined the atrial activation during atrial fibrillation to validate the rationale behind simplified surgical procedures. Intraoperative mapping of the entire atrial epicardium was performed in 21 patients with permanent atrial fibrillation and mitral valve disease using a 256-channel, 3-dimensional dynamic mapping system. Concurrent multiple repetitive activations arose from the posterior left atrium adjacent to the pulmonary veins or the left atrial appendage in all patients. The fastest activation propagated toward the right atrium conducting through Bachmann's bundle, leaving the other activations confined to a small atrial region. As the activation propagated toward the right atrium, there was a progressive conduction delay or block in the pathway. As a result, the activation in the right atrium desynchronized with the left atrial activation and became irregular and complex. The average cycle length measured at the right atrial appendage was significantly longer than that at the left atrial foci (206 +/- 32 milliseconds vs 175 +/- 23 milliseconds, P <.001). In addition to the passive activation, a focal activation and reentrant activation were also observed in the right atrium in 5 and 6 patients, respectively. The number of wave fronts in the right atrium was significantly greater than that in the left atrium (2.9 +/- 0.8 vs 0.6 +/- 0.7, P <.001). Multiple left atrial focal activations with fibrillatory conduction and right atrial focal or reentrant activations are the mechanism in permanent atrial fibrillation associated with mitral valve disease. Intraoperative mapping would facilitate the indication for simplified procedures confined to the left atrium or the pulmonary veins.


Conformational analysis and receptor docking of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (taranabant, MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist.
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.


Artificial neural network method for predicting HIV protease cleavage sites in protein.
Knowledge of the polyprotein cleavage sites by HIV protease will refine our understanding of its specificity, and the information thus acquired will be useful for designing specific and efficient HIV protease inhibitors. The search for inhibitors of HIV protease will be greatly expedited if one can find an accurate, robust, and rapid method for predicting the cleavage sites in proteins by HIV protease. In this paper, Kohonen's self-organization model, which uses typical artificial neural networks, is applied to predict the cleavability of oligopeptides by proteases with multiple and extended specificity subsites. We selected HIV-1 protease as the subject of study. We chose 299 oligopeptides for the training set, and another 63 oligopeptides for the test set. Because of its high rate of correct prediction (58/63 = 92.06%) and stronger fault-tolerant ability, the neural network method should be a useful technique for finding effective inhibitors of HIV protease, which is one of the targets in designing potential drugs against AIDS. The principle of the artificial neural network method can also be applied to analyzing the specificity of any multisubsite enzyme.


Molecular profile of non-coding RNA-mediated glycolysis control in human cancers.
The glycolysis is a common characteristic of cancer and it is responsible for providing enough energy to ensure growth. The glycolysis suppression is beneficial in tumor growth reduction. The stimulation/inhibition of glycolysis in cancer is tightly regulated by ncRNAs. The regulation of glycolysis by ncRNAs can influence proliferation and therapy response of tumor. The miRNAs are capable of inactivating enzymes responsible for glycolysis and suppressing signaling networks resulting in glycolysis induction. By regulation of glycolysis, miRNAs can affect therapy response. The lncRNAs and circRNAs follow a same pathway and by targeting glycolysis, they affect progression and therapy response of tumor. Noteworthy, lncRNAs and circRNAs sponge miRNAs in glycolysis mechanism control in tumor cells. Furthermore, ncRNA-mediated regulation of glycolysis mechanism can influence metastasis to organs of body. The ncRNAs regulating glycolysis are reliable biomarkers in cancer patients and more importantly, exosomal ncRNAs due to their presence in body fluids, are minimally-invasive biomarkers.


LNA modification of single-stranded DNA oligonucleotides allows subtle gene modification in mismatch-repair-proficient cells.
Synthetic single-stranded DNA oligonucleotides (ssODNs) can be used to generate subtle genetic modifications in eukaryotic and prokaryotic cells without the requirement for prior generation of DNA double-stranded breaks. However, DNA mismatch repair (MMR) suppresses the efficiency of gene modification by >100-fold. Here we present a commercially available ssODN design that evades MMR and enables subtle gene modification in MMR-proficient cells. The presence of locked nucleic acids (LNAs) in the ssODNs at mismatching bases, or also at directly adjacent bases, allowed 1-, 2-, or 3-bp substitutions in MMR-proficient mouse embryonic stem cells as effectively as in MMR-deficient cells. Additionally, in MMR-proficient Escherichia coli, LNA modification of the ssODNs enabled effective single-base-pair substitution. In vitro, LNA modification of mismatches precluded binding of purified E. coli MMR protein MutS. These findings make ssODN-directed gene modification particularly well suited for applications that require the evaluation of a large number of sequence variants with an easy selectable phenotype.


Acetylation of human fetal hemoglobin occurs throughout erythroid cell maturation.
The biosynthesis of human acetylated fetal hemoglobin (Hb F1) has been examined by incubating the following cell types with [3H]leucine: (a) burst-forming unit erythroid cells cultured from umbilical cord mononuclear cells, (b) infant bone marrow, (c) umbilical cord blood, and (d) peripheral blood cells from adults with elevated fetal hemoglobin. Newly synthesized Hb F1 was 18-20% that of Hb F0 in burst-forming unit erythroid cells which were immature, mature, or in an intermediate state of development. In infant marrow and in infant and adult peripheral blood the extant Hb F1 comprised 10.8 +/- 1.8% of the total Hb F. In marrow cells the specific radioactivity (cpm/mg) of Hb F1 was 1.4-2.0-times greater than that of Hb F0. In peripheral blood cells these ratios were slightly greater. [3H]Leucine-labeled infant bone marrow, umbilical cord blood, and adult peripheral blood cells were subjected to density gradient ultracentrifugation. The ratios of specific radioactivity for Hb F1/Hb F0 increased from 1.0-1.8 in the lightest cell zone to 5.2-9.0 in the more dense cells. Thus the biosynthesis of Hb F1 is enhanced in cells which are more mature than those responsible for the bulk of hemoglobin synthesis, and the acetylation of Hb F provides a marker of erythroid cell maturation.


Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1.
The purpose of this study was to explore the expression changes of Sirtuin 6 in diabetic renal tissues and the molecular mechanisms affecting renal tubular gluconeogenesis and reabsorption. The type 1 diabetic C57BL/6 mice model as well as high glucose cultured proximal tubular cells and cell lines were established. Sirt6 siRNA, the SGLT2 inhibitor (dapagliflozin), and insulin were pre-treated to make Sirtuin 6 levels, gluconeogenesis, and reabsorption changes. Immunofluorescence was used for Sirtuin 6 renal localization, and molecular biological detection was adopted for transcription factors, FoxO1, transporters (SGLT2 and GLUT2) as well as rate-limiting enzyme. Nuclear/plasma proteins were extracted to detect Sirtuin 6 and FoxO1 levels in the subcellular structure. Sirtuin 6 was decreased in STZ-induced diabetic renal outer medulla, and lower both in high glucose-induced primary proximal tubular cells and cell lines. Sirtuin 6 reversed the glucose reabsorption and gluconeogenesis effect via regulating FoxO1 and affecting nuclear translocation of FoxO1 in high glucose-induced proximal tubular cells. Sirtuin 6 affects renal glucose reabsorption and gluconeogenesis in type 1 diabetes by regulating FoxO1 nuclear import.


Cervical deformity patients with baseline hyperlordosis or hyperkyphosis differ in surgical treatment and radiographic outcomes.
Patients with symptomatic cervical deformity (CD) requiring surgical correction often present with hyperkyphosis (HK), though patients with hyperlordotic curves may require surgery as well. Few studies have investigated differences in CD-corrective surgery with regards to HK and hyperlordosis (HL). Operative CD patients (C2-C7 Cobb >10°, cervical lordosis [CL] >10°, cervical sagittal vertical axis [cSVA] >4 cm, chin-brow vertical angle >25°) with baseline (BL) and 1Y radiographic data. Patients were stratified based on BL C2-7 lordosis (CL) angle: those >1 standard deviation (SD) from the mean (-6.96° ±21.47°) were hyperlordotic (>14.51°) or hyperkyphotic (≤28.43°) depending on directionality. Patients within 1 SD were considered the control group. One hundred and two surgical CD pts (61 years, 65%F, 30 kg/m2) with BL and 1Y radiographic data were included. Twenty pts met definitions for HK and 21 pts met definitions for HL. No differences in demographics or disability were noted. HK had higher estimated blood loss (EBL) with anterior approaches than HL but similar EBL with the posterior approach. Op-time did not differ between groups. Control, HL, and HK groups differed in BL TS-CL (36.6° vs. 22.5° vs. 60.7°, P < 0.001) and BL-sagittal vertical axis (SVA) (10.8 vs. 7.0 vs. -47.8 mm, P = 0.001). HL pts had less discectomies, less corpectomies, and similar osteotomy rates to HK. HL had × 3 revisions of HK and controls (28.6 vs. 10.0 vs. 9.2%, respectively, P = 0.046). At 1Y, HL pts had higher cSVA, and trended higher SVA and SS than HK. In terms of BL-upper cervical alignment, HK pts had higher McGregor's-slope (16.1° vs. -3.3°, P = 0.001) and C0-C2 Cobb (43.3° vs. 26.9°, P < 0.001), however postoperative differences in McGregor's slope and C0-C2 were not significant. HK drivers of deformity were primarily C (90%), whereas HL had primary computed tomography (38.1%), upper thoracic (23.8%), and C (14.3%) drivers. Hyperlodotic patients trended higher revision rates with greater radiographic malalignment at 1Y postoperative, perhaps due to undercorrection compared to kyphotic etiologies.


Comparison of PI-RADS version 2.1 and PI-RADS version 2 regarding interreader variability and diagnostic accuracy for transition zone prostate cancer.
To compare the diagnostic performance of PI-RADS version 2.1 (PI-RADS v2.1) and PI-RADS v2 for transition zone prostate cancer (TZPC), and analyse its performance for readers with different experience levels. Eighty-five patients with suspected prostate cancer who underwent biopsy after MRI scan between January and December 2017 were retrospectively enrolled. One junior radiologist (reader 1, 1 year of experience in using PI-RADS v2) and one senior radiologist (reader 2, 6 years of experience) independently reviewed and assigned a score for each lesion according to PI-RADS v2.1 and v2. The template-guided transperineal prostate biopsy was used for standard of reference. To compare the diagnostic performance of the two methods, the AUC was calculated. The sensitivity, specificity, and accuracy were calculated at predefined positive values (PI-RADS ≥ 3). The interreader agreement and frequency of prostate cancer for each PI-RADS category were also calculated. Among the 85 patients, 27 had prostate cancers, and 25 were clinically significant prostate cancer (csPCa). The AUC values for diagnosing clinically significant prostate cancer significantly increased with PI-RADS v2.1 for reader 2 (0.766 vs. 0.902, P = 0.009). The specificity and accuracy for both readers also increased with PI-RADS v2.1 (specificity: reader 1, 41.7% vs. 78.3% and reader 2, 33.3% vs. 81.7%; accuracy: reader 1, 52.9% vs. 76.5% and reader 2, 48.2% vs. 83.5%, all P < 0.05). The interreader agreement was good for both versions. The percentage of prostate cancer decreased in lower PI-RADS categories (PI-RADS 2) and increased in higher PI-RADS categories (PI-RADS 3 ~ 4). Compared with PI-RADS v2, PI-RADS v2.1 may improve radiologists' diagnostic performance for TZPC.


microRNAs are important players in head and neck carcinoma: a review.
The results of treatment of head and neck tumors remain poor for decades. It means that after surgery, chemotherapy is not a proper choice, as tumors of this region are relatively resistant to cytotoxic drugs. A little progress was noted only for radiotherapy outcome. Consequently, clinicians and researchers' expectations are focused on targeted therapy, where microRNAs (miRNAs, miRs) seem to be the most promising target. After the year 2000, miRNAs became new players on the scene of cancer science. Since then, extensive investigations have been performed with a hope of finding a new prognostic and diagnostic tool and bridging them with a bright new way of understanding the basis of molecular carcinogenesis. miRNAs display astonishing specificity and thus are associated with pathoclinical parameters of the disease. After more than a decade of ongoing studies, in this review we attempt to summarize the current knowledge of miRNAs in malignancies arising in head and neck sites and with a majority of squamous cells of the epithelium.


A balance of interleukin-12 and -23 in cancer.
Interleukin (IL)-12 and IL-23 share the IL-12p40 molecule. IL-12 promotes T helper (Th)1 immunity and IL-23 promotes Th17 immunity, and it has recently become apparent that the balance between IL-12 and IL-23 is important in carcinogenesis. A series of studies demonstrated that, where tumor initiation, growth, and metastasis are concerned, IL-12 may act independently of interferon (IFN)-γ, and IL-23 independently of IL-17A. This review explores the activity of IL-23 in carcinogenesis. In the context of the tumor-inhibitory effects of IL-12, and tumor-promoting effects of IL-23, we discuss the use of anti-IL-12p/23 monoclonal antibodies (mAbs) in autoimmune inflammatory disorders and the alternative specific neutralization of IL-23.


Evaluation of API 20 NE in routine diagnostics of nonfermenting gram-negative rod-shaped bacteria.
292 strains of non-fermenting Gram-negative rod-shaped bacteria were determined by standard methods and tested in a new commercial microidentification-system, the API 20 NE (api Biomérieux). A total of 282 (= 96,6%) strains were identified conformably; 130 (= 46,1%) after 24 h and 77 (= 27,3%) within 48 h. In 75 (= 26,6%) cases different conventional additional tests for determination to species level were necessary. The reasons for divergent results of 10 strains are discussed. The new microidentification system API 20 NE might be a simple and reliable tool in hand of the skilled medical microbiologist.


Frequent plateletpheresis does not clinically significantly decrease platelet counts in donors.
In October 2005, the US Food and Drug Administration (FDA) issued draft guidance on collecting platelets (PLTs) by automated methods. The FDA proposed limiting collections to 24 components, rather than 24 procedures, annually with up to 3 components per procedure. The rationale was from literature suggesting frequent PLT collection resulted in significant declines in donor PLT counts. Additional requirements for minimal interdonation intervals were proposed. Plateletpheresis records at a regional blood center with predonation PLT counts were used to assess the impact of the restriction on PLT collections. They were reviewed to demonstrate the effects of collection frequency, number of products collected, and interdonation interval on donor PLT counts. Total protein and albumin levels were compared in a subset of 24-times-per-year PLT donors and control whole-blood donors. A limit of 24 components would require replacement of approximately 20 percent of the donor base to recover lost components. No clinically important decrease in PLT counts before donation was seen in donors donating multiple PLT components up to 24 times per year, regardless of interdonation interval. No frequent donor was deferred for a PLT count less than 150 x 10(9) per L. Short interdonation intervals were associated with statistically but not clinically important decreases in PLT counts. Protein levels were not distinguishable between PLT donors and controls. The proposed restrictions are not required to prevent thrombocytopenia in frequent PLT donors and would adversely impact the supply of apheresis PLTs. Protein levels are maintained in these high-frequency donors.


Two mutations in the dispensable part of alanine tRNA synthetase which affect the catalytic activity.
Two previously described chromosomal mutant alleles, alaS4 and alaS5, of Escherichia coli Ala-tRNA synthetase have been analyzed. Each causes a sharp diminution in aminoacylation activity and disrupts the alpha 4 tetramer structure of identical chains of 875 amino acids; neither mutation significantly disturbs the activity for synthesis of alanyladenylate. The location of each mutation within the structural gene has been mapped by marker rescue with specific gene fragments. Each mutant allele was cloned from the genome by reciprocal recombination with a multicopy plasmid that contains segments of alaS which flank the respective mutations. Further analysis established: 1) a single G----A transition results in a Gly----Asp change for each mutant allele at codon 674 (alaS4) and at codon 677 (alaS5). 2) The mutations are in the oligomerization domain, about 200 amino acids beyond the C-terminal side of the catalytic domain that previously was mapped by deletion analysis; the mutations are, thus, in a part of the polypeptide which is dispensable for catalytic activity. 3) For both mutant enzymes, there is little effect of the mutation on the Km for tRNAAla; kcat for aminoacylation is decreased by an order of magnitude. These point mutations reveal a subtle integration of the catalytic core with parts of the polypeptide that are not essential for catalytic activity.


Clinical identifiers for detecting underlying closed cervical fractures.
Although uncommon, closed cervical fractures (CCFs) may present in orthopedic clinical settings despite previous workup. The objective of this study was to describe the characteristics associated with missed CCF. The study was a retrospective database exploration of a cohort of subjects within a department of surgery with cervical pain. The sample consisted of 162 patients seen for a surgical consult for a number of cervical conditions. The examination time frame represented a clinical examination and imaging confirmation of diagnosis after an original initial visit by another provider. Descriptive and diagnostic accuracy values including sensitivity/specificity and positive/negative likelihood ratios (LR+/LR-) were calculated for each targeted variable. Clustered analyses were calculated using the patient history and situational characteristics. Eleven patients in the sample were diagnosed with CCF (6.7%). Six variables were significantly associated with a missed CCF. Using these six variables, it was found that failure to exhibit a condition of 2 of the 6 variables (1 or fewer) was the strongest in ruling out the condition (LR- = 0.0; post-test probability with a negative finding = 0%), whereas a finding of 4 of 6 was the most diagnostic for ruling in the condition (LR+ = 32; post-test probability with a positive finding = 70%). The findings in this sample suggest that select patient history or situational factors are still useful even after initial examination and clinicians must stay vigilant because CCFs may be missed during emergent care screens.


Feasibility of using mobile point-of-sale technology in Baltimore City corner stores tracking sales: A brief report.
Small food retail stores in many underserved urban settings keep no electronic records, making documentation of program impact on sales difficult to obtain. We examined the feasibility of introducing a point-of-sale tablet (POST) application to track sales of foods and beverages in Baltimore City corner stores. A sample of four geographically and ethnically diverse corner store owners were trained to use POST to track sales of 14 items for eleven days. Feasibility was documented via a structured survey and open-ended interviews. POST had high economic and cultural acceptability, operability, and perceived sustainability, regardless of language differences or familiarity with mobile technology. All store owners reported willingness to use POST again. It is feasible to train corner store owners to use a point-of-sale application for sales monitoring. An upcoming trial will help to ensure that POST provides sufficient value added for corner store owners.


The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats.
Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6 h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.


Glycation and inactivation of human Cu-Zn-superoxide dismutase. Identification of the in vitro glycated sites.
The nonenzymatic glycosylation (glycation) of Cu-Zn-superoxide dismutase led to gradual inactivation of the enzyme (Arai, K. Iizuka, S., Tada, Y., Oikawa, K., and Taniguchi, N. (1987) Biochim. Biophys. Acta 924, 292-296). The purified superoxide dismutase from human erythrocytes comprises both glycated and nonglycated forms. The nonglycated Cu-Zn-superoxide dismutase was isolated by boronate affinity chromatography. Incubation of the nonglycated superoxide dismutase with D-[6-3H]glucose in vitro resulted in the gradual accumulation of radioactivity in the enzyme protein, and Schiff base adducts were trapped by NaBH4. The sites of glycation of the superoxide dismutase were identified by amino acid analysis after reverse-phase high performance liquid chromatography of the trypsin-treated peptides. Lysine residues, i.e. Lys3, Lys9, Lys30, Lys36, Lys122, and Lys128, were found to be glycated. Three of the glycated sites lie in Lys-Gly, two in Lys-Ala, and one in Lys-Val. The inactivation of the superoxide dismutase on the glycation is due mainly to the glycation of Lys122 and Lys128, which are supposed to be located in an active site liganding loop. The remaining five sites, such as Lys-Glu, Lys-Asp, Lys-His, and Lys-Thr are relatively inactive as to the formation of either a Schiff base or an Amadori adduct.


A new coumarin from Murraya paniculata.
A new natural product, 2'-O-ethylmurrangatin (1) was isolated along with two previously known compounds murranganone (2) and paniculatin (3) from the leaves of Murraya paniculata. The structure of compound 1 was elucidated with the help of spectroscopic studies and by chemical reactions. Compounds 2 and 3 have been found to be cholinesterase inhibitors.


Automatic control of anesthesia using two feedback variables.
A new controller of an ON/OFF type was implemented for halothane anesthesia. A proportional-plus-integral controller with time-delay compensation proved not to be robust enough for the known clinical situation, as shown both in computer simulations and in animal trials. The ON/OFF controller proved to be less sensitive to parameter mismatches, and repeated animal trials showed a short response time and acceptable steady-state tracking. A method for switching the controlled effect of the drug was also developed, since anesthetic agents have multiple effects. Mean arterial blood pressure and a measure of EEG frequency were chosen as controlled variables, both being depressed by halothane. A coordinator forces the system state as near the desired values of these variables as possible, given that only one drug is used.


Symptomatic and counterregulatory hormonal responses to acute hypoglycaemia induced by insulin aspart and soluble human insulin in Type 1 diabetes.
The aim of this study was to assess hypoglycaemia awareness with the insulin analogue, insulin aspart. The counterregulatory hormonal and symptomatic responses to hypoglycaemia induced by insulin aspart were compared with soluble human insulin in a double-blind, randomised, two-period crossover trial in patients with Type 1 diabetes. The primary objective was to compare the blood glucose threshold for autonomic activation during hypoglycaemia induced by insulin aspart and soluble human insulin. Secondary objectives were to compare the counterregulatory, symptomatic and physiological responses to hypoglycaemia. 20 patients were screened, 17 were randomised and 16 completed the study. Acute hypoglycaemia was induced by intravenous infusion of insulin aspart or soluble human insulin (100 U ml(-1) at a rate of 2 mU kg(-1) min(-1)). No statistical difference between insulin aspart and soluble human insulin was shown for the primary blood glucose endpoint; mean arterialised blood glucose concentrations (+/-SD) at the onset of autonomic activation were 1. 88+/-0.39 mmol L(-1) for insulin aspart and 1.89+/-0.43 mmol L(-1) for soluble human insulin (not significant). No statistical differences were observed between the two insulins for the secondary endpoints: counterregulatory hormonal responses, autonomic responses, hypoglycaemia symptom scores, cognitive function and blood glucose responses. No serious adverse events were reported during the study. Insulin aspart and soluble human insulin elicit the same counterregulatory and symptomatic responses to acute hypoglycaemia in patients with Type 1 diabetes.


Modified Active Disturbance Rejection Predictive Control: A fixed-order state-space formulation for SISO systems.
This paper presents a novel control strategy that provides active disturbance rejection predictive control on constrained systems with no nominal identified model. The proposed loop relaxes the modelling requirement to a fixed discrete-time state-space realisation of a first-order plus integrator plant despite the nature of the controlled process. A third-order discrete Extended State Observer (ESO) estimates the model mismatch and assumed plant states. Moreover, the constraints handling is tackled by incorporating the compensation term related to the total perturbation in the definition of the optimisation problem constraints. The proposal merges in a new way state-space Model Predictive Control (MPC) and Active Disturbance Rejection Control (ADRC) into an architecture suitable for the servo-regulatory operation of linear and non-linear systems, as shown through validation examples.


[False images of foreign bodies of plant matter in the limbs of children. Apropos of 3 case reports].
Vegetal foreign bodies in the limbs cannot be demonstrated by X-ray examination and may lead to erroneous diagnosis. The answer should be given by surgical exploration, however, and this is particularly true for mobile foreign bodies in the joint, a high degree of suspicion is necessary at surgery. Three observations are presented in this paper which emphasize practical recommendations to perform without delay the simple efficient surgical procedure consisting in removal of the foreign body.


The effects of beta-blockers on dobutamine-atropine stress echocardiography: early protocol versus standard protocol.
To study the effects of Beta-blockers during Dobutamine Stress Echocardiography (DSE) comparing the hemodynamic benefits of an early administration of atropine in patients taking or not Beta-blockers. One hundred and twenty-one patients were submitted to dobutamine stress echocardiography for the investigation of myocardial ischemia. The administration of atropine was randomized into two groups: A or B (early protocol when atropine was administered at 10 and 20 mcg/kg/min of dobutamine, respectively) and C (standard protocol with atropine at 40 mcg/kg/min of dobutamine). Analysis of the effects of Beta-blockers was done regarding the behavior pattern of heart rate and blood pressure, test time, number of conclusive and inconclusive (negative sub-maximum test) results, total doses of atropine and dobutamine, and general complications. Beta-blocked patients who received early atropine (Group A&B) had a significantly lower double product (p = 0.008), a higher mean test time (p = 0.010) and required a higher dose of atropine (p = 0.0005) when compared to the patients in this group who were not Beta-blocked. The same findings occurred in the standard protocol (Group C), however the early administration of atropine reduced test time both in the presence and absence of this therapy (p = 0.0001). The patients with Beta-blockers in Group A&B had a lower rate of inconclusive tests (26%) compared to those in Group C (40%). Complications were similar in both groups. The chronotropic response during dobutamine stress echocardiography was significantly reduced with the use of Beta-blockers. The early administration of atropine optimized the hemodynamic response, reduced test time in patients with or without Beta-blockers and reduced the number of inconclusive tests in the early protocol.


An optimized two-vial formulation lipid nanoemulsion of paclitaxel for targeted delivery to tumor.
The discovery of new intravenous drug delivery carrier for water-insoluble drug is a challenging task. In this paper, novel two-vial formulation of paclitaxel (PTX)-loaded lipid nanoemulsions (TPLEs) with particle sizes of 110nm (TPLE-1), 220nm (TPLE-2) and 380nm (TPLE-3), which were formed by mixing a PEG400 solution of PTX and 10% (w/w) blank lipid emulsions (BLEs) with different particle size prior to use, were developed and comparatively evaluated for their pharmaceutics, pharmacokinetics, biodistribution, in vitro and in vivo anticancer efficiency. Among them, TPLE-1 displayed higher PTX-loading, slower PTX-release and larger PTX-distribution in oil-phase, significantly reduced extraction by RES organs, increased tumor-uptake, showed stronger cytotoxicity against MCF-7 cells and more potent anticancer efficacy on MCF-7 tumor-bearing nude mice, and had greater plasma AUC0-∞ value, smaller plasma clearance (CL), longer mean residence time (MRT) and elimination half-life (T1/2) in SD rats. It also exhibited the same in vivo efficacy as Taxol® and even produced less hemolysis and intravenous irritation. Moreover, its LD50 was 4.3-fold higher than that of Taxol®. All results demonstrate that TPLE-1 is a promising candidate drug due to its high tumor-accumulation and effectiveness, low toxicity, good safety and druggability in clinical application for the cancer therapy.


The joint association of ambient air pollution and different sleep posture with mild obstructive sleep apnea: A study conducted at Taipei Sleep Center.
Growing evidence suggests the detrimental impact of supine position and air pollution on obstructive sleep apnea (OSA), as well as the potential benefits of nonsupine positions. However, their interaction effects on OSA remain unclear. To evaluate the interaction effects of air pollution (NO2/PM2.5) and sleep position on OSA on additive and multiplicative scales. This study included 3330 individuals. Personal exposure to air pollution was assessed using a spatiotemporal model. OSA was diagnosed through polysomnography. The associations of supine and nonsupine positions and air pollutants with mild-OSA and their interaction effects on mild-OSA. were explored through generalized logistic regression. Supine position and high NO2 level independently increased the risk of mild-OSA, while PM2.5 was not associated with mild-OSA. Significant interactions were observed between supine position and NO2 at different lag periods (0-7 days, 0-1 year, and 0-2 years) (P = 0.042, 0.013, and 0.010, respectively). The relative excess risks due to interactions on the additive scale for 1-week, 1-year, and 2-year NO2 exposure and supine position were 0.63 (95 % CI: 0.10-1.16), 0.56 (95 % CI: 0.13-0.99), and 0.64 (95 % CI: 0.18-1.10); the corresponding odds ratios for interactions on the multiplicative scale were 1.45 (95 % CI: 1.01-2.07), 1.55 (95 % CI: 1.09-2.22), and 1.60 (95 % CI: 1.12-2.28). The positive interactions persisted in men and participants with obesity. No interaction was observed between nonsupine position and NO2 levels; nevertheless, significant interactions were noted on both the negative additive and multiplicative scales in men. Prolonged supine sleep significantly increased the risk of mild-OSA, particularly in men and individuals with obesity. Although the benefits of nonsupine position are considerably less than the risks of NO2 exposure, avoiding prolonged supine sleep may reduce the risk of mild-OSA caused by high levels of NO2 in men.


Methods for studying microtubule binding site interactions: zampanolide as a covalent binding agent.
In this chapter, we describe the methods used to determine the binding site and binding profile of zampanolide, a novel microtubule-stabilizing agent (MSA) that binds covalently to tubulin. These methods can be applied to other novel MSAs in which the binding site and mechanism of binding are unknown. Using the described methods, we have shown that zampanolide binds to the taxoid site on β-tubulin, but unlike most other MSAs is able to covalently modify this site. The purpose of this chapter is to provide a step-by-step protocol for determining the binding site of a novel MSA.


Comparison of two adsorbents for the removal of pentavalent arsenic from aqueous solutions.
Two adsorbents, magnesia-loaded fly ash cenospheres (MGLC) and manganese-loaded fly ash cenospheres (MNLC), were prepared by wet impregnation of fly ash cenospheres with MgCl(2) solution or a mixed solution of MnCl(2) and KMnO(4), respectively. Their physicochemical properties were characterized by scanning electron microscopy, X-ray diffractometry, X-ray fluorescence spectrometry, and Fourier transform infrared spectrometry. Sorption experiments were conducted to examine the effects of adsorbent dosage, pH, time, temperature, ionic strength and competing anions on As(V) removal by MGLC and MNLC. Both MGLC and MNLC had greater pH buffering capacity and were less affected by changes in ionic strength. Competing anions (carbonate and dihydric phosphate) had a larger impact on As(V) removal by MNLC than by MGLC. Adsorption on MNLC reached equilibrium at 60 min, while adsorption on MGLC reached equilibrium at 120 min. The Langmuir adsorption isotherm was a good fit for the experimental data of As(V) adsorption on MGLC and MNLC, and the adsorption kinetics for both followed the pseudo-second-order rate equation. MGLC and MNLC had a larger removal capacity for As(V) than the cenospheres. Compared with MNLC, MGLC is a better absorbent.


Immune response of sheep to oral and subcutaneous administration of live aromatic-dependent mutant of Salmonella typhimurium (SL1479).
The major objective of the present study was to determine whether oral immunization with a live aromatic-dependent strain of Salmonella typhimurium (SL1479) was capable of stimulating an intestinal immune response in sheep similar to that induced by combined intraperitoneal injection followed by oral boosting. The results showed that repeated oral immunization was incapable of stimulating an anti-flagella antibody containing cell (ACC) response in the lamina propria of the intestine even though primary oral administration of 5 x 10(9) live SL1479 gave rise to an ACC response in intestinal lymph which was predominantly of the IgM isotype. ACC reached a peak 9-10 days after oral administration when ACC comprised 0.5-1% of total lymphocytes in lymph. An ACC response of similar isotope specificity also occurred in popliteal prefemoral lymph of unprimed sheep following regional subcutaneous injection of SL1479. Oral administration of SL1479 to orally primed sheep did not reinvoke an ACC response in lymph although IgG1-ACC were observed in medullary cords of mesenteric lymph nodes of sheep 6-8 days after the booster dose of SL1479. The results suggest that the protective immunity elicited by oral administration of SL1479 cannot be attributed to induction of a local intestinal antibody production.


MiR-203a-3p suppresses cell proliferation and metastasis through inhibiting LASP1 in nasopharyngeal carcinoma.
miR-203a-3p was reported as a tumor suppressor and disregulated in many malignancies including nasopharyngeal carcinoma (NPC). However, its function in tumor growth and metastasis in NPC has rarely been reported. The expression level of miR-203a-3p in human NPC tissues and cell lines was detected via real-time PCR (RT-PCR). Cell proliferation, migration and invasion were assessed in vitro by MTT, colony formation and transwell assay, respectively. The function of miR-203a-3p in vivo was detected through NPC xenograft tumor growth and lung metastatic mice model. Dual-luciferase reporter assay was used to identify the direct target of miR-203a-3p. The expression of miR-203a-3p was decreased in NPC tissues and cell lines in comparison with normal nasopharyngeal tissues and cell line. Ectopic expression of miR-203a-3p inhibited while inhibiting miR-203a-3p expression increased NPC cell proliferation, migration and invasion in vitro. MR-203a-3p overexpression suppressed xenograft tumor growth and lung metastasis in vivo. LASP1 was identified as a direct target of miR-203a-3p, which was confirmed by real-time PCR and western blotting assay. Ectopic expression of LASP1 partially reversed miR-203a-3p-mediated inhibition on proliferation, migration and invasion in NPC cells. Collectively, miR-203a-3p suppresses tumor growth and metastasis through targeting LASP1 in NPC. The newly identified miR-203a-3p/LASP1 pathway provides further insights into the initiation and progression of NPC, which may represent a novel therapeutic target for NPC.


Changes in Cardiovascular Risk Factors Over 6 Years in Young Adults in a Randomized Trial of Weight Gain Prevention.
This study aimed to determine the impact of weight gain prevention interventions on changes in cardiovascular risk factors over 6 years. The Study of Novel Approaches to Weight Gain Prevention (SNAP) randomized 599 participants (ages 18-35; 46% with BMI 21-25; 54% with BMI 25-30) to Large Changes (produce buffer by losing 5-10 pounds initially), Small Changes (daily small changes in intake and activity) or Control and followed 355 participants with ongoing intervention and assessments through 6 years. There were no significant differences among interventions for changes in weight or cardiovascular disease (CVD) risk factors from baseline to 6 years. However, 44% of participants gained ≥5%, and only 14% lost ≥5% over 6 years. Weight changes, from baseline to year 6, were significantly associated with changes in risk factors, especially insulin and high-density lipoprotein cholesterol. Earlier weight changes (e.g., weight cycling) had no beneficial or adverse effect on changes in CVD risk factors at 6 years, independent of 6-year weight changes. Despite participation in a weight gain prevention trial, almost half of these young adults gained ≥5% or more over 6 years, with significant worsening in CVD risk factors. Greater attention to long-term weight gain prevention in young adults is needed.


Out-of-Pocket Health Care Expenditures Among United States Children: Parental Perceptions and Past-Year Expenditures, 2016 to 2017.
To examine the association between parental perceptions of out-of-pocket (OOP) health care costs for their child and the total amount of OOP health care expenditures for that child during the past year. We used data from the 2016 and 2017 National Surveys of Children's Health, cross-sectional, parent-reported, and nationally representative surveys of noninstitutionalized US children, ages 0 to 17 years. We conducted bivariate analyses to assess characteristics associated with the amount of OOP expenditures and parental perceptions of these costs. We estimated adjusted prevalence ratios for parental perceptions of OOP costs using logistic regression. Based on parent report, nearly two thirds (65.7%) of children incurred some amount of past-year OOP expenditures, with 13.3% of children incurring expenditures of ≥$1000. Parents reported that costs were unreasonable for 35.3% of children with past-year expenditures. The amount of OOP spending was associated with parents' perceptions that costs were unreasonable, with 16.5% of those with $1 to 249 in expenditures reporting unreasonable costs compared to 77.5% of those with >$5,000 in expenditures (P < .05). In adjusted analyses, high OOP expenditures, non-Hispanic white race/ethnicity, lack of health insurance, low household income, parental education levels less than a college degree, and foreign-born nativity status were associated with reports of unreasonable costs (P < .05). This study demonstrates an association between attitudinal and economic measures of health care expenditures for children while demonstrating differences in the perception of costs by measures of family economic vulnerability. Results may inform efforts to assess adequacy of health insurance coverage.


Distal sensory nerve transfers in lower-type injuries of the brachial plexus.
To report the results of sensory nerve transfers to reconstruct sensation on the ulnar side of the hand in lower-type palsies of the brachial plexus. From 2007 to 2009, we operated on 6 men and 2 women with a lower-type injury of the brachial plexus and observed them for a minimum of 24 months. The mean interval between the injury and surgery was 8 months (SD ± 8.6 mo). Before surgery, we documented anesthesia on the ulnar side of the hand in all patients. Donor nerves included cutaneous branches of the median nerve to the palm (n = 5) or the palmar cutaneous branch of the median nerve (n = 3). The ulnar proper digital nerve of the little finger was the recipient nerve. We evaluated sensory recovery by assessing static 2-point discrimination and sensation to Semmes-Weinstein monofilaments. According to the British Medical Council system of evaluation, 5 patients scored S3 and 3 scored S3+. In lower-type injuries of the brachial plexus, transfer of median nerve branches that innervate the palm of the hand to the ulnar proper digital nerve of the little finger predictably restored protective sensation on the ulnar side of the hand. Therapeutic IV.


Effect of a computerized brain exercise program on cognitive performance in older adults.
Research indicates an association between stimulating mental activities and better memory performance as people age, but studies on computerized mental stimulation programs are limited. We explored whether computerized brain training exercises improved cognitive performance in older adults. In local retirement communities, a convenience sample was randomized into an intervention group (N = 36), who used a computer program 5 days a week for 20-25 minutes each day, or a wait-list control group (N = 33). All were older adults without dementia (mean age: 81.8 years; SD: 6.1; 67% female). Neuropsychological testing was completed at baseline (Time 1), 2 months (Time 2), and 6 months (Time 3). Three cognitive domains (Immediate Memory, Delayed Memory, Language) were compared in the two groups as a function of time using mixed models. The intervention group used the computerized program (Brain Fitness, Dakim Inc., Santa Monica, CA) for an average of 43 (SD: 4.4) sessions by Time 2 and 81 (SD: 37.5) sessions by Time 3. Mixed models examining cognitive domains as function of time revealed significant group differences in Delayed Memory (F(2,72) = 4.7, p = 0.01) but not Immediate Memory and Language; no significant improvements were noted for the control group. Among all participants, anyone playing at least 40 sessions over the 6 months improved in all three domains (Immediate Memory, Delayed Memory, and Language). Participating in a computerized brain exercise program over 6 months improves cognitive abilities in older adults. These results extend literature indicating the benefit of training exercises, whether in a classroom format or via a computerized self-paced program.


NPPB block of Ca(++)-activated Cl- currents in Xenopus oocytes.
NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), a member of the novel class of Cl- channel blockers related to diphenylamine-2-carboxylate, was studied for its effect on the Ca(++)-activated Cl- current (ICl(Ca)) in frog (Xenopus laevis) oocytes. ICl(Ca) was activated by bath application of 5 mM Ca++ to oocytes that had been Ca++ permeabilized with the Ca++ ionophore A23187. In order to prevent the inactivation of ICl(Ca) that occurs with repetitive applications of Ca++, oocytes were also treated with H-7 (1,5-isoquinolinesulfonyl-1,2 methylpiperazine), an inhibitor of protein kinases. NPPB reversibly blocked both the fast transient (Ifast) and slow (Islow) components of ICl(Ca) with inhibition constants of 22 microM and 68 microM, respectively. NPPB block of ICl(Ca) was voltage dependent and potentiated by depolarization of the oocyte membrane. Our results indicate that NPPB is a potent blocker of the oocyte endogenous ICl(Ca), and may prove useful in the study of exogenously expressed Cl channels.


Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease.
The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4. These cells are also present in the basal epithelium. Such changes are likely hallmarks of epithelial mesenchymal transition (EMT). We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells. Endobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells). The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope". Slides were double stained for S100A4 and cytokeratin(s). In the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p < 0.003. Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p < 0.003. Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4. These data provide additional support for active EMT in COPD airways.


Evaluation of MRI-only based online adaptive radiotherapy of abdominal region on MR-linac.
A hybrid magnetic resonance linear accelerator (MRL) can perform magnetic resonance imaging (MRI) with high soft-tissue contrast to be used for online adaptive radiotherapy (oART). To obtain electron densities needed for the oART dose calculation, a computed tomography (CT) is often deformably registered to MRI. Our aim was to evaluate an MRI-only based synthetic CT (sCT) generation as an alternative to the deformed CT (dCT)-based oART in the abdominal region. The study data consisted of 57 patients who were treated on a 0.35 T MRL system mainly for abdominal tumors. Simulation MRI-CT pairs of 43 patients were used for training and validation of a prototype convolutional neural network sCT-generation algorithm, based on HighRes3DNet, for the abdominal region. For remaining test patients, sCT images were produced from simulation MRIs and daily MRIs. The dCT-based plans were re-calculated on sCT with identical calculation parameters. The sCT and dCT were compared in terms of geometric agreement and calculated dose. The mean and one standard deviation of the geometric agreement metrics over dCT-sCT-pairs were: mean error of 8 ± 10 HU, mean absolute error of 49 ± 10 HU, and Dice similarity coefficient of 55 ± 12%, 60 ± 5%, and 82 ± 15% for bone, fat, and lung tissues, respectively. The dose differences between the sCT and dCT-based dose for planning target volumes were 0.5 ± 0.9%, 0.6 ± 0.8%, and 0.5 ± 0.8% at D2% , D50% , and D98% in physical dose and 0.8 ± 1.4%, 0.8 ± 1.2%, and 0.6 ± 1.1% in biologically effective dose (BED). For organs-at-risk, the dose differences of all evaluated dose-volume histogram points were within [-4.5%, 7.8%] and [-1.1 Gy, 3.5 Gy] in both physical dose and BED. The geometric agreement metrics were within typically reported values and most average relative dose differences were within 1%. Thus, an MRI-only sCT-based approach is a promising alternative to the current clinical practice of the abdominal oART on MRL.


Three-Pronged Attack by Hybrid Nanoplatform Involving MXenes, Upconversion Nanoparticle and Aggregation-Induced Emission Photosensitizer for Potent Cancer Theranostics.
Inspired by the excellent photothermal conversion ability and inherent nanomedicine platform property of MXenes, efficient reactive oxygen species production and prominent fluorescence emission feature of aggregation-induced emission (AIE)-active photosensitizers (PSs), as well as the extending excitation wavelength capability of upconversion nanoparticles (UCNPs), a versatile nanoplatform comprised of Ti3 C2 nanosheets (NSs), AIE-active PSs and UCNPs is intelligently fabricated. This three-pronged strategy takes advantages of each component simultaneously, and realizes fluorescence imaging/photoacoustic imaging/photothermal imaging triple-modal imaging-guided photothermal/photodynamic synergetic therapy under 808 nm laser irradiation. The introduction of UCNPs actualizes the long wavelength-activation of AIE-active PSs, which significantly increases the tissue penetration depth. Spatially isolation of AIE-active PSs and Ti3 C2 NSs is beneficial for suppressing the fluorescence quenching effect of Ti3 C2 NSs, bringing about ultimately brilliant fluorescence. The covalently bonded polymer surface endows the nanoplatform with excellent physiological stability and efficient tumor accumulation. These outputs reveal a win-win cooperation of multiple inorganic/organic nanocomposites for phototheranostics, and present great potential for future clinical translations.


Total laparoscopic hysterectomy without uterine manipulator at big uterus weight (>280 g).
The retrospective study included the total laparoscopic hysterectomy without uterus manipulator at big uterus >280 g (Group A), proceeding the same technique as known to show feasibility and safety of its technique, compared with a randomized patient group of a uterus weight below 280 g (Group B). Statistical measurement was proceeded in typical clinical parameters. No statistical differences in age, body mass index, further abdominal surgery, blood loss, and hospital stay were observed. Operating time was significantly different favouring the uterus below 280 g (111.74 min Group A/90.68 min Group B). No increase in intra- or postoperative complications in both groups was observed. Total hysterectomy at big uterus (>280 g) is safe and feasible. Statistical analysis shows a significant shorter operating time only in one parameter (Group B). The technique of hysterectomy without uterus manipulator offers a surgical advancement also at vaginal stenosis, early staged cervix, or endometrial cancer and exhibits an opportunity for laparoscopic advancement in these cases too.


Electro-peroxone with solid polymer electrolytes: A novel system for degradation of plasticizers in natural effluents.
Electro-peroxone (EP) reaction has been considered as a promising process for real effluent treatments. However, the use of the technology in natural water conditions is limited by low electrical conductivity and high operating costs. Herein, a novel electrochemical system was designed to overcome this constrain by coupling EP with a solid polymer electrolyte (EP-SPE). Performances of EP-SPE system were thoroughly evaluated by comparing the decomposition and energy efficiencies of various plasticizers in different systems. The EP-SPE system achieved 50% of pollutants mineralization in only 10 min with the electrolysis energy consumption of 1.0kWh·m-3, While the conventional EP system (not) adding salt compounds (CEP-(N) AS) need 30 (60) min to reach 50% of pollutants mineralization with 3.8(26.6)kWh·m-3. Kinetics and mechanisms of EP-SPE were investigated in detail, while electronic paramagnetic resonance (EPR) detection and kinetic model revealed the occurrence, transient concentration and degradation contribution of reactive oxidizing species (ROS). Furthermore, tests of variety of SPEs and natural waters demonstrated universal applicability of EP-SPE. Additionally, EP-SPE did not show any performance deterioration after 15 runs. Therefore, this work provides a feasible technology for plasticizer purification in natural water.


Bilateral undisplaced insufficiency neck of femur fractures associated with short-term steroid use: a case report.
We present an interesting and unusual case of a 61-year-old woman with bilateral, undisplaced, stress neck of femur fractures associated with short-term steroid use. Insufficiency fractures of the neck of femur without preceding trauma have been described in the literature, although bilateral involvement is infrequent. These fractures have been associated with strenuous exercise, seizures, renal osteodystrophy, fluoride treatment, long-term corticosteroid use, amenorrhoea, abnormal anatomy and osteomalacia due to nutritional and/or hormonal factors. The case we present differs from other published reports, in that the patient's symptoms developed acutely after only a short course of steroids and with no associated trauma or strenuous exercise. It is also the only case described where no operative intervention was required. Our case reiterates the importance of considering insufficiency or stress fractures in high-risk patients who present with musculoskeletal pain. Institution of bone protection should also be considered in these patients. Morbidity related to delayed treatment has been well documented, so a high level of clinical suspicion is imperative.


Analysis of a Step-Up Approach Versus Primary Open Surgical Necrosectomy in the Management of Necrotizing Pancreatitis: Experience in a Cohort of Patients at a US Academic Medical Center.
An increasing number of providers have begun to use a minimally invasive step-up approach as opposed to traditional surgical necrosectomy in the management of acute necrotizing pancreatitis. Studies have shown mixed results, thus we hypothesized that the step-up approach is safer and associated with decreased mortality and length of stay (LOS). This is a retrospective cohort study of patients admitted from January 2010 to March 2015 who underwent interventions for walled-off pancreatic necrosis (WOPN). Primary outcomes included LOS after intervention and mortality, in-hospital and 90-day, with secondary outcomes of procedural complications. Sixty-nine patients developed WOPN requiring intervention during the study period. In-hospital mortality was 5.6% (n = 2) in the step-up cohort compared with 18.2% (n = 6) in the surgical cohort (relative risk, 3.27; 95% confidence interval, 0.71-15.09). Ninety-day mortality was 9.1% (n = 3) in the step-up cohort and 21.9% (n = 7) in the surgical cohort (relative risk, 2.41; 95% confidence interval, 0.68-8.50). Postintervention LOS was 8 days in the step-up cohort and 17 days in the surgical cohort (P = 0.62). A step-up approach, as compared with primary surgical necrosectomy in the management of WOPN, results in clinically significant decreases in mortality and LOS.


Calorimetric approach for comparison of Angiopoietin-like protein 4 with other pancreatic lipase inhibitors.
Pancreatic lipase (PNLIP) is a digestive enzyme that is a potential drug target for the treatment of obesity. A better understanding of its regulation mechanisms would facilitate the development of new therapeutics. Recent studies indicate that intestinal lipolysis by PNLIP is reduced by Angiopoietin-like protein 4 (ANGPTL4), whose N-terminal domain (nANGPTL4) is a known inactivator of lipoprotein lipase (LPL) in blood circulation and adipocytes. To elucidate the mechanism of PNLIP inhibition by ANGPTL4, we developed a novel approach, using isothermal titration calorimetry (ITC). The obtained results were compared with those of well-described inhibitors of PNLIP - ε-polylysine (EPL), (-)-epigallocatechin-3-gallate (EGCG) and tetrahydrolipstatin. We demonstrate that ITC allows to investigate PNLIP inhibition mechanisms in complex substrate emulsions and that the ITC-based assay is highly sensitive - the lowest concentration for quantification of PNLIP is 1.5 pM. Combining ITC with surface plasmon resonance and fluorescence measurements, we present evidence that ANGPTL4 is a lipid-binding protein that influences PNLIP activity through interactions with components of substrate emulsions (bile salts, phospholipids and triglycerides), and this promotes the aggregation of triglyceride emulsions similarly to the PNLIP inhibitors EPL and EGCG. In the absence of substrate emulsion, unlike in the case of LPL, ANGPTL4 did not induce the inactivation of PNLIP. Our data also prove that due to various interactions with components of substrate systems, the effect of a PNLIP inhibitor depends on whether its effect is measured in a complex substrate emulsion or in a simple substrate system.


Syndromology: an updated conceptual overview. IX. Facial dysmorphology.
The role of minor anomalies in dysmorphology is discussed followed by consideration of facial measurements. Photographic documentation, facial change with time, and facial gestalt are emphasized in the process of syndrome diagnosis. Finally, several recent techniques for craniofacial evaluation are presented including facial anthropometry, cephalometrics, laser scanning, three-dimensional craniofacial surface imaging from CT scans, and magnetic resonance imaging.


Antioxidant activity of an aminothiazole compound: possible mechanisms.
Oceans are among the richest natural sources of many bioactive compounds. Several of these compounds have shown pharmacological activities for many diseases. Dendrodoine (5-[(3-N-dimethylamino)-1,2,4-thiadiazolyl]-3-indanyl methanone) is an alkaloid extracted from the marine tunicate Dendrodoa grossularia. Aminothiazoles have a wide range of biological activities including anti-tumor and antioxidant properties. The aim of our study was to examine the antioxidant ability of an aminothiazole derivative, dendrodoine analogue (DA) [(4-amino-5-benzoyl-2-(4-methoxy phenylamino) thiazole] which has been chemically synthesized and is similar to dendrodoine. In all the biochemical assays used in our study, corresponding to different levels of protection, DA showed concentration dependent antioxidant ability. DA (3.07 microM) showed an ability to inhibit 2,2'-azobis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) radical formation to the extent of 0.17 microM of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). The ferric complex reducing ability of 3.07 microM DA was equivalent to 110 microM Trolox. 3.07 microM DA gave 84% protection against deoxyribose degradation, a measure of hydroxyl radical scavenging. DA also has an ability to scavenge NO radical, 3.07 microM DA effecting 20% scavenging. Concentration dependent inhibition of lipid peroxidation and protein oxidation induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and ascorbate-Fe2+ was observed with low concentrations of DA (1.5-3.07 microM). Mechanistic studies using pulse radiolysis revealed that DA scavenges peroxyl radicals with a bimolecular rate constant of 3 x 10(8)M(-1)s(-1). Moreover, the initially formed nitrogen-centered radical gets transformed into sulfur-centered radical before furnishing any final product. Our results indicated that DA can be a free radical scavenger and potential antioxidant for future application.


Brefeldin A affects the cellular distribution of endocytic receptors differentially.
The cell surface expression of three endocytic receptors was studied in human hepatoma Hep G2 cells treated with brefeldin A (BFA). Ligand binding and cell surface iodination revealed that BFA increased the number of mannose 6-phosphate/insulin-like growth factor II receptors twofold and decreased the amount of asialoglycoprotein and transferrin receptors by 40-60%. The altered expression of receptors at the cell surface was paralleled by changes in the respective ligand uptake. The implications of this finding on our understanding of intracellular trafficking are discussed.


Draft Genome Sequence of Vibrio owensii Strain SH-14, Which Causes Shrimp Acute Hepatopancreatic Necrosis Disease.
We sequenced Vibrio owensii strain SH-14, which causes serious acute hepatopancreatic necrosis disease (AHPND) in shrimp. Sequence analysis showed a large extrachromosomal plasmid, which encoded pir toxin genes and shared highly sequence similarity with the one observed in AHPND-causing Vibrio parahaemolyticus strains. The results suggest that this plasmid appears to play an important role in shrimp AHPND.


Newly Developed System for the Robust Detection of Listeria monocytogenes Based on a Bioelectric Cell Biosensor.
Human food-borne diseases caused by pathogenic bacteria have been significantly increased in the last few decades causing numerous deaths worldwide. The standard analyses used for their detection have significant limitations regarding cost, special facilities and equipment, highly trained staff, and a long procedural time that can be crucial for foodborne pathogens with high hospitalization and mortality rates, such as Listeria monocytogenes. This study aimed to develop a biosensor that could detect L. monocytogenes rapidly and robustly. For this purpose, a cell-based biosensor technology based on the Bioelectric Recognition Assay (BERA) and a portable device developed by EMBIO Diagnostics, called B.EL.D (Bio Electric Diagnostics), were used. Membrane engineering was performed by electroinsertion of Listeria monocytogenes homologous antibodies into the membrane of African green monkey kidney (Vero) cells. The newly developed biosensor was able to detect the pathogen's presence rapidly (3 min) at concentrations as low as 102 CFU mL-1, demonstrating a higher sensitivity than most existing biosensor-based methods. In addition, lack of cross-reactivity with other Listeria species, as well as with Escherichia coli, was shown, thus, indicating biosensor's significant specificity against L. monocytogenes.


A simulation study to improve quality of care in the emergency department of a community hospital.
In this article, a computer simulation study to improve the quality of care at the emergency department at a community hospital in Lexington, Kentucky, is presented. The simulation model is capable of evaluating the quality of care in terms of length of stay, waiting times, and patient elopement and has been validated by being compared with the data collected in the emergency department. Sensitivity analyses have been carried out to investigate the impact of workforce and diagnosis equipment on quality performance. The results suggest that, to ensure better clinical outcome, more nurses are needed; in addition, an additional computed tomography scanner is recommended. The model also shows that implementing team nursing policy (for 2 nurses) could lead to significant improvement in the emergency department's quality of care. Such a model provides a quantitative tool for continuous improvement and flow control in the emergency department and is also applicable to other departments in the hospital.


Bronchiectasis: moving from an orphan disease to an unpleasant socioeconomic burden.
Bronchiectasis has received increasing attention in recent years. At the same time, studies have shown a high incidence of this disease, especially in older populations, associated with high health-related costs and economic burden. https://bit.ly/2WPfVZ7.


In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia.
Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.


Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol.
In conclusion, the discovery of the resveratrol-PDE link suggests that PDE4 inhibitors, possibly in combination with other PDE inhibitors, may be useful for mimicking CR and for treating aging-related diseases.


[The demonstration of proliferating cells by using monoclonal antibodies to 5-bromo-2'-deoxyuridine in the peroxidase-antiperoxidase method].
Monoclonal antibodies (MAb) to the thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) and to horseradish peroxidase (HRPO) have been produced and characterized. On the basis of Mab to HRPO, complexes of the antibodies and HRPO (PAP-complexes) for immunochemical investigations are prepared. The possibility to identify proliferating cells in cultures of mouse myeloma Sp2/0 and mouse fibroblasts NIH 3T3 using Mab to BrdURd by the PAP-method is shown. The conditions of performing the analysis were optimized. The effect of various techniques ot cell fixation and cell DNA denaturation on cell morphology and on specific staining of nuclei of BrdUrd-containing cells in investigated.