Will insured citizens give up benefit coverage to include the uninsured?
To describe the willingness of insured citizens to trade off their own health benefits to cover the uninsured. Descriptive study of individual and group decisions and decision making using quantitative and qualitative methods. Twenty-nine groups of citizens (N = 282) residing throughout Minnesota. Groups participated in Choosing Healthplans All Together (CHAT), a simulation exercise in which participants choose whether and how extensively to cover health services in a hypothetical health plan constrained by limited resources. We describe individual and group decisions, and group dialogue concerning whether to allocate 2% of their premium to cover uninsured children in Minnesota, or 4% of their premium to cover uninsured children and adults. While discussing coverage for the uninsured, groups presented arguments about personal responsibility, community benefit, caring for the vulnerable, social impact, and perceptions of personal risk. All groups chose to insure children; 22 of 29 groups also insured adults. More individuals chose to cover the uninsured at the end of the exercise, after group deliberation, than before (66% vs 54%; P < .001). Individual selections differed from group selections more often for the uninsured category than any other. Nevertheless, 89% of participants were willing to abide by the health plan developed by their group. In the context of tradeoffs with their own health insurance benefits, groups of Minnesotans presented value-based arguments about covering the uninsured. All 29 groups and two thirds of individuals chose to contribute a portion of their premium to insure all children and most groups chose also to insure uninsured adults.


Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism.
Phytochemicals have provided an abundant source of novel therapeutics for the treatment of human cancers. We have previously described a novel plant toxin, persin, derived from avocado leaves, which has unique in vivo actions in the mammary epithelium and Bim-dependent, cytotoxic effects in human breast cancer cells in vitro. Compounds structurally similar to persin, such as the polyunsaturated fatty acid, conjugated linoleic acid, can attenuate steroid hormone receptor signaling and modulate the response of breast cancer cells to antiestrogens. Here, we provide evidence that persin may have similar effects by showing its potent proapoptotic synergy with the antiestrogen 4-hydroxytamoxifen. However, although persin transcriptionally down-regulates estrogen receptor (ER) expression, unlike conjugated linoleic acid, it also shows efficacy in ER-negative breast cancer cells, both alone and in combination with 4-hydroxytamoxifen, whereas normal breast epithelial cells are unaffected, suggesting it may act via a distinct, ER-independent mechanism. These proapoptotic synergistic interactions are associated with increased de novo ceramide synthesis and are dependent on expression of the proapoptotic protein Bim. These data show that persin should be further investigated as a potential novel cancer therapeutic agent because it significantly enhances the sensitivity of breast cancer cells to the cytotoxic effects of tamoxifen, regardless of their ER status, while displaying apparent specificity for the malignant phenotype.


Combined impact of healthy lifestyle factors on lifespan: two prospective cohorts.
The impact of multiple healthy lifestyle factors on survival time is unclear. The aim of this study was to examine differences in survival time associated with a healthy lifestyle versus a less healthy lifestyle. This study consisted of 33 454 men (Cohort of Swedish Men) and 30 639 women (Swedish Mammography Cohort) aged 45-83 years and free of cancer and cardiovascular disease at baseline. The healthy lifestyle factors included the following: (i) nonsmoking; (ii) physical activity at least 150 min per week; (iii) alcohol consumption of 0-14 drinks per week; (iv) and healthy diet defined as a modified Dietary Approaches to Stop Hypertension Diet score above the median. Cox proportional hazards regression models and Laplace regression were used to estimate, respectively, hazard ratios of all-cause mortality and differences in survival time. During follow-up from 1998 through 2014, 8630 deaths amongst men and 6730 deaths amongst women were ascertained through linkage to the Swedish Cause of Death Register. Each of the four healthy lifestyle factors was inversely associated with all-cause mortality and increased survival time. Compared with individuals with no or one healthy lifestyle factor, the multivariable hazard ratios of all-cause mortality for individuals with all four health behaviours were 0.47 (95% 95% confidence interval [CI]: 0.44-0.51) in men and 0.39 (95% CI: 0.35-0.44) in women. This corresponded to a difference in survival time of 4.1 (95% CI: 3.6-4.6) years in men and 4.9 (95% CI: 4.3-5.6) years in women. Adopting healthy lifestyle behaviours may markedly increase lifespan.


Methodological challenges in research on sexual risk behavior: I. Item content, scaling, and data analytical options.
Investigation of sexual behavior involves many challenges, including how to assess sexual behavior and how to analyze the resulting data. Sexual behavior can be assessed using absolute frequency measures (also known as counts) or with relative frequency measures (e.g., rating scales that range from never to always). We discuss these 2 assessment approaches in the context of research on HIV risk behavior. We conclude that these 2 approaches yield nonredundant information and, more important, that only data yielding information about the absolute frequency of risk behavior have the potential to serve as valid indicators of HIV contraction risk. However, analyses of count data may be challenging because of non-normal distributions with many outliers. Therefore, we identify new and powerful data analytical solutions that have been developed recently to analyze count data and discuss limitations of a commonly applied method (viz., analysis of covariance using baseline scores as covariates).


Acute pancreatitis: assessment of severity with clinical and CT evaluation.
Treatment of patients with acute pancreatitis is based on the initial assessment of disease severity. Severe pancreatitis occurs in 20%-30% of all patients with acute pancreatitis and is characterized by a protracted clinical course, multiorgan failure, and pancreatic necrosis. Early staging is based on the presence and degree of systemic failure (cardiovascular, pulmonary, renal) and on the presence and extent of pancreatic necrosis. Individual laboratory indexes (markers of pancreatic injury, markers of inflammatory response), while promising, have not yet gained clinical acceptance. Numeric grading systems with sensitivities of about 70% are commonly used today as indicators of organ failure and disease severity. Contrast material-enhanced computed tomography is used in addition to help evaluate local pancreatic morphology and the presence and extent of pancreatic necrosis. Advantages and limitations of the clinical, laboratory, and imaging prognostic indexes are analyzed and discussed.


Cu(I)-catalyzed highly enantioselective [3 + 3] cycloaddition between two different 1,3-dipoles, phthalazinium dicyanomethanides and iminoester-derived azomethine ylides.
The Cu(I)-catalyzed highly enantioselective [3 + 3] cycloaddition between two different 1,3-dipoles, phthalazinium dicyanomethanides and iminoester-derived azomethine ylides, has been achieved under mild reaction conditions, providing novel chiral heterocyclic compounds, 2,3,4,11b-tetrahydro-1H-pyrazino[2,1-a]phthalazine derivatives, in high yields with excellent diastereo- and enantioselectivies (up to 99% yield, 99% ee, >20:1 dr).


Tin(IV) chloride-chiral pyrogallol derivatives as new Lewis acid-assisted chiral Brønsted acids for enantioselective polyene cyclization.
[reaction: see text] New Lewis acid-assisted Brønsted acids (LBAs), tin(IV) chloride-2,6-dialkoxyphenols, serve as artificial cyclases for biomimetic polyene cyclization. For example, the enantioselective cyclization of 4-(homogeranyl)toluene using tin(IV) chloride-2,6-di[(1'R,2'R)-trans-2'-(3' ',5' '-xylyl)cyclohexanoxy]phenol gave a trans-fused tricyclic compound with 85% ee.


Structure-Activity Analysis of Cyclic Multicomponent Lipopeptide Self-Adjuvanting Vaccine Candidates Presenting Group A Streptococcus Antigens.
Group A Streptococcus (GAS) infection causes a range of life-threatening diseases, including rheumatic heart disease. Cyclic peptides offer an attractive solution for presentation of short peptide antigens due to their stability and structurally constrained conformation. We investigated a cyclic carrier decapeptide incorporating a B cell GAS peptide epitope, a universal T helper epitope, and a synthetic toll-like receptor 2-targeting moiety as a possible self-adjuvanting GAS vaccine. A structure-activity relationship of the cyclic lipopeptide vaccine showed successful induction of J8-specific systemic immunoglobulin G (IgG) antibodies when administered subcutaneously without an additional adjuvant. Interestingly, the physical mixture control induced the highest titers of all vaccine compounds, with antibodies from mice immunized with this physical mixture control shown to effectively opsonize multiple strains of clinically isolated GAS bacteria. This study showed the capability for a self-adjuvanting cyclic delivery system to act as a vehicle for the delivery of GAS peptide antigens to treat GAS infections.


Predicting kidney transplant survival using tree-based modeling.
Predicting the outcome of kidney transplantation is clinically important and computationally challenging. The goal of this project was to develop the models predicting probability of kidney allograft survival at 1, 3, 5, 7, and 10 years. Kidney transplant data from the United States Renal Data System (January 1, 1990, to December 31, 1999, with the follow-up through December 31, 2000) were used (n = 92,844). Independent variables included recipient demographic and anthropometric data, end-stage renal disease course, comorbidity information, donor data, and transplant procedure variables. Tree-based models predicting the probability of the allograft survival were generated using roughly two-thirds of the data (training set), with the remaining one-third left aside to be used for models validation (testing set). The prediction of the probability of graft survival in the independent testing dataset achieved a good correlation with the observed survival (r = 0.94, r = 0.98, r = 0.99, r = 0.93, and r = 0.98) and relatively high areas under the receiving operator characteristic curve (0.63, 0.64, 0.71, 0.82, and 0.90) for 1-, 3-, 5-, 7-, and 10-year survival prediction, respectively. The models predicting the probability of 1-, 3-, 5-, 7-, and 10-year allograft survival have been validated on the independent dataset and demonstrated performance that may suggest implementation in clinical decision support system.


Safety identifying of integral abutment bridges under seismic and thermal loads.
Integral abutment bridges (IABs) have many advantages over conventional bridges in terms of strength and maintenance cost. Due to the integrity of these structures uniform thermal and seismic loads are known important ones on the structure performance. Although all bridge design codes consider temperature and earthquake loads separately in their load combinations for conventional bridges, the thermal load is an "always on" load and, during the occurrence of an earthquake, these two important loads act on bridge simultaneously. Evaluating the safety level of IABs under combination of these loads becomes important. In this paper, the safety of IABs--designed by AASHTO LRFD bridge design code--under combination of thermal and seismic loads is studied. To fulfill this aim, first the target reliability indexes under seismic load have been calculated. Then, these analyses for the same bridge under combination of thermal and seismic loads have been repeated and the obtained reliability indexes are compared with target indexes. It is shown that, for an IAB designed by AASHTO LRFD, the indexes have been reduced under combined effects. So, the target level of safety during its design life is not provided and the code's load combination should be changed.


Dissecting RNA recombination in vitro: role of RNA sequences and the viral replicase.
Molecular mechanisms of RNA recombination were studied in turnip crinkle carmovirus (TCV), which has a uniquely high recombination frequency and non-random crossover site distribution among the recombining TCV-associated satellite RNAs. To test the previously proposed replicase-driven template-switching mechanism for recombination, a partially purified TCV replicase preparation (RdRp) was programed with RNAs resembling the putative in vivo recombination intermediates. Analysis of the in vitro RdRp products revealed efficient generation of 3'-terminal extension products. Initiation of 3'-terminal extension occurred at or close to the base of a hairpin that was a recombination hotspot in vivo. Efficient generation of the 3'-terminal extension products depended on two factors: (i) a hairpin structure in the acceptor RNA region and (ii) a short base-paired region formed between the acceptor RNA and the nascent RNA synthesized from the donor RNA template. The hairpin structure bound to the RdRp, and thus is probably involved in its recruitment. The probable role of the base-paired region is to hold the 3' terminus near the RdRp bound to the hairpin structure to facilitate 3'-terminal extension. These regions were also required for in vivo RNA recombination between TCV-associated sat-RNA C and sat-RNA D, giving crucial and direct support for a replicase-driven template-switching mechanism of RNA recombination.


The interplay between transcription and mRNA degradation in Saccharomyces cerevisiae.
The cellular transcriptome is shaped by both the rates of mRNA synthesis in the nucleus and mRNA degradation in the cytoplasm under a specified condition. The last decade witnessed an exciting development in the field of post-transcriptional regulation of gene expression which underscored a strong functional coupling between the transcription and mRNA degradation. The functional integration is principally mediated by a group of specialized promoters and transcription factors that govern the stability of their cognate transcripts by "marking" them with a specific factor termed "coordinator." The "mark" carried by the message is later decoded in the cytoplasm which involves the stimulation of one or more mRNA-decay factors, either directly by the "coordinator" itself or in an indirect manner. Activation of the decay factor(s), in turn, leads to the alteration of the stability of the marked message in a selective fashion. Thus, the integration between mRNA synthesis and decay plays a potentially significant role to shape appropriate gene expression profiles during cell cycle progression, cell division, cellular differentiation and proliferation, stress, immune and inflammatory responses, and may enhance the rate of biological evolution.


Olefin-linked covalent organic frameworks: synthesis and applications.
Covalent organic frameworks (COFs) with high specific porosity, easy functionalization, and tailored structure are an emerging class of crystalline porous polymers that have been extensively exploited as ideal materials in various fields. Among them, sp2-carbon linked COFs with high chemical stability, porous backbone, and unique π-electron conjugated architectures structure have raised widespread attention. Specifically, the porous channels of olefin-linked COFs could be packed with active sites for catalysis and guest molecules, while π-π stacking interactions and conjugation systems pave the way for electron transfer. In recent years, many efforts have been devoted to the development of sp2-carbon linked COFs for applications in catalysis, energy storage, gas adsorption, and separation. In this review, we highlight the design principles, synthesis strategies, and impactful applications of olefin-linked COFs. We are looking forward to this review to deepen the understanding of the synthesis of olefin-linked COFs and motivate the further development of these novel conjugated organic materials with distinctive physicochemical properties, as well as their applications in a variety of fields.


Evolutionary analyses of the avirulence effector AvrStb6 in global populations of Zymoseptoria tritici identify candidate amino acids involved in recognition.
We analysed the population genetic diversity of AvrStb6, the first avirulence gene cloned from the wheat pathogen Zymoseptoria tritici, using 142 Z. tritici strains sampled from four wheat fields growing on three continents. Although AvrStb6 was located in a recombination hotspot, it was found in every strain, with 71 polymorphic sites that produced 41 distinct DNA haplotypes encoding 30 AvrStb6 protein isoforms. An AvrStb6 homologue was found in the closest known relative, Z. pseudotritici, but not in three other closely related Zymoseptoria species, indicating that this gene has emerged in Zymoseptoria quite recently. Two AvrStb6 homologues with nucleotide similarities greater than 70% were identified on chromosome 10 in all Z. tritici isolates, suggesting that AvrStb6 belongs to a multigene family of candidate effectors that has expanded recently through gene duplication. The AvrStb6 sequences exhibited strong evidence for non-neutral evolution, including a large number of non-synonymous mutations, with significant positive diversifying selection operating on nine of the 82 codons. It appears that balancing selection is operating across the entire gene in natural field populations. There was also evidence for co-evolving codons within the gene that may reflect compensatory mutations associated with the evasion of recognition by Stb6. Intragenic recombination also appears to have affected the diversity of AvrStb6.


Uses of Ultrasound in a Surgical Practice.
The applications of sonography multiply year by year. The technology initially progressed from a simple A-mode signal, to contact scanners which produced B-mode images. These, in turn, were supplanted by real-time instruments capable of defining motion. The next development was the duplex Doppler machines which characterised flow from an image in a specific area. Now, colour coding of vascularity and high resolution imagery have become the standards of excellence.


[Effect of ABA on transcriptionally active Ty1-copia retrotransposons in Dendrobium officinale].
Using universal primer Tyl-copia retrotransposon RT, the conserved reverse transcriptase domain of about 260 bp was amplified by RT-PCR from the Dendrobium officinale which induced by 100 micromol x L(-1) abscisic acid (ABA), indicating these retrotransposons activated by 100 micromol x L(-1) ABA. The amplicons were recovered and cloned,then sequenced and analyzed by related bioinformatics software. Forty-two Ty1-copia like retrotransposon RT transcriptionally activated were obtained with high heterogeneity. The length of these sequences varied from 247 to 266 bp, and was rich in AT and homology ranged from 46.3% to 98.9%. The same to Ty1-copia like retrotransposon RT of genome, different c/s-acting regulatory elements induced by stress conditions and the starting transcription signals, corresponding to CAAT box, TATA box conserved sequences and some other regulatory elements. The c/s-acting regulatory elements induced by stress conditions of reverse transcriptase transcriptionally activated of Tyl-copia retrotransposons were significantly increased than that of Ty1-copia like retrotransposon RT of genome. When being translated into amino acids, fifteen sequences presented stop codon mutation, nineteen sequences presented frameshift mutation, and all sequences presented conserved sequence "SLYGKQ" mutation. Five categories were identified through phylogenic analysis after alignment analyses of their amino acid sequences, and with Ty1-copia like retrotransposon RT of genome having low homology, which indicated that reverse transcriptase transcriptionally activated of Ty1-copia retrotransposons which induced by ABA had Significantly differences with Ty1-copia like retrotransposon RT of genome.


Para-aortic lymph node involvement revisited in the light of the revised 2018 FIGO staging system for cervical cancer.
This dual-institutional, retrospective study aimed to determine the clinicopathological risk factors for para-aortic lymph node (LN) metastasis among women who underwent radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy for 2009 FIGO stage IB1-IIA2 cervical cancer. Institutional cervical cancer databases of two high-volume gynecologic cancer centers in Ankara, Turkey were retrospectively analyzed. Women with 2009 FIGO stage IB1-IIA2 cervical cancer that had undergone radical hysterectomy with pelvic and para-aortic lymphadenectomy between January 2006 and December 2018 were included in the study. Patient data were analyzed with respect to para-aortic LN involvement and all potential clinicopathological risk factors for para-aortic LN metastasis were investigated. A total of 522 women met the inclusion criteria. Pelvic LN metastasis was detected in 190 patients (36.4%), para-aortic LN metastasis in 48 patients (9.2%), isolated para-aortic LN metastasis in 4 (0.8%), and both pelvic and para-aortic LN metastasis in 44 (8.4%) women, respectively. The independent risk factors identified for para-aortic LN involvement included parametrial invasion (odds ratio [OR]: 3.57, 95% confidence interval [CI]: 1.65-7.72; p = 0.001), metastasized pelvic LN size > 1 cm (OR: 4.51, 95% CI: 1.75-11.64; p = 0.002), multiple pelvic LN metastases (OR: 3.83, 95% CI: 1.46-10.01; p = 0.006), and common iliac LN metastasis (OR: 2.97, 95% CI: 1.01-8.68; p = 0.04). A total of 196 (37.5%) patients exhibited at least one risk factor for para-aortic nodal disease. Parametrial invasion, metastasized pelvic LN size > 1 cm, multiple pelvic LN metastases, and common iliac LN metastasis seem to be independent predictors of para-aortic LN involvement.


Penicillin-binding protein 7/8 of Escherichia coli is a DD-endopeptidase.
Penicillin-binding protein 7 (PBP7) and its proteolytic degradation product PBP8 are shown to be soluble proteins, which can be set free from whole cells of Escherichia coli by an osmotic shock. The proteins are loosely associated with the membranes and are totally released into the supernatant in the presence of 1 M NaCl. Partial purification of PBP8 was accomplished by hydroxyapatite, heparin-Sepharose and MonoS chromatography. Murein meso-diaminopimelate-D-alanine DD-endopeptidase activity was demonstrated for both PBP7 and PBP8, which specifically hydrolyse the DD-diaminopimelate-alanine bonds in high-molecular-mass murein sacculi but fail to cleave these bonds in isolated dimeric muropeptides. The enzyme is inhibited by the 'penem' beta-lactam antibiotic CGP31608 at a concentration of 0.25 micrograms/ml by 50%. Thus besides PBP4 and the mepA gene product, a third endopeptidase exists in E. coli.


Carcinoma of the esophagus and esophagogastric junction: sensitivity of radiographic diagnosis.
The purpose of this study was to determine the sensitivity of barium studies in revealing carcinoma of the esophagus and esophagogastric junction. We retrospectively reviewed 50 cases of squamous cell carcinoma of the esophagus (n = 25) and adenocarcinoma of the esophagus (n = 14) or esophagogastric junction (n = 11) in which double-contrast (n = 46) or single-contrast (n = 4) barium studies had been done. The original radiology reports were reviewed to determine whether the lesions had been seen on barium studies and whether cancer had been diagnosed. Records were also reviewed to determine the number of patients who underwent esophageal endoscopy because of findings suggestive of cancer on barium studies at some point from January 1992 through December 1992. Pathology records were then reviewed to determine the number of true- and false-positive barium studies during this same period. Lesions were shown on barium studies in 49 (98%) of 50 patients, and carcinoma of the esophagus or esophagogastric junction was diagnosed or suspected in 48 patients (96%). In a separate part of the study, we found that endoscopy had been recommended to rule out malignant tumor in only 26 (1%) of 2484 patients who underwent barium studies at some point from January 1992 through December 1992. Endoscopy revealed cancer in 11 of those 26 patients; the remaining 15 were assumed to have false-positive radiologic examinations. Barium studies therefore had a positive predictive value of 42%. The double-contrast barium study is a sensitive technique for the diagnosis of carcinoma of the esophagus and esophagogastric junction. This high sensitivity can be achieved while recommending endoscopy in only about 1% of all patients who undergo barium studies.


Characterisation of the Major Extracellular Proteases of Stenotrophomonas maltophilia and Their Effects on Pulmonary Antiproteases.
Stenotrophomonas maltophilia is an emerging global opportunistic pathogen that has been appearing with increasing prevalence in cystic fibrosis (CF). A secreted protease from S. maltophilia has been reported as its chief potential virulence factor. Here, using the reference clinical strain S. maltophilia K279a, the major secreted proteases were identified. Protein biochemistry and mass spectrometry were carried out on K279a culture supernatant. The effect of K279a culture supernatant on cleavage and anti-neutrophil elastase activity of the three majors pulmonary antiproteases was quantified. A deletion mutant of S. maltophilia lacking expression of a protease was constructed. The serine proteases StmPR1, StmPR2 and StmPR3, in addition to chitinase A and an outer membrane esterase were identified in culture supernatants. Protease activity was incompletely abrogated in a K279a-ΔStmPR1: Erm mutant. Wild type K279a culture supernatant degraded alpha-1 antitrypsin (AAT), secretory leucoprotease inhibitor (SLPI) and elafin, important components of the lung's innate immune defences. Meanwhile SLPI and elafin, but not AAT, retained their ability to inhibit neutrophil elastase. StmPR3 together with StmPR1 and StmPR2, is likely to contribute to protease-mediated innate immune dysfunction in CF.


Differentials in sex ratio at birth among natives and immigrants in Greece: an analysis employing nationwide micro-data.
This study uses micro-level information on the live births registered in Greece for 2006 to assess differentials in the propensity to have a male offspring between natives and immigrants. The sex ratio at birth for the whole population is 106.3 but it is considerably higher among immigrants (110.9) than among natives (105.4). Relatively high sex ratios at birth are observed for several migrant groups; differentials between natives, on the one hand, and Albanians (109.5) and Asians (129.0), on the other, are significant. The high sex ratio at birth for Albanians seems typical of that population. For Asians, the result is consistent with international findings though it may also be partly related to the small number of observations.


Unraveling the Marine Microplastic Cycle: The First Simultaneous Data Set for Air, Sea Surface Microlayer, and Underlying Water.
Microplastics (MP) including tire wear particles (TWP) are ubiquitous. However, their mass loads, transport, and vertical behavior in water bodies and overlying air are never studied simultaneously before. Particularly, the sea surface microlayer (SML), a ubiquitous, predominantly organic, and gelatinous film (<1 mm), is interesting since it may favor MP enrichment. In this study, a remote-controlled research catamaran simultaneously sampled air, SML, and underlying water (ULW) in Swedish fjords of variable anthropogenic impacts (urban, industrial, and rural) to fill these knowledge gaps in the marine-atmospheric MP cycle. Polymer clusters and TWP were identified and quantified with pyrolysis-gas chromatography-mass spectrometry. Air samples contained clusters of polyethylene terephthalate, polycarbonate, and polystyrene (max 50 ng MP m-3). In water samples (max. 10.8 μg MP L-1), mainly TWP and clusters of poly(methyl methacrylate) and polyethylene terephthalate occurred. Here, TWP prevailed in the SML, while the poly(methyl methacrylate) cluster dominated the ULW. However, no general MP enrichment was observed in the SML. Elevated anthropogenic influences in urban and industrial compared to the rural fjord areas were reflected by enhanced MP levels in these areas. Vertical MP movement behavior and distribution were not only linked to polymer characteristics but also to polymer sources and environmental conditions.


[Synchronous and bilateral inverted papilloma of the kidney pelvis. Conservative treatment].
Contribution of a new case of inverted papilloma (IP) of the upper urinary tract (UUT) with the idiosyncrasy of being bilateral and synchronic, a fact not found in the reviewed literature, treated with radical surgery on the left side and conservatively on the right one. Discussion on this pathology is addressed, emphasising its benign biological behaviour, which does not eliminate some cases of malignization. Treatment has to be conservative, and so we stress the relevance of defining a suspicion state to make pre- and peri- operative diagnosis in which endourological methods, that allow both direct visualization and the taking of a biopsy, play a preeminent role. Subsequent strict monitoring is essential due to the likelihood of relapse and malignant changes.


Patient information on nebulised antibiotics.
The importance of providing patients with high-quality information is highlighted in several government reports. The aim of this project was to develop written information specifically designed for patients with non-cystic fibrosis bronchiectasis who are prescribed nebulised colistimethate sodium. This involved evaluating current literature and best practice, which was achieved through multidisciplinary collaboration. The leaflet produced meets the recommendations of the British Thoracic Society and Department of Health, as well as NHS trusts' legal obligations to promote equality and diversity. It is available as a printed document in a variety of formats and languages, and can be downloaded from the hospital website.


[Effects of La on the growth of kidney bean seedling under Cd stress].
In this study, kidney bean (Phaseolus vulgaris) was used as experiment-material, and effects of lanthanum on growth and metabolism of kidney bean seedling under cadmium stress was studied by water culture. The results showed that kidney bean seedling was chronically harmed by 30 mumol.L-1 Cd2+, however, its height and main root were reduced about 31.1% and 39.2%, meanwhile, leaf area, fresh and dry weight of leaf, stem and root were decreased 48.0%, 42.7%, 29.6%, 61.3% and 49.4% respectively. With acute damage of 50 mumol.L-1 Cd2+, physiological and biochemical characteristics of seedling changed greatly, e.g., chlorophyll content and root activity were decreased about 23.5% and 28.7%, cell membrane permeability, the malonydialdehyde (MDA) content, activities of catalase (CAT) and peroxidase (POD) were increased 5.58%, 28.6%, 0.6% and 7.0% respectively. And with longer treatment time, the damage became more serious. When 10 mg.L-1 La was used to spray on kidney bean seedling under cadmium stress one time, growth and metabolism of seedling was obviously reconditioned and the damage of Cd pollution was reduced. It is proved, by the experiment, that La can improve chlorophyll content(30.0%) and reduce cell membrane permeability (0.87%) and content of MDA(9.5%), and keep the activities of CAT (0.1%) and POD(1.6%) of kidney bean seedling.


Ephexin1 Is Required for Eph-Mediated Limb Trajectory of Spinal Motor Axons.
The precise assembly of a functional nervous system relies on the guided migration of axonal growth cones, which is made possible by signals transmitted to the cytoskeleton by cell surface-expressed guidance receptors. We investigated the function of ephexin1, a Rho guanine nucleotide exchange factor, as an essential growth-cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situ mRNA detection, we first show that ephexin1 is expressed in LMC neurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Ephexin1 loss of function and gain of function using in ovo electroporation in chick LMC neurons, of either sex, perturbed LMC axon trajectory selection, demonstrating an essential role of ephexin1 in motor axon guidance. In addition, ephexin1 loss in mice of either sex led to LMC axon trajectory selection errors. We also show that ephexin1 knockdown attenuates the growth preference of LMC neurites against ephrins in vitro and Eph receptor-mediated retargeting of LMC axons in vivo, suggesting that ephexin1 is required in Eph-mediated LMC motor axon guidance. Finally, both ephexin1 knockdown and ectopic expression of nonphosphorylatable ephexin1 mutant attenuated the retargeting of LMC axons caused by Src overexpression, implicating ephexin1 as an Src target in Eph signal relay in this context. In summary, our findings demonstrate that ephexin1 is essential for motor axon guidance and suggest an important role in relaying ephrin:Eph signals that mediate motor axon trajectory selection.SIGNIFICANCE STATEMENT The proper development of functioning neural circuits requires precise nerve connections among neurons or between neurons and their muscle targets. The Eph tyrosine kinase receptors expressed in neurons are important in many contexts during neural-circuit formation, such as axon outgrowth, axon guidance, and synaptic formation, and have been suggested to be involved in neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer's disease. To dissect the mechanism of Eph signal relay, we studied ephexin1 gain of function and loss of function and found ephexin1 essential for the development of limb nerves toward their muscle targets, concluding that it functions as an intermediary to relay Eph signaling in this context. Our work could thus shed new light on the molecular mechanisms controlling neuromuscular connectivity during embryonic development.


Subdissociative intranasal ketamine plus standard pain therapy versus standard pain therapy in the treatment of paediatric sickle cell disease vaso-occlusive crises in resource-limited settings: study protocol for a randomised controlled trial.
Pediatric sickle cell disease, highly prevalent in sub-Saharan Africa, carries great morbidity and mortality risk. Limited resources and monitoring make management of acute vaso-occlusive crises challenging. This study aims to evaluate the efficacy and safety of subdissociative intranasal ketamine as a cheap, readily available and easily administered adjunct to standard pain therapy. We hypothesise that subdissociative, intranasal ketamine may significantly augment current approaches to pain management in resource-limited settings in a safe and cost-effective manner. This is a multicentred, randomised, double-blind, placebo-controlled trial enrolling children 4-16 years of age with sickle cell disease and painful vaso-occlusive pain crises. Study sites include two sub-Saharan teaching and referral hospitals with acute intake areas. All patients receive standard analgesic therapy during evaluation. Patients randomised to the treatment arm receive 1 mg/kg intranasal ketamine at onset of therapy, while placebo arm participants receive volume-matched intranasal normal saline. All participants and clinical staff are blinded to the treatment allocation. Data will be analysed on an intention-to-treat basis. Primary endpoints are changes in self-report pain scales (Faces Pain Scale-Revised) at 30, 60 and 120 minutes and rates of adverse events. Secondary endpoints include hospital length of stay, total analgesia use and quality of life assessment 2-3 weeks postintervention. The research methods for this study have been approved by the Cameroon Baptist Convention Health Board Institutional Review Board (IRB2015-07), the Tanzanian National Institute for Medical Research (NIMR/HQ/R.8a/Vol. IX/2299), Muhimbili National Hospital IRB (MNH/IRB/I/2015/14) and the Tanzanian Food and Drugs Authority (TFDA0015/CTR/0015/9). Data reports will be provided to the Data and Safety Monitoring Board (DSMB) periodically throughout the study as well as all reports of adverse events. All protocol amendments will also be reviewed by the DSMB. Study results, regardless of direction or amplitude, will be submitted for publication in relevant peer-reviewed journals. ClinicalTrials.Gov, NCT02573714. Date of registration: 8 October 2015. Pre-results.


Bacterial flora and antimicrobial resistance in raw frozen cultured seafood imported to Denmark.
Intensified aquaculture includes the use of antimicrobials for disease control. In contrast to the situation in livestock, Escherichia coli and enterococci are not part of the normal gastrointestinal flora of fish and shrimp and therefore not suitable indicators of antimicrobial resistance in seafood. In this study, the diversity and phenotypic characteristics of the bacterial flora in raw frozen cultured and wild-caught shrimp and fish were evaluated to identify potential indicators of antimicrobial resistance. The bacterial flora cultured on various agar media at different temperatures yielded total viable counts of 4.0 × 10(4) to 3.0 × 10(5) CFU g(-1). Bacterial diversity was indicated by 16S rRNA sequence analysis of 84 isolates representing different colony types; 24 genera and 51 species were identified. Pseudomonas spp. (23% of isolates), Psychrobacter spp. (17%), Serratia spp. (13%), Exiguobacterium spp. (7%), Staphylococcus spp. (6%), and Micrococcus spp. (6%) dominated. Disk susceptibility testing of 39 bacterial isolates to 11 antimicrobials revealed resistance to ampicillin, amoxicillin-clavulanic acid, erythromycin, and third generation cephalosporins. Resistance to third generation cephalosporins was found in Pseudomonas, a genus naturally resistant to most β-lactam antibiotics, and in Staphylococcus hominis. Half of the isolates were susceptible to all antimicrobials tested. Results indicate that identification of a single bacterial resistance indicator naturally present in seafood at point of harvest is unlikely. The bacterial flora found likely represents a processing rather than a raw fish flora because of repeated exposure of raw material to water during processing. Methods and appropriate indicators, such as quantitative PCR of resistance genes, are needed to determine how antimicrobials used in aquaculture affect resistance of bacteria in retailed products.


Spontaneous swine glomerulonephritis in littermates from a leukemic sow.
Spontaneous glomerulonephritis was found in seven six-month-old littermates from a leukemic sow. Light microscopy of the glomerular lesions showed proliferation of the mesangial cells and increase of the mesangial matrix with deposition of homogeneous materials. All glomeruli were affected, but the severity of the lesions varied among pigs. The glomerular capillary walls had local and segmental changes such as thickening and/or irregularity. Electron microscopy revealed dense deposits in the mesangial, paramesangial, subendothelial, subepithelial, and intramembranous areas. The mesangial and paramesangial deposits were most characteristic and prominent. In five of seven pigs, the clusters of extracellular spherical microparticles with a diameter ranging from 25 to 60 nm were observed in the subepithelial, intramembranous, subendothelial, and mesangial areas. No conspicuous lesions were noted in other organs.


Prenatal determinants of childhood obesity: a review of risk factors 1.
Childhood obesity is a predictor of adult obesity and has its roots in the pre-pregnancy or pregnancy period. This review presents an overview of the prenatal risk factors for childhood obesity, which were categorized into 2 groups: biological risk factors (maternal pre-pregnancy body mass index, gestational weight gain, diabetes in pregnancy, and caesarean section), and environmental and behavioural risk factors (maternal smoking and exposure to obesogens, maternal dietary patterns, maternal intestinal microbiome and antibiotics exposure, and maternal psychosocial stress). Identifying modifiable predisposing prenatal factors for obesity will inform further development of inventions to prevent obesity over the life course, and future directions for research and intervention are discussed.


Evidence by peptide mapping that the region CD4(81-92) is involved in gp120/CD4 interaction leading to HIV infection and HIV-induced syncytium formation.
Peptide fragments of the CD4 molecule were compared in their ability to 1) inhibit CD4-dependent HIV-induced cell fusion; 2) inhibit CD4-dependent HIV infection in vitro; and 3) block gp120 envelope glycoprotein binding to CD4. Peptides from the region CD4(81-92), although inactive when underivatized, were equipotent inhibitors of CD4-dependent virus infection, cell fusion, and CD4/gp120 binding when derivatized via benzylation and acetylation. Peptides of identical chemical composition, but altered sequence and derivatization pattern that blocked gp120 binding to either CD4-positive cells or solubilized CD4, also blocked infection and fusion with similar potencies. Those that did not block gp120/CD4 interaction were also inactive in HIV-1 infection and cell fusion assays. No other peptide fragments of the CD4 molecule inhibited fusion, infection, or CD4/gp120 interaction. The peptide CD4(23-56), derived from a region of CD4 implicated in binding of CD4 antibodies that neutralize HIV infection and cell fusion, had no effect on CD4-dependent cell fusion, HIV-1 infection, or CD4/gp120 binding, but did reverse OKT4A and anti-Leu 3a blockade of gp120 binding to CD4. These data provide evidence that the 81-92 region of CD4 is directly involved in gp120 binding leading to CD4-dependent HIV infection and syncytium formation. Previous observations with structural mutants of CD4 suggest that the CDR2-homologous region of CD4 is also involved, either directly or indirectly, in binding of gp120 to CD4. The CDR2- and CDR3-like domains of CD4 may both contribute to the binding of the HIV envelope necessary for HIV-1 infection and HIV-1-induced cell fusion.


WITHDRAWN: A Comparison of Internet Monitoring with Continuous Glucose Monitoring in Insulin-Requiring Type 2 Diabetes Mellitus.
To compare the effects of real-time continuous glucose monitoring (RT-CGM) and an Internet blood glucose monitoring system (IBGMS) on glycated hemoglobin levels in patients with type 2 diabetes mellitus treated with insulin. Fifty-seven patients with type 2 diabetes treated with insulin were assigned randomly to 1 of 2 groups. Group 1 had the results of their self-monitoring of blood glucose level monitored biweekly using an IBGMS. Group 2 used RT-CGM and were monitored biweekly. Both groups used a secure website to upload data and to receive feedback from their endocrinologist. A1C and laboratory test results were collected at 0, 3 and 6 months. The baseline parameters were not significantly different. After a 6-month follow-up period, both IBGMS and RT-CGM showed significant within-group improvements in A1C level. In the IBGMS group, the A1C level decreased from 8.79%±1.25% to 7.96%±1.30% (p<0.05). The RT-CGM group decreased from 8.80%±1.37% to 7.49%±0.70% (p<0.001). IBGMS and RT-CGM did not show significantly different A1C levels at baseline, 3 and 6 months (p>0.05). The use of both IBGMS and RT-CGM significantly improved A1C levels in patients with type 2 diabetes treated with insulin in a randomized trial over a 6-month period. There were no significant differences in A1C values between groups after 6 months.


Cellular effects of gastric electrical stimulation on antral smooth muscle cells in rats.
The cellular effects of gastric electrical stimulation (GES), which has recently been introduced as a potential therapy for the treatment of gastroparesis and obesity, were investigated in rat antrum smooth muscle cells (SMCs). Effects on cell membrane potentials of single electrical current pulses (pulse width from 0.1 ms to 200 ms) and 2-s pulse train stimuli with different pulse widths (0.1-4 ms), different frequencies (20-200 Hz), and different intensities were studied: 1) the stimulus amplitude had an exponential relationship to the pulse width from 2 ms to 200 ms, along with a rapidly rising strength-duration curve at pulse widths less than 5 ms, and a relatively flat curve at pulse widths greater than 50 ms; 2) when the pulse frequency was at 80 Hz or above, pulse train electrical stimulation, with a pulse width of 2 ms or above but not < or = 1 ms, was able to depolarize cell membrane potentials to above -30 mV and/or generate action potentials. Electrical stimulation with a single long pulse and a width of 50 ms or greater is effective in depolarizing cell membrane potentials of SMCs with low amplitude. Pulse train electrical stimulation with a pulse width of < or = 1 ms fails to generate action potentials in SMCs, whereas pulse train electrical stimulation with a pulse width of 2-4 ms and a sufficiently high pulse frequency is able to generate action potentials. These cellular findings may be useful in optimizing stimulation parameters of GES.


Understanding the Connection between Cognitive Impairment and Mobility: What Can Be Gained from Neuropsychological Assessment?
The ability of neuropsychological tests to predict rehabilitation outcome is unclear, particularly when other ratings of cognition are available. Neuropsychological test scores and functional ratings of cognition (Functional Independence Measure (FIM) Cognition score) were used to predict improvement in patient mobility and self-care skill, as measured by the FIM Motor score. Regression models used both raw neuropsychology test scores and age-adjusted scores. Retrospective chart review was performed for patients on an inpatient rehabilitation unit and referred for neuropsychological assessment. The group included 126 subjects (average age 64.2 ± 17.1 years) and a variety of medical diagnoses. Neuropsychological tests included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). After forcing the Admission FIM Cognition score into the model, RBANS scores and duration of rehabilitation predicted FIM Motor improvements (F = 11.42, p < 0.0001). Raw neuropsychological test scores performed better than the model with age-adjusted test scores. FIM Cognition alone did not predict FIM Motor improvements. Neuropsychological tests, combined with duration of rehabilitation, predicted mobility gains for patients undergoing inpatient rehabilitation beyond what was predicted by another, readily available, assessment of cognition. Neuropsychology raw scores performed better than age-adjusted scores, raising questions about the standard use of demographic adjustments for predicting real-world function.


13 C NMR quantification of polyamine syntheses in rat prostate.
Currently, many prostate cancer patients, detected through the prostate specific antigen test, harbor organ-confined indolent disease that cannot be differentiated from aggressive cancer according to clinically and pathologically known measures. Spermine has been considered as an endogenous inhibitor for prostate-confined cancer growth and its expression has shown correlation with prostate cancer growth rates. If established clinically, measurements of spermine bio-synthesis rates in prostates may predict prostate cancer growth and patient outcomes. Using rat models, we tested the feasibility of quantifying spermine bio-synthesis rates with 13 C NMR. Male Copenhagen rats (10 weeks, n = 6) were injected with uniformly 13 C-labeled L-ornithine HCl, and were sacrificed in pairs at 10, 30, and 60 min after injection. Another two rats were injected with saline and sacrificed at 30 min as controls. Prostates were harvested and extracted with perchloric acid and the neutralized solutions were examined by 13 C NMR at 600 MHz. 13 C NMR revealed measurable ornithine, as well as putrescine-spermidine-spermine syntheses in rat prostates, allowing polyamine bio-synthetic and ornithine bio-catabolic rates to be calculated. Our study demonstrated the feasibility of 13 C NMR for measuring bio-synthesis rates of ornithine to spermine enzymatic reactions in rat prostates. The current study established a foundation upon which future investigations of protocols that differentiate prostate cancer growth rates according to the measure of ornithine to spermine bio-synthetic rates may be developed.


High Accuracy Ultrafast Spatiotemporal Pump-Probe Measurement of Electrical Thermal Transport in Thin Film Gold.
A high resolution spatiotemporal ultrafast pump-probe system is developed to examine the interactions and transport phenomena between the electrical and the lattice thermal subsystems during ultrafast laser-matter interactions. This system incorporates an ultrafast pump-probe scheme with a stationary probe beam that interrogates the response to a spatial scanning pump beam, providing a full spatiotemporal mapping of a material's response due to an ultrafast pump excitation. The material's response, which is highly sensitive to its transport properties, is measured with a high spatial accuracy of up to ±10 nm and subpicosecond time resolution. Details of achieving this high spatial accuracy are described, and a study of the ultrafast transport processes in thin film gold is demonstrated. With the aid of transport and optical response models, the electrical thermal transport properties of gold and the electron-lattice coupling constant are simultaneously determined.


Comparative Analysis of the Gut Microbiota of Mongolian Gazelle (Procapra gutturosa) Under Fragmented Habitats.
The existence of man-made facilities such as pasture fences makes the grassland ecosystem fragmented and endangers the survival of local wild animals. The Mongolian gazelle is highly sensitive to hunting and habitat destruction, and is one of the most threatened artiodactyls in Eurasia. It provides a critical model to studying gut microbiota under fragmented habitats. Therefore, we applied metagenomics sequencing to analyze the gut microbiota communities and functions of Mongolian gazelle under fragmented habitats. The results demonstrated that there were no significant differences in gut microbial communities between the different groups at both the phylum and genus level. The functional analyses showed that the Mongolian gazelle in fragmented habitat had a stronger ability to degrade naphthalene, but their ability to absorb carbohydrates was weaker. This study provided fundamental information about the gut microbiota of Mongolian gazelle, and we recommend reducing habitat fragmentation to better protect the Mongolian gazelle.


Lifelong caloric restriction increases working memory in mice.
Caloric restriction (CR) is argued to positively affect general health, longevity and the normally occurring age-related reduction of cognition. This issue is well examined, but most studies investigated the effect of short-term periods of CR. Herein, 4 weeks old female mice were fed caloric restricted for 4, 20 and especially for 74 weeks. CR mice received 60% of food eaten by their ad libitum (AL) fed littermates, and all age-matched groups were behaviorally analyzed. The motor coordination, which was tested by rotarod/accelerod, decreased age-related, but was not influenced by the different periods of CR. In contrast, the age-related impairment of spontaneous locomotor activity and anxiety, both being evaluated by open field and by elevated plus maze test, was found aggravated by a lifelong CR. Measurement of cognitive performance with morris water maze showed that the working memory decreased age-related in AL mice, while a lifelong CR caused a better cognitive performance and resulted in a significantly better spatial memory upon 74 weeks CR feeding. However, a late-onset CR feeding in 66 weeks old mice did not ameliorate the working memory. Therefore, a lifelong CR seems to be necessary to improve working memory.


A Quick Test of Cognitive Speed: patterns of age groups 15 to 95 years.
A Quick Test of Cognitive Speed color, form, and color-form naming were administered to 300 normal participants (ages 15-95 years) to explore the effects of age on perceptual (single-dimension naming) and cognitive speed (dual-dimension naming). Naming time means (sec.) were consistent with previous findings. Correlations between age and naming time were low, but significant. Linear regression with age as a factor indicated time increases of 1 sec. per decade for colors and color-form combination naming and of 6 sec. per decade for form naming. Participants were divided into age cohorts, each covering a decade, and naming times were transformed to normalized z scores. The normalized means were similar for color, form, and color-form naming and increased by about 1 SD between ages 15-25 and 75-85 years. The ranges were similar across cohorts, about 2 SD. The findings concur with age patterns for visual-pattern comparison speed, fluid intelligence, and working memory reported by Salthouse in 2004.


[Analysis of the pregnancy outcomes of 13 723 tubes of sperm specimens from the sperm bank].
To investigate the safety of assisted reproductive technology (ART) with donated sperm from the sperm bank and the differences in the pregnancy outcomes of different means of promoting pregnancy. We analyzed and compared the feedback data on promoting pregnancy with donated sperm from the sperm bank by artificial insemination by donor (AID), in vitro fertilization (IVF), and intracytoplasm sperm injection (ICSI). Totally, 13 723 tubes of sperm specimens were used for ART. The number of specimens used differed in different clinical reproductive centers, some using 1 tube and others using 2 tubes per cycle. The 13 723 tubes were used for a total of 7 743 cycles. Among the 7 123 cycles of AID, there were 1 415 clinical pregnancies (19.87%), 1 221 normal births (86.29%), 169 abortions (11.94%), 6 cases of birth defects (0.43%), 19 ectopic pregnancies (1.34%), and 0 sexually transmitted infection. Among the 571 cycles of IVF, there were 367 clinical pregnancies (64.27%), 330 normal births (89.92%), 35 abortions (9.54%), 0 birth defect, 2 ectopic pregnancies (0.54%), and 0 sexually transmitted infection. Among the 49 cycles of ICSI, there were 28 clinical pregnancies (57.14%), 25 normal births (89.29%), 3 abortions (10.71%), 0 birth defect, 0 ectopic pregnancy, and 0 sexually transmitted infection. There were statistically significant differences in the rate of clinical pregnancy among AID, IVF and ICSI (P < 0.05), but not between IVF and ICSI (P > 0.05), nor were there any significant differences in the rates of abortion, birth defects and ectopic pregnancy among AID, IVF and ICSI (P > 0.05). None of the recipients of the donated sperm from the sperm bank was infected with sexually transmitted diseases. AID, IVF and ICSI showed no significant differences from natural conception in the rates of abortion, birth defects and ectopic pregnancy. ART with donated sperm from the sperm bank is safe. IVF and ICSI are associated with a higher rate of pregnancy than AID, though the latter costs less than the former two.


ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.
Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. GOV: NCT03219164.


Premature termination of transcription can be induced on an injected alpha-tubulin gene in Xenopus oocytes.
The Xenopus laevis alpha-tubulin gene X alpha T14, which is highly expressed during oogenesis, exhibits accurate and efficient transcription initiation when microinjected into X. laevis oocytes. However, we found previously in nuclease protection assays of transcripts from injected X alpha T14 that many protected fragments that were shorter than expected could be produced. We show here by exonuclease VII mapping, Northern (RNA) blotting, and gel fractionation of RNA that these fragments were caused by truncated transcripts that share the same initiation sites as mature transcripts but whose 3' ends are located in the 5' leader just 45 to 72 nucleotides downstream. We present evidence from the analysis of in vitro pulse-labeled RNA that these truncated transcripts are formed by premature transcription termination rather than by RNA processing. At low template levels, very little premature termination occurred, but as more DNA was injected, the proportion of transcripts that were prematurely terminated increased steadily, even at template levels at which the initiation machinery was unsaturated. At high template levels, most transcripts were prematurely terminated. These results suggest that some sort of saturable antitermination function operates in oocytes in a manner that is dependent on the number of appropriate templates available rather than on the number of polymerases that initiate transcription. They also suggest that measures of initiation frequency may not always be a reliable means of assessing the amount of transcription of injected genes in oocytes.


[Serial T2 short inversion time inversion recovery images in a patient with medullary hemorrhage].
A 52-year-old man was admitted to our hospital because of hypesthesia on the right side of his body. He had no medical history. On admission, he exhibited hypesthesia and disturbance of the touch and the vibratory sense on the right side of his body excluding the face. A brain T2* -weighted image revealed the a dot like lesion surrounded by an iso-signal lesion in the medial medulla oblongata. Therefore a diagnosis of medullary hemorrhage was made. Although a vascular malformation was considered as the cause of the hemorrhage, cerebral angiography did not reveal any vascular malformations. After admission, he developed left hypoglossal nerve palsy on day 6, and intractable hiccups on day 11. A T2* -weighted image and a FLAIR image disclosed edema surrounding the hematoma in the medial medullary lesion. T2* weighted images are useful for diagnosing and evaluating serial changes of medullary hemorrhage.


Associated Risk Factors and Diagnostic Value of Fiberoptic Bronchoscopy for Protracted Bacterial Bronchitis in Children.
Untreated protracted bacterial bronchitis (PBB), a chronic wet cough prevalent in children, may lead to chronic suppurative lung disease. However, clinical diagnostic criteria are currently nonspecific; thus, PBB may be misdiagnosed. Thus, we assessed the diagnostic value of fiberoptic bronchoscopy (FOB) and the risk factors associated with PBB. Children with chronic cough at The First Affiliated Hospital of Anhui Medical University from January 2015 to May 2020 were enrolled and allocated to a suspected PBB (n = 141) or a non-PBB (n = 206) group. All children underwent extensive laboratory, chest imaging, and allergen tests. Children with suspected PBB underwent FOB with bronchoalveolar lavage; lavage and sputum samples were cultured. All 347 children had a chronic wet cough for approximately 2 months. Of 141 children with suspected PBB, 140 received FOB with bronchoalveolar lavage. Visible tracheal changes included pale mucosa, mucosal congestion, edema, swelling, and increased secretions attached to the wall. Sputum was visible primarily in the left main bronchus (78.7%), left lower lobe (59.6%), right upper lobe (62.4%), and right lower lobe (64.5%). Sputum properties and amounts significantly differed between children with vs. without PBB (P < 0.05). Dermatophagoides (odds ratio (OR), 2.642; 95% CI, 1.283-5.369), milk protein (OR, 2.452; 95% CI, 1.243-4.836) allergies, and eczema (OR, 1.763; 95% CI, 1.011-3.075) were risk factors significantly associated with PBB. Dermatophagoides, milk protein, and eczema were associated with an increased risk of PBB. Sputum distribution and tracheal wall changes observed through FOB may distinguish PBB and assist in its diagnosis.


Evaluation of a distal pericallosal aneurysm visualized with 3-dimensional digital subtraction angiography: case report and treatment implications.
Digital subtraction angiography (DSA) is considered the gold standard in the evaluation of cerebrovascular structures. Recently, 3-dimensional DSA (3D-DSA) has been increasingly used to obtain detailed information about the morphology and dimensions of intracranial aneurysms. We report the case of a patient who presented with a distal pericallosal artery aneurysm, which appeared by 2D imaging to be a fusiform, possible mycotic aneurysm. This was then revealed to be a saccular bifurcation aneurysm by 3D-DSA. This additional information changed the treatment plan for this patient from medical management to a surgical approach. The patient is a 56-year-old man with a history of hypertension and alcohol abuse with withdrawal seizures, who presented with a large intracranial hemorrhage on initial computed tomography scan. After stabilization with intracranial pressure management, the patient underwent magnetic resonance angiography and 4-vessel DSA. These initial studies showed a distal, fusiform pericallosal aneurysm consistent with a mycotic aneurysm. Rotational DSA was then used to generate 3D images of the structure that revealed a saccular bifurcation aneurysm. This enabled the decision to offer operative treatment rather than conservative medical management. This report highlights the value of 3D-DSA in establishing the appropriate treatment plan for patients with unique cerebral aneurysms. The higher resolution images used in this case provided information that was crucial in shifting the treatment focus from medical management, for what appeared to be a mycotic aneurysm by traditional DSA, to surgical intervention, for a clear hemodynamic aneurysm at a vessel bifurcation seen with 3D-DSA. Accurate pre-interventional evaluation and differential diagnosis are critical to designing the most effective lowest risk treatment plan. The standard method in the diagnosis of cerebral aneurysms has been DSA. Yet, higher resolution images of unclear or high-risk aneurysms are often required to guide clinical decision making. The emergence of new, less invasive endovascular techniques for securing intracranial aneurysms has placed greater emphasis on precisely defining the shape and dimensions of an aneurysm. Three-dimensional DSA is currently the highest resolution imaging modality available for the evaluation of intracranial aneurysms. 3D-DSA was used to evaluate a small, distal pericallosal artery aneurysm and revealed a saccular bifurcation aneurysm not visualized with magnetic resonance angiography and conventional DSA. This additional resolution permitted the team to consider a surgical approach for a patient who would otherwise have been treated medically. This high-resolution technique is particularly useful in guiding clinical decision making in the context of aneurysms that carry a relatively broad differential diagnosis, potentially high interventional risk, and unclear morphology.


Characteristic odor components of Citrus sphaerocarpa Tanaka (Kabosu) cold-pressed peel oil.
The volatile components of Citrus sphaerocarpa Tanaka (Kabosu) cold-pressed peel oil were investigated by chemical and sensory analyses. Monoterpene hydrocarbons (more than 94.6%) were predominant in Kabosu peel oil, with limonene and myrcene accounting for the major proportions (70.5% and 20.2%, respectively). The Kabosu oxygenated fraction was characterized by quantitative abundance in aldehydes and a relatively wide variety of alcohols. The weight percentages of aldehydes, alcohols, and esters in Kabosu cold-pressed oil were 1.3%, 0.1%, and 0.1%, respectively. Aroma extract dilution analysis was employed for determination of the odors of Kabosu volatile components, flavor dilution factors, and relative flavor activities. Gas chromatography/olfactometry using Kabosu cold-pressed oil and its oxygenated fraction completed by a chiral analysis revealed that (R)-(+)-citronellal is a characteristic element of Kabosu peel oil odor. Careful sniff testing demonstrated that aqueous solutions of both 0.25% and 0.016% (R)-(+)-citronellal gave an odor similar to that of Kabosu.


Alternation in mitral valve and septal movements in a patient with pulsus alternans.
In a patient with recent aortic valve replacement, echocardiography, phonocardiography, and external pulse recordings were employed to evaluate a prolonged period of pulsus alternans. Alternation in left ventricular end-diastolic and end-systolic diameters, systolic diameter shortening, diastolic ventricular filling, systolic ejection time and diastolic period (A2Q) were seen. In addition, two features were noted which have not been previously reported: (1) Alternation in the timing of mitral valve motion, such that prior to the weak beats, closure of the mitral valve did not occur until 40-70 msec. after the onset of the Q-wave on the ECG. Before the strong beats, however, mitral closure coincided approximately with the Q-wave. (2) Alternation of the movement of the interventricular septum with abnormal or paradoxical movement during weak beats and normal movement during the strong beats. The first observation lends credence to the theory that stretch-tension relationships are important in the maintenance of pulsus alternans in some patients. The paradoxical septal motion during the weak beats may be due either to a discordant right and left ventricular alternans or alternate contractile defection of the septum.


Perspectives of aging among persons living with chronic obstructive pulmonary disease.
Among pulmonary rehabilitation attendees, we explored their tendency to downplay versus acknowledge physical and psychosocial health limitations, and the subsequent impact either strategy had on how they perceive their own aging process. Participants (N = 87) were 44 to 82 years of age, and diagnosed with chronic obstructive pulmonary disease (COPD). The St. George's Respiratory Questionnaire measured their health limitations. The Attitudes to Aging Questionnaire captured their perspectives of aging. Participants downplayed their symptoms and psychosocial impact, and remained most positive about psychosocial loss and carefully reserved about psychological growth. Acknowledged activity impairment had negative consequences, however, for their perspectives of physical change. These findings signify a balanced identity and perspective of aging that supports the Identity Process Theory. We encourage nurses and other practitioners, and researchers in pulmonary rehabilitation setting, to use this theory to better understand how people with COPD adapt to aging.


Superelastic supercapacitors with high performances during stretching.
A fiber-shaped supercapacitor that can be stretched over 400% is developed by using two aligned carbon nanotube/polyaniline composite sheets as electrodes. A high specific capacitance of approximately 79.4 F g(-1) is well maintained after stretching at a strain of 300% for 5000 cycles or 100.8 F g(-1) after bending for 5000 cycles at a current density of 1 A g(-1). In particular, the high specific capacitance is maintained by 95.8% at a stretching speed as high as 30 mm s(-1).


[Effect of Pranlukast on tissue remodeling in experimental guinea pig allergic rhinitis model].
To explore the impact of Pranlukast in nasal mucosal remodeling in experimental allergic rhinitis. Fourteen male guinea pigs were randomly divided into 3 groups: control group, ovalbumin (OVA) group and OVA + Pranlukast group. In the OVA group and OVA + Pranlukast group, OVA sensitized Hartley guinea pigs were exposured intranasally to OVA for a total of 12 weeks, the OVA + Pranlukast group received additional Pranlukast treatment from the second week to the 12th week. Paraffin embedded sections were stained with hematoxylin and eosin (HE), alcian blue-periodic acid-Schiff (AB-PAS), and Masson's Trichrome (MT). Infiltrating eosinophils, the number of goblet cells in the surface epithelium and gland cells in subepithelial nasal septal mucosa were counted. The damage of epithelium in nasal septum and extracellular matrix of nasal septal mucosa and conchae were determined. Compared with the control, the prolonged OVA exposure protocol caused significant pathological changes in the nasal mucosa, which included eosinophils infiltration into epithelium and submucosa (106.90 +/- 13.66), significant goblet hyperplasia (22.05 +/- 5.81/mm), epithelial damage (intact epithelium: 47.25% +/- 7.67%) and deposition of extracellular matrix. These changes were significantly inhibited by Pranlukast, in which group, there were few eosinophils(8.95 +/- 2.32) , few goblet cells (5.73 +/- 1.07/mm), and relative intact epithelium (intact epithelium: 83.15% +/- 8.05%), and no significant ECM deposition. Early Pranlukast intervention could inhibit nasal mucosal remodeling in allergic rhinitis.


Eigenmodes and symmetry selection mechanisms in circular large-aperture vertical-cavity surface-emitting lasers.
The characteristics of the spatial eigenmodes of vertical-cavity surface-emitting lasers with a large circular aperture are considered close to the lasing threshold. Experiments yield patterns based on rotational symmetry ("flowerlike" patterns) or on Cartesian symmetry (stripelike patterns) for very close operating conditions. The former are compatible with the boundary conditions whereas the latter are expected in infinite devices. Theoretically, the problem is considered in the framework of an eigenmode analysis of a linear partial differential equation for the optical field valid at threshold. This formulation allows for a simple implementation of asymmetries due to the reflection properties of Bragg mirrors as well as of transverse variations of gain and refractive index due to the device structure or due to imperfections in the growth process. A sharp transition between flowerlike modes and stripelike modes is shown to occur, if the device aperture is increased.


Oral health of 12-year-old Bangladeshi children.
Previous dental caries studies in Bangladesh have been performed on non-randomized samples, using various clinical criteria. Estimates of dental caries prevalence in 12-year-olds are therefore uncertain. In the present study a clustered, stratified random sampling procedure was used. Dental caries was stored as DMFT in accordance with the WHO recommendations and related to oral hygiene and various behavioral and social variables. The caries experience was found to be low, with a mean DMFT score of experience was 0.97. Poor oral hygiene and bleeding gingiva were frequently detected. Dental caries associated with sex, oral hygiene (girls), and use of dental services (more caries among frequent users than non-users). A Correlation matrix analyzing the most influential independent variables indicated that sex and oral hygiene seemed to have an independent effect, whereas a web of social factors interfered with the use of dental services' variable.


Updates in Robotic Head and Neck Reconstructive Surgery.
The use of robotics in head and neck surgery has drastically increased over the past two decades. Transoral robotic surgery has revolutionized the surgical approach to the upper aerodigestive tract including the oropharynx and supraglottic larynx. The expanded use and improving technology of robotics have allowed for new approaches in both the ablative and reconstructive aspects of head and neck surgery. Here, we discuss the recent updates in robotics in head and neck surgery and future directions the field may turn.


[Comparison whole-body muscle mass assessed by dual-energy X-ray absorptiometry and multi-frequency bioelectrical impedance in overweight and obese adults].
Objective: To investigate consistency of whole-body muscle mass (WBMM) assessed using multi-frequency bioelectrical impedance analysis (MF-BIA) and dual energy X-ray Absorptiometry (DXA) measurement, and to delvelop the correction regression formulas for the method of MF-BIA. Methods: 1 488 participants who resided in Beijing longer than one year, under 22 to 55 years of age, with self-report BMI ≥24 kg/m(2) were voluntarily recruited based on convenience sampling in Beijing, from April 1(st) 2014 to May 2(nd) 2014. After excluded 171 participants who BMI ≤24 kg/m(2) or with organic diseases when physical examination, Finally 1 317 overweight/obese participants were enrolled into the current study. All the subjects received the measurement of WBMM using both MF-BIA and DXA methods. The paired-samples T test was used to compare the difference of measurement values between MF-BIA and DXA methods. We evaluated the agreement of WBMM measured by MF-BIA and DXA using the interclass correlation coefficients (ICC) and the Bland-Altman plots, and using linear regression method established correction regression formulas. Results: The differences of overweight male, obese male, overweight female, and obese female were (3.29 ± 1.94), (2.05 ± 2.65), (0.17 ± 1.85), and (-2.22 ± 2.89) kg between methods of MF-BIA and DXA, respectively; Except the overweight female, the others groups had the statistically significant difference (P<0.05). The ICC for overweight male, obese male, overweight female, and obese female were 0.958, 0.956, 0.911, and 0.851, respectively (P<0.001). Bland-Altman plots showed that the limit of agreement for four groups were -0.51-7.09, -3.14-7.24, -3.46-3.80, and -7.88-3.44 kg, respectively. Correction regression formulas: overweight male population: y(DXA)=-0.648+ 0.952 x(MF-BIA); obese male population: y(DXA)=-3.646 + 1.026x(MF-BIA); overweight female groups: y(DXA)=-4.800 + 1.117 x(MF-BIA); obese female group: y(DXA)=-9.884+ 1.287x(MF-BIA). Conclusion: The correlation and agreement of WBMM measured by the methods of BIA and DXA were relative weak in Chinese excess weight male and obese female adults. Therefore, measuring WBMM by MF-BIA method in these adults should be corrected to reduce bias compared with the DXA method.


Current diagnosis and treatment of oligodendroglioma.
The strategies used to diagnose and treat oligodendroglial tumors have changed significantly over the past decade. The purpose of this paper is to review the topic of oligodendroglioma, emphasizing the new developments. Information was obtained by conducting a Medline search in which the term oligodendroglioma was used. Recent editions of standard textbooks were also studied. Because of tools such as magnetic resonance imaging, oligodendrogliomas are being diagnosed earlier, and they are being recognized more frequently histologically than in the past. Seizures are common in these patients. Functional mapping and image-guided surgery may now allow for a safer and more complete resection, especially when tumors are located in difficult areas. Genetic analysis and positron emission tomography may provide data that supplement the standard diagnostic tools. Unlike other low-grade gliomas, patients in whom residual or recurrent oligodendroglioma (World Health Organization Grade II) is present may respond to chemotherapy. Although postoperative radiotherapy prolongs survival of the patient, increasingly this therapeutic modality is being delayed until tumor recurrence, especially if a gross-total tumor resection has been achieved. Oligodendrogliomas are the first type of brain tumor for which "molecular" characterization gives important information. The most significant finding is that allelic losses on chromosomes 1p and 19q indicate a favorable response to chemotherapy. Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted, primarily because of the lesion's relative chemosensitivity. Molecular characterization of oligodendrogliomas may become a standard practice in the near future.


Induction of tumor cell death by high hydrostatic pressure as a novel supporting technique in orthopedic surgery.
As vegetative forms of microorganisms are impaired by high hydrostatic pressure (HHP) in the range of 400-600 MPa, the non-thermal inactivation of vegetative bacteria, yeasts, and moulds present in foods such as jams, fruit juices, and dressings by HHP is now well-established. Eukaryotic cells, when subjected to HHP are also damaged. In the present study, the effect of HHP on cell viability of human osteoblasts (HOB), human fibroblasts (HFB), and different tumor cell lines such as osteosarcoma cells SAOS-2, human histiocytic leukemia cells U-937, and the ovarian cancer cell line OV-MZ-6 was investigated. Therefore the different cell lines were subjected to pressures between 50 and 400 MPa and tested for viability. At HHP of 100 MPa (10 min) about 80% of the various cell lines were still alive. At 350 MPa all of the cells were damaged and dead. The three tumor cell lines investigated were slightly more resistant to HHP (50% dead at 170-193 MPa) than HOB and HFB (50% dead at 130-145 MPa). The present study demonstrates that both normal cells and tumor cells are rapidly inactivated by HHP treatment.


Exposure to cobalt causes transcriptomic and proteomic changes in two rat liver derived cell lines.
Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.


Two structural relaxations in protein hydration water and their dynamic crossovers.
We study the translational single particle dynamics of hydration water of lysozyme upon cooling by means of molecular dynamics simulations. We find that water close to the protein exhibits two distinct relaxations. By characterizing their behavior upon cooling, we are able to assign the first relaxation to the structural α-relaxation also present in bulk water and in other glass-forming liquids. The second, slower, relaxation can be ascribed to a dynamic coupling of hydration water motions to the fluctuations of the protein structure. Both relaxation times exhibit crossovers in the behavior upon cooling. For the α-process, we find upon cooling a crossover from a fragile behavior to a strong behavior at a temperature which is about five degrees higher than that of bulk water. The long-relaxation time appears strictly connected to the protein motion as it shows upon cooling a temperature crossover from a strong behavior with a lower activation energy to a strong behavior with a higher activation energy. The crossover temperature coincides with the temperature of the protein dynamical transition. These findings can help experimentalists to disentangle the different information coming from total correlators and to better characterize hydration water relaxations in different biomolecules.


Human wastewater tracking in tropical Hawaiian island streams using qualitative and quantitative assessments of combined fecal indicating bacteria and sucralose, an organic micropollutant of emerging concern.
Prevalence of cesspools on tropical islands suggests that high concentrations of enteric bacteria in streams and coastal waters are an indicator of groundwater contamination by human wastewater. But enterococci bacteria may also be from homeothermic animals common to these watersheds or bacteria living in sediments. Sucralose, a manufactured chemical not destroyed in passage through the human gut, cesspools, septic systems, or wastewater treatment facilities, was used to test for the presence of human wastewater in streams on the island of Kauai, Hawaii. Effluent from six municipal wastewater treatment plants showed an average concentration of 39,167 ng/L of sucralose, roughly back-calculated to 9 ng/L per person, enough to present itself in cesspool effluent contaminated waters. Of 24 streams tested, 79% were positive for sucralose at least once in four sets of sampling. All streams tested positive for enterococci bacteria above established standards. Serial testing of the pair of indicators in the same location over time and applying the Multiplication Rule to the independent samples provide a probabilistic certainty level that the water is chronically polluted by human waste. When repeatedly paired with tests for enterococci, sucralose testing is a cost-effective means for assessing human health risk and for developing proper waste management programs that has been underutilized in under-developed tropical and island settings.


[Pigmentary orthochromatic leukodystrophy. Van Bogaert and Nyssen disease].
A 43 year old woman with a strong likelihood of familial history, developed progressively a spastic tetraparesis associated with intellectual deterioration and terminal epileptic fits. She died 11 years after onset of the clinical disorders. Neuropathological study revealed an orthochromatic leukodystrophy. Macrophages and glial cells of the white matter contained a brown-yellow, autofluorescent pigment which stained positively with PAS, Perls stain for iron and Masson-Fontana. Electron microscopy showed electron dense, membrane bound intracytoplasmic lamellar inclusions with curved or straight parallel arrangement or fingerprint pattern, in white matter macrophages, astrocytes and oligodendrocytes. Cortical cells contained lipofuscin which was normal in type and amount. This suggests that the material in white matter glial cells and macrophages is ceroid pigment; however, the distribution is not that seen in ceroid-lipofuscinosis. Similar inclusions have been found in oligodentrocytes in other forms of orthochromatic leucodystrophy. Ten similar cases of pigmentary type of orthochromatic leucodystrophy have been reported previously; only one had had an ultrastructural study.


[The Choay domain -- the structure responsible for the anticoagulant action of heparins].
We describe the common structural basis for the anticoagulant action of the many different heparins available to the clinician. From different types of heparin we prepared fractions of virtually single molecular weight. We determined the molar concentration of material (HAM) containing the antithrombin (AT) binding pentasaccharide (A-domain), the specific catalytic activity in thrombin- and factor Xa inactivation and the capacity to inhibit thrombin generation (TG). We also calculated the molar concentration of A-domain with 12 sugar units at its non-reducing end, i.e. the structure that carries anti-thrombin activity (Choay- or C-domain). The anti-thrombin activity and the effects on TG are determined by the concentration of C-domain and independent of the source material or Mr. High Mr fractions (> 15,000) are less active, probably through interaction with non-AT plasma proteins. Anti-factor Xa activity is not indicative of anticoagulant potency but is a sensitive indicator of Mr and therefore predicts favourable pharmacokinetic properties: long half-life in the circulation and high bioavailability.


Utility of Minimal Physiologically Based Pharmacokinetic Models for Assessing Fractional Distribution, Oral Absorption, and Series-Compartment Models of Hepatic Clearance.
Minimal physiologically based pharmacokinetic (mPBPK) models are physiologically relevant, require less information than full PBPK models, and offer flexibility in pharmacokinetics (PK). The well-stirred hepatic model (WSM) is commonly used in PBPK, whereas the more plausible dispersion model (DM) poses computational complexities. The series-compartment model (SCM) mimics the DM but is easier to operate. This work implements the SCM and mPBPK models for assessing fractional tissue distribution, oral absorption, and hepatic clearance using literature-reported blood and liver concentration-time data in rats for compounds mainly cleared by the liver. Further handled were various complexities, including nonlinear hepatic binding and metabolism, differing absorption kinetics, and sites of administration. The SCM containing one to five (n) liver subcompartments yields similar fittings and provides comparable estimates for hepatic extraction ratio (ER), prehepatic availability (Fg ), and first-order absorption rate constants (ka ). However, they produce decreased intrinsic clearances (CLint ) and liver-to-plasma partition coefficients (Kph ) with increasing n as expected. Model simulations demonstrated changes in intravenous and oral PK profiles with alterations in Kph and ka and with hepatic metabolic zonation. The permeability (PAMPA P) of the various compounds well explained the fitted fractional distribution (fd ) parameters. The SCM and mPBPK models offer advantages in distinguishing systemic, extrahepatic, and hepatic clearances. The SCM allows for incorporation of liver zonation and is useful in assessing changes in internal concentration gradients potentially masked by similar blood PK profiles. Improved assessment of intraorgan drug concentrations may offer insights into active moieties driving metabolism, biliary excretion, pharmacodynamics, and hepatic toxicity. SIGNIFICANCE STATEMENT: The minimal physiologically based pharmacokinetic model and the series-compartment model are useful in assessing oral absorption and hepatic clearance. They add flexibility in accounting for various drug- or system-specific complexities, including fractional distribution, nonlinear binding and saturable hepatic metabolism, and hepatic zonation. These models can offer improved insights into the intraorgan concentrations that reflect physiologically active moieties often driving disposition, pharmacodynamics, and toxicity.


Acoustic analysis in stuttering: a machine-learning study.
Stuttering is a childhood-onset neurodevelopmental disorder affecting speech fluency. The diagnosis and clinical management of stuttering is currently based on perceptual examination and clinical scales. Standardized techniques for acoustic analysis have prompted promising results for the objective assessment of dysfluency in people with stuttering (PWS). We assessed objectively and automatically voice in stuttering, through artificial intelligence (i.e., the support vector machine - SVM classifier). We also investigated the age-related changes affecting voice in stutterers, and verified the relevance of specific speech tasks for the objective and automatic assessment of stuttering. Fifty-three PWS (20 children, 33 younger adults) and 71 age-/gender-matched controls (31 children, 40 younger adults) were recruited. Clinical data were assessed through clinical scales. The voluntary and sustained emission of a vowel and two sentences were recorded through smartphones. Audio samples were analyzed using a dedicated machine-learning algorithm, the SVM to compare PWS and controls, both children and younger adults. The receiver operating characteristic (ROC) curves were calculated for a description of the accuracy, for all comparisons. The likelihood ratio (LR), was calculated for each PWS during all speech tasks, for clinical-instrumental correlations, by using an artificial neural network (ANN). Acoustic analysis based on machine-learning algorithm objectively and automatically discriminated between the overall cohort of PWS and controls with high accuracy (88%). Also, physiologic ageing crucially influenced stuttering as demonstrated by the high accuracy (92%) of machine-learning analysis when classifying children and younger adults PWS. The diagnostic accuracies achieved by machine-learning analysis were comparable for each speech task. The significant clinical-instrumental correlations between LRs and clinical scales supported the biological plausibility of our findings. Acoustic analysis based on artificial intelligence (SVM) represents a reliable tool for the objective and automatic recognition of stuttering and its relationship with physiologic ageing. The accuracy of the automatic classification is high and independent of the speech task. Machine-learning analysis would help clinicians in the objective diagnosis and clinical management of stuttering. The digital collection of audio samples here achieved through smartphones would promote the future application of the technique in a telemedicine context (home environment).


Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.
Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS), immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients.


Soluble PD1 levels are increased with disease activity in paediatric onset autoimmune hepatitis and inflammatory bowel disease.
Introduction: Immune mediated liver diseases entail a broad category which are associated with increased morbidity and mortality amongst the paediatric population. Programmed Death 1 (PD1) is an inhibitory receptor mainly expressed by T cells, and when activated shed into plasma as soluble PD1(sPD1). The AIM of this study was to evaluate sPD1 levels in plasma of paediatric patients with Autoimmune Hepatitis (AIH), Primary Sclerosing Cholangitis (PSC), AIH and PSC overlap, Inflammatory Bowel Disease (IBD) alone, and concurrent PSC/IBD and AIH/IBD in order to identify a biomarker to response or predict relapse verses remission.Methods: Plasma samples were collected from 41 paediatric patients. AIH patients were further categorized into active, incomplete responders and responders, based on response to standard therapy. sPD1 levels were measured and compared between PSC, PSC/AIH, IBD alone, PSC/IBD and AIH/IBD patients and between active AIH, incomplete responders and responders. Flow cytometry was performed to further analyze CD45RA+, CD3CD4, CD8, CCR7, CXCR3, CD38 and PD1.Results: In the AIH group, those with active disease demonstrated a significantly higher sPD1 levels in comparison to responders (*p > .001). However, the incomplete responders didn't show a reduction in sPD1 in comparison to active AIH and patients with IBD alone. Interestingly, patients with PSC showed significantly lower level of sPD1 compared to active AIH (*p < .002), whereas, patients with PSC in conjunction with AIH (*p < .006) or IBD (*p < .02) demonstrated a significant increase in sPD1. In addition, we have observed increased levels of circulating CD4 and CD8 bound PD1 in active AIH but not in PSC or responders suggesting T cells activation. CD4+ PD1 double positive cells demonstrated increased expression of CXCR3. Thus, suggesting the activation of PD1 + T cells is mediating through CXCR3 in Autoimmune hepatitis.Conclusions: Our study demonstrates that sPD1 levels correlate with active disease state of AIH and IBD. sPD1 levels did not correlate with PSC. However, PSC in conjunction with AIH or IBD showed higher levels of sPD1. This suggests that T cell activation plays a critical role in active AIH and IBD but not in PSC. Soluble PDI levels could be used as a clinical biomarker to assess response in patients with AIH and for prospectively monitoring PSC patients for development of IBD or AIH.


Antiatherosclerotic Effect of Canarium odontophyllum Miq. Fruit Parts in Rabbits Fed High Cholesterol Diet.
The effect of C. odontophyllum (CO) fruit parts was investigated in hypercholesterolemic rabbits. Forty-nine rabbits, which were randomly divided into seven groups of seven animals (n = 7), received a diet containing different parts of CO fruit parts for 8 weeks. The groups were as follows: (1) normal diet: NC group and (2) hypercholesterolemic diet: PC, HS (10 mg/kg/day simvastatin), HPO (20 g kg(-1) oil extracted from the pulp of CO), HKO (20 g kg(-1) oil extracted from the kernel of CO), HF (50 g kg(-1) fullfat pulp of CO), and HD (50 g kg(-1) defatted pulp of CO). Among these groups, rabbits receiving defatted pulp of CO showed the greatest cholesterol lowering effect as it had reduced plasma LDL-C, TC, and thiobarbiturate reactive substance (TBARS) levels as well as atherosclerotic plaques. The presence of high dietary fiber and antioxidants activity are potential factors contributing to the cholesterol lowering effect. Consequently, these results indicate the potential use of CO defatted pulp as a cholesterol lowering and antioxidant agent.


Insulin-mediated suppression of apolipoprotein B mRNA translation requires the 5' UTR and is characterized by decreased binding of an insulin-sensitive 110-kDa 5' UTR RNA-binding protein.
Insulin has been shown to acutely regulate hepatic apolipoprotein B (apoB) secretion at both translational and post-translational levels; however, mechanisms of apoB mRNA translational control are largely unknown. Recent studies of apoB untranslated regions (UTRs) revealed a potentially important role for cis-trans interactions at the 5' and 3' UTRs. In the present paper, deletion constructs of the UTR regions of apoB revealed that the 5' UTR was necessary and sufficient for insulin to inhibit synthesis of apoB15. Metabolic radiolabeling and in vitro translation experiments in the presence of protease inhibitors confirmed that the effect of insulin on the apoB 5' UTR was translational in nature. Using the nondenaturing electrophoretic mobility shift assay (EMSA), protein-RNA complexes were detected binding to the apoB 5' and 3' UTRs. Denaturing EMSA identified a 110-kDa protein interacting at the 5' UTR. Nondenaturing EMSA determined that insulin altered binding of large protein complexes to the 5' UTR. Binding specificity was determined by competition with both specific and nonspecific competitors. Insulin treatment decreased binding of the 110-kDa protein to the 5' UTR as visualized by EMSA. Absence of insulin increased binding of this trans-acting factor to the 5' UTR by 2-fold. Analysis of the 3' UTR showed no significant insulin-mediated changes in binding of trans-acting factors. We thus propose the existence of a novel RNA-binding insulin-sensitive factor that binds to the 5' UTR and may regulate apoB mRNA translation. Perturbations in hepatic insulin signaling as observed in insulin-resistant states may alter cis-trans interactions at the 5' UTR, leading to alterations in the rate of apoB mRNA translation, thus contributing to apoB-lipoprotein overproduction.