The effect of novel chromosome position and variable dose on the genetic behavior of the Responder (Rsp) element of the Segregation distorter (SD) system of Drosophila melanogaster.
In the Segregation distorter (SD) system of meiotic drive, a minimum of two trans-acting elements [Sd and E(SD)] act in concert to cause a certain probability of dysfunction for sperm carrying a sensitive allele at the Responder (Rsp) target locus. By employing a number of insertional translocations of autosomal material into the long arm of the Y chromosome, Rsp can be mapped as the most proximal locus in the 2R heterochromatin as defined both by cytology and lethal complementation tests. Several of these insertional translocations result in the transposition of Rsp to the Y chromosome, where its sensitivity remains virtually unaltered. This argues that Rsp is separable from the second chromosome centromere, that its behavior does not depend on its gross chromosomal position, and that meiotic pairing of the chromosomes carrying the various SD elements is not a prerequisite for sperm dysfunction. Several other translocations apparently leave both resulting chromosomes at least partially sensitive to SD action, suggesting that Rsp is a large subdivisible genetic element. This view is compatible with observations published elsewhere that suggest that Rsp is a cytologically large region of highly repetitive AT-rich DNA. The availability of Y-linked copies of Rsp also allows the construction of SD males carrying two independently segregating Rsp alleles; this in turn allows the production of sperm with zero, one or two Rsp copies from the same male. Examination of the relative recovery proportions of progeny arising from these gametes suggests that sperm with two Rsp copies survive at much lower frequencies than would be predicted if each Rsp acted independently in causing sperm dysfunction. Possible explanations for such behavior are discussed.


Genetic variants in frizzled-related protein (FRZB) and the risk of colorectal neoplasia.
The Wnt/APC/beta-catenin signaling pathway, which includes frizzled-related protein (FRZB), plays a critical role in the development of colorectal cancer, and recent evidence suggests that the functional polymorphism, FRZB Arg324Gly, may be associated with risk for this disease. To determine if this finding could be replicated, we investigated the association between two FRZB polymorphisms (Arg324Gly and Arg200Trp) and the risk of colorectal adenoma and cancer in nested case-control studies. Participants consisted of 1,709 adenoma cases, 620 cancer cases, and 1,849 controls within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations with colorectal neoplasia. No association was observed for either polymorphism or any haplotypes with colorectal adenoma or colorectal cancer (p>0.05 for all). Our study does not support the previously observed association between the FRZB 324Gly variant and colorectal cancer risk. However, further study of additional genetic variants within this pathway is still warranted, given the important role of the Wnt signaling pathway in colorectal carcinogenesis.


Decisions about life-sustaining measures in children: in whose best interests?
As the community of physicians and nurses dedicated to the care of critically ill children has gained ever more well-developed skill sets, the decision to either continue or forego life-sustaining measures has become less time-sensitive. As a result, there is greater opportunity for careful consideration and discussion. The core principle in making decisions about whether to continue or forego life-sustaining measures is the best interests of the child. However, there are many clinical situations wherein factors other than the child's best interests may influence treatment decisions. The present report seeks to examine the notion that in the arena of paediatric critical care medicine, the decision-making process regarding life-sustaining measures may place insufficient priority upon the child's best interests. We examine actual, de-identified clinical situations, encountered in the critical care arena in two categories: (i) cases that challenge the imperative to act in the child's best interests, and (ii) cases that compromise the ability of parents and caregivers to use child-centred, best-interests approaches to decision-making. Clarity surrounding the implications of a clinical decision for the patient is essential. Decisions that are not focused squarely on the child's best interests may compromise the delivery of optimally ethical end-of-life care. The cases and analysis may benefit parents and caregivers as they struggle with the difficult ethical issues that accompany decisions to continue or forego life-sustaining measures in children.


Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition.
As the outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Hubei Province, China, at the end of 2019. It has brought great challenges and harms to global public health. SARS-CoV-2 mainly affects the lungs and is mainly manifested as pulmonary disease. However, one of the biggest crises arises from the emergence of COVID-19-induced fibrosis. At present, there are still many questions about how COVID-19 induced pulmonary fibrosis (PF) occurs and how to treat and regulate its long-term effects. In addition, as an important process of fibrosis, the effect of COVID-19 on epithelial-mesenchymal transition (EMT) may be an important factor driving PF. This review summarizes the main pathogenesis and treatment mechanisms of COVID-19 related to PF. Starting with the basic mechanisms of PF, such as EMT, transforming growth factor-β (TGF-β), fibroblasts and myofibroblasts, inflammation, macrophages, innate lymphoid cells, matrix metalloproteinases and tissue inhibitors of metalloproteinases, hedgehog pathway as well as Notch signaling. Further, we highlight the importance of COVID-19-induced EMT in the process of PF and provide an overview of the related molecular mechanisms, which will facilitate future research to propose new clinical therapeutic solutions for the treatment of COVID-19-induced PF.


Vernier acuity with opposite-contrast stimuli.
Vernier acuity has usually been tested with stimuli of the same contrast polarity (SC). This traditional vernier acuity was compared to that obtained with stimuli of opposite-contrast (OC) in which one target was brighter than the background and the other was darker. For both bar and dot targets vernier acuity with OC stimuli was about half as good as with SC stimuli. There were large individual differences in the size of the disadvantage with OC stimuli, although thresholds remained within the hyperacuity range. There were also individually-differing biases to see a dark vernier stimulus on one or the other side of a bright stimulus. Differences between OC and SC vernier acuities persisted over a wide range of interstimulus spacings, widths, and contrasts. At extremes of these spatial manipulations acuities became similar, but only because SC acuities were degraded to the level of OC acuities. Subjects showed little improvement in OC vernier acuity, even after 50,000 trials. It is concluded that finest judgements of spatial position arise in a level of the visual system at which light and dark stimuli are treated independently.


Structures of mixed manganese ruthenium oxides (Mn1-xRux)O2 crystallised under acidic hydrothermal conditions.
A synthesis method for the preparation of mixed manganese-ruthenium oxides is presented along with a detailed characterisation of the solids produced. The use of 1 M aqueous sulfuric acid mediates the redox reaction between KRuO4, KMnO4 and Mn2+ to form ternary oxides. At reaction temperature of 100 °C the products are mixtures of α-MnO2 (hollandite-type) and β-MnO2 (rutile-type), with some evidence of Ru incorporation in each from their expanded unit cell volumes. At reaction temperature of 200 °C solid-solutions β-Mn1-xRuxO2 are formed and materials with x ≤ 0.6 have been studied. The amount of Ru included in the oxide is greater than expected from the ratio of metals used in the synthesis, as determined by elemental analysis, implying that some Mn remains unreacted in solution. Powder X-ray diffraction (XRD) shows that while the unit cell volume expands in a linear manner, following Vegard's law, the tetragonal lattice parameters, and the a/c ratio, do not follow the extrapolated trends: this anisotropic behaviour is consistent with the different local coordination of the metals in the end members. Powder XRD patterns show increased peak broadening with increasing ruthenium content, which is corroborated by electron microscopy that shows nanocrystalline material. X-ray absorption near-edge spectra show that the average oxidation state of Mn in the solid solutions is reduced below +4 while that of Ru is increased above +4, suggesting some redistribution of charge. Analysis of the extended X-ray absorption fine structure provides complementary local structural information, confirming the formation of a solid solution, while X-ray photoelectron spectroscopy shows that the surface oxidation states of both Ru and Mn are on average lower than +4, suggesting a disordered surface layer may be present in the materials.


Four Cases of Coronavirus Disease 2019 Transferred from a Cruise Ship.
An outbreak of coronavirus disease 2019 (COVID-19) that began in Wuhan, China, has spread rapidly to many countries. We herein report four cases of COVID-19 confirmed in Japan among passengers of the cruise ship Diamond Princess and describe the clinical features, clinical course, and progression of chest computed tomographic images, chest radiographs, and treatment. Although these four patients had symptoms that included a fever, malaise, runny nose, and cough, one patient had no symptoms on admission. Two of the four patients needed mechanical ventilation due to respiratory deterioration. One of the patients who required mechanical ventilation was transferred to a higher-level medical institution. Except for that patient, the other three patients were able to return home under their own power. Every patient took lopinavir/ritonavir, which was considered the most effective treatment at the time. We used it after receiving approval from the ethics committee in our hospital. In this case report, we emphasize that some patients need to be carefully monitored, even if their respiratory condition is stable at the initial presentation, as their respiratory status may deteriorate rapidly within a few days after oxygen administration begins.


Phase separation of comb polymer nanocomposite melts.
In this work, the spinodal phase demixing of branched comb polymer nanocomposite (PNC) melts is systematically investigated using the polymer reference interaction site model (PRISM) theory. To verify the reliability of the present method in characterizing the phase behavior of comb PNCs, the intermolecular correlation functions of the system for nonzero particle volume fractions are compared with our molecular dynamics simulation data. After verifying the model and discussing the structure of the comb PNCs in the dilute nanoparticle limit, the interference among the side chain number, side chain length, nanoparticle-monomer size ratio and attractive interactions between the comb polymer and nanoparticles in spinodal demixing curves is analyzed and discussed in detail. The results predict two kinds of distinct phase separation behaviors. One is called classic fluid phase boundary, which is mediated by the entropic depletion attraction and contact aggregation of nanoparticles at relatively low nanoparticle-monomer attraction strength. The second demixing transition occurs at relatively high attraction strength and involves the formation of an equilibrium physical network phase with local bridging of nanoparticles. The phase boundaries are found to be sensitive to the side chain number, side chain length, nanoparticle-monomer size ratio and attractive interactions. As the side chain length is fixed, the side chain number has a large effect on the phase behavior of comb PNCs; with increasing side chain number, the miscibility window first widens and then shrinks. When the side chain number is lower than a threshold value, the phase boundaries undergo a process from enlarging the miscibility window to narrowing as side chain length increases. Once the side chain number overtakes this threshold value, the phase boundary shifts towards less miscibility. With increasing nanoparticle-monomer size ratio, a crossover of particle size occurs, above which the phase separation is consistent with that of chain PNCs. The miscibility window for this condition gradually narrows while the other parameters of the PNCs system are held constant. These results indicate that the present PRISM theory can give molecular-level details of the underlying mechanisms of the comb PNCs. It is hoped that the results can be used to provide useful guidance for the future design control of novel, thermodynamically stable comb PNCs.


The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits.
Nuclear receptors (NRs) are transcription factors that regulate essential biological processes in response to cognate ligands. An important part of NR function involves ligand-induced conformational changes that recruit coregulator proteins to the activation function surface (AFS), ~15 Å away from the ligand-binding pocket. Ligands must communicate with the AFS to recruit appropriate coregulators and elicit different transcriptional outcomes, but this communication is poorly understood. These studies illuminate allosteric communication networks underlying activation of liver receptor homolog-1 (LRH-1), a NR that regulates development, metabolism, cancer progression, and intestinal inflammation. Using >100 μs of all-atom molecular dynamics simulations involving 74 LRH-1 complexes, we identify distinct signaling circuits used by active and inactive ligands for AFS communication. Inactive ligands communicate via strong, coordinated motions along paths through the receptor to the AFS. Activating ligands disrupt the "inactive" circuit and induce connectivity with a second allosteric site. Ligand-contacting residues in helix 7 help mediate the switch between circuits, suggesting new avenues for developing LRH-1-targeted therapeutics. We also elucidate aspects of coregulator signaling, showing that localized, destabilizing fluctuations are induced by inappropriate ligand-coregulator pairings. These studies have uncovered novel features of LRH-1 allostery, and the quantitative approach used to analyze many simulations provides a framework to study allosteric signaling in other receptors.


Sex-Biased Dispersal Obscures Species Boundaries in Integrative Species Delimitation Approaches.
Accurate delimitation of species is crucial for a stable taxonomy, which provides the foundation for the study of evolutionary biology, ecology, and essentially all biological disciplines. Several approaches toward impartial and repeatable taxonomic practices are available but all existing methods have potentially unacceptable shortcomings. In particular, problems can arise when the underlying model assumptions are violated, for instance, in the presence of reduced gene flow. This is observed in the context of sex-biased dispersal, which is a common but underappreciated feature in many groups of organisms. Previously, simulations have indicated that sex-biased dispersal may lead to erroneous estimations of the true species numbers. However, this phenomenon has never been examined using empirical data. We evaluate the bias introduced by extreme female philopatry on a range of de novo [GMYC, PTP, ABGD, statistical parsimony, trinomial distribution of triplets model (tr2)] and validation (STACEY, iBPP) approaches to species delimitation in the scarab beetle genus Pachypus. Since female philopatry exhibited in this genus in particular can affect mitochondrial gene flow, we compared the results from analyses of single loci, mitochondrial loci, nuclear loci and combined data, as well as the performance of morphometric data as a secondary data source in a fully integrative Bayesian framework. Large overestimation of species numbers was observed across all analyses of combined and mitochondrial DNA data sets, suggesting specimens from nearly every sampling location as separate species. The use of nuclear data resulted in more reasonable estimations of species boundaries, which were largely supported by morphometrics of linear measurements, while geometric morphometrics of body outlines resulted in stronger splitting. Simulations of population divergence with migration, corresponding to the biology of Pachypus, showed that female philopatry strongly increases reciprocal monophyly of mitochondrial markers and may substantially contribute to over-splitting in species delimitation. Robust results recovered using nuclear DNA and morphological data nevertheless enabled us to reach novel conclusions about species boundaries in Pachypus. Our findings suggest that mitochondrial DNA will be less suited to species delimitation in many cases, in particular in the presence of sex-biased dispersal.


Posttransplant survival in pediatric fulminant hepatic failure: the SPLIT experience.
Pediatric patients with fulminant hepatic failure (FHF) tend to be the sickest and have the most urgent need for a liver transplant. The purpose of this analysis was to identify factors associated with posttransplant survival in this subset of patients. Data on all FHF patients registered in the Studies of Pediatric Liver Transplantation (SPLIT) registry from 1995 to 2002 were analyzed. Demographics such as age, gender, race, weight, and etiology of liver disease were recorded. Pretransplant degree of encephalopathy; intubation; dialysis; laboratory parameters such as serum bilirubin and international normalized ratio of coagulopathy (INR); and type of graft: cadaveric whole, cadaveric technical variant, or living donor were analyzed to determine effects on patient survival. Overall, FHF accounted for 12.9% (141 / 1,092) of primary transplants performed between 1995 and 2002. The etiology of liver disease was unknown in the vast majority of children (126 / 141; 89.4%). Mortality while on the waiting list for FHF children is significantly higher than for children with other liver disease (P < .0001). Six-month survival posttransplant for patients with FHF (74.5%) is significantly lower (P < .0001) than those with chronic liver disease (88.9%). A multivariate model demonstrates that the highest risk group includes those children with grade 4 encephalopathy (P < .0001), infants less than 1 year of age (P = .018), and children requiring dialysis prior to transplantation (P = .002). Pretransplant bilirubin and INR were not significant predictors of posttransplant survival after controlling for the other significant factors. Living donor and split / reduced grafts did not have a significantly increased risk of posttransplant death compared to whole grafts. In conclusion, despite advances in the surgical techniques and changes in organ allocation, pediatric patients with FHF continue to have a high pretransplant mortality and less successful posttransplant survival compared to children with chronic liver disease.


Dynamics of NF kappa B and Ikappa Balpha studied with green fluorescent protein (GFP) fusion proteins. Investigation of GFP-p65 binding to DNa by fluorescence resonance energy transfer.
We investigated the dynamics of nuclear transcription factor kappaB (NF-kappaB) by using fusion proteins of the p65 subunit with mutants of green fluorescent protein (GFP). GFP-NF-kappaB chimeras were functional both in vitro and in vivo, as demonstrated by electrophoretic mobility shift assays and reporter gene studies. GFP-p65 was regulated by IkappaBalpha similar to wild type p65 and associated with its inhibitor even if both proteins were linked to a GFP protein. This finding was also verified by fluorescence resonance energy transfer (FRET) microscopy and studies showing mutual regulation of the intracellular localization of both GFP chimerae. Incubation of GFP-p65 with fluorescently labeled NF-kappaB-binding oligonucleotides also resulted in FRET. This effect was DNA sequence-specific and exhibited saturation characteristics. Application of stopped-flow fluorometry to measure the kinetics of FRET between GFP-p65 and oligonucleotides revealed a fast increase of acceptor fluorescence with a plateau after about 10 ms. The observed initial binding rate showed a temperature-dependent linear correlation with the oligonucleotide concentration. The association constant calculated according to pre-steady state kinetics was 3 x 10(6) m(-1), although equilibrium binding studies implied significantly higher values. This observation suggests that the binding process involves a rapid association with a rather high off-rate followed by a conformational change resulting in an increase of the association constant.


An engineered membrane to measure electroporation: effect of tethers and bioelectronic interface.
This article reports on the construction and predictive models for a platform comprised of an engineered tethered membrane. The platform provides a controllable and physiologically relevant environment for the study of the electroporation process. The mixed self-assembled membrane is formed via a rapid solvent exchange technique. The membrane is tethered to the gold electrode and includes an ionic reservoir separating the membrane and gold surface. Above the membrane, there is an electrolyte solution, and a gold counterelectrode. A voltage is applied between the gold electrodes and the current measured. The current is dependent on the energy required to form aqueous pores and the conductance of each pore. A two-level predictive model, consisting of a macroscopic and a continuum model, is developed to relate the pore dynamics to the measured current. The macroscopic model consists of an equivalent circuit model of the tethered membrane, and asymptotic approximations to the Smoluchowski-Einstein equation of electroporation that is dependent on the pore conductance and the energy required to form aqueous pores. The continuum model is a generalized Poisson-Nernst-Planck (GPNP) system where an activity coefficient to account for steric effects of ions is added to the standard PNP system. The GPNP is used to evaluate the conductance of aqueous pores, and the electrical energy required to form the pores. As an outcome of the setup of the device and the two-level model, biologically important variables can be estimated from experimental measurements. To validate the accuracy of the two-level model, the predicted current is compared with experimentally measured current for different tethering densities.


The hypervirulence of Agrobacterium tumefaciens A281 is encoded in a region of pTiBo542 outside of T-DNA.
We used a binary-vector strategy to study the hypervirulence of Agrobacterium tumefaciens A281, an L,L-succinamopine strain. Strain A281 is hypervirulent on several solanaceous plants. We constructed plasmids (pCS65 and pCS277) carrying either the transferred DNA (T-DNA) or the remainder of the tumor-inducing (Ti) plasmid (pEHA101) from this strain and tested each of these constructs in trans with complementary regions from heterologous Ti plasmids. Hypervirulence on tobacco could be reconstructed in a bipartite strain with the L,L-succinamopine T-DNA and the vir region on separate plasmids. pEHA101 was able to complement octopine T-DNA to hypervirulence on tobacco and tomato plants. Nopaline T-DNA was complemented better on tomato plants by pEHA101 than it was by its own nopaline vir region, but not to hypervirulence. L,L-Succinamopine T-DNA could not be complemented to hypervirulence on tobacco and tomato plants with either heterologous vir region. From these results we suggest that the hypervirulence of strain A281 is due to non-T-DNA sequences on the Ti plasmid.


Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma.
The purpose of our present study is to identify a tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. We established a lung adenocarcinoma cell line, designated as F1121L, and induced tumor-specific CTL clone H1 from regional lymph node lymphocytes of patient F1121. CTL clone H1 lysed autologous tumor cells in an HLA-B*1507-restricted manner, but not autologous EBV-B, phytohemagglutinin-blast cells, and K562. The CTL clone also recognized allogeneic HLA-B*1501- or 1507-positive lung cancer cell lines in the HLA-restricted manner. Using the CTL clone, we identified an antigen-coding gene by cDNA expression cloning technique. The gene consisted of 556 bp, including an open reading frame consisted of 113 amino acids, designated as Kita-kyushu lung cancer antigen 1 (KK-LC-1). A 9-mer peptide (KK-LC-1(76-84); RQKRILVNL) was identified as an epitope peptide. The genomic DNA of this antigen was located in chromosome Xq22. A reverse transcription-PCR analysis revealed that the mRNA of this gene was only expressed in the testis among normal tissues. It was expressed in 9 of 18 (50%) allogeneic non-small-cell lung cancer cell lines and in 40 of 100 (40%) non-small-cell lung cancer tissues. We thus identified a new tumor antigen-coding gene categorized as a cancer/germline gene by an autologous lung cancer and CTL system. The new cancer/germline gene was located in Xq22, which is apparently different from the locations of previously reported cancer/germline genes.


A Part-Of-Speech term weighting scheme for biomedical information retrieval.
In the era of digitalization, information retrieval (IR), which retrieves and ranks documents from large collections according to users' search queries, has been popularly applied in the biomedical domain. Building patient cohorts using electronic health records (EHRs) and searching literature for topics of interest are some IR use cases. Meanwhile, natural language processing (NLP), such as tokenization or Part-Of-Speech (POS) tagging, has been developed for processing clinical documents or biomedical literature. We hypothesize that NLP can be incorporated into IR to strengthen the conventional IR models. In this study, we propose two NLP-empowered IR models, POS-BoW and POS-MRF, which incorporate automatic POS-based term weighting schemes into bag-of-word (BoW) and Markov Random Field (MRF) IR models, respectively. In the proposed models, the POS-based term weights are iteratively calculated by utilizing a cyclic coordinate method where golden section line search algorithm is applied along each coordinate to optimize the objective function defined by mean average precision (MAP). In the empirical experiments, we used the data sets from the Medical Records track in Text REtrieval Conference (TREC) 2011 and 2012 and the Genomics track in TREC 2004. The evaluation on TREC 2011 and 2012 Medical Records tracks shows that, for the POS-BoW models, the mean improvement rates for IR evaluation metrics, MAP, bpref, and P@10, are 10.88%, 4.54%, and 3.82%, compared to the BoW models; and for the POS-MRF models, these rates are 13.59%, 8.20%, and 8.78%, compared to the MRF models. Additionally, we experimentally verify that the proposed weighting approach is superior to the simple heuristic and frequency based weighting approaches, and validate our POS category selection. Using the optimal weights calculated in this experiment, we tested the proposed models on the TREC 2004 Genomics track and obtained average of 8.63% and 10.04% improvement rates for POS-BoW and POS-MRF, respectively. These significant improvements verify the effectiveness of leveraging POS tagging for biomedical IR tasks.


ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation.
Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1β release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis.


[Clinical evaluation of amitriptyline in the treatment of psychogenic disorders].
Clinical evaluation of amytyptiline in the treatment of psychogenic disorders was performed, using one or more 25 mg doses daily per os. Of the patients, 19 were male and 11 female; ages were between 18 and 55. Treatment for each lasted 12 weeks, and clinical improvement was observed from the second to the fifth week, with mild side effects that did not require treatment. Psychotherapy was instituted during treatment. ;inal results were: 23 good improvement, 4 some improvement and 3, no change.


Fibrillarin-associated box C/D small nucleolar RNAs in Trypanosoma brucei. Sequence conservation and implications for 2'-O-ribose methylation of rRNA.
We report the identification of 17 box C/D fibrillarin-associated small nucleolar RNAs (snoRNAs) from the ancient eukaryote, Trypanosoma brucei. To systematically isolate and characterize these snoRNAs, the T. brucei cDNA for the box C/D snoRNA common protein, fibrillarin, was cloned and polyclonal antibodies to the recombinant fibrillarin protein were generated in rabbits. Immunoprecipitations from T. brucei extracts with the anti-fibrillarin antibodies indicated that this trypanosomatid has at least 30 fibrillarin-associated snoRNAs. We have sequenced seventeen of them and designated them TBR for T. brucei RNA 1-17. All of them bear conserved box C, D, C', and D' elements, a hallmark of fibrillarin-associated snoRNAs in eukaryotes. Fourteen of them are novel T. brucei snoRNAs. Fifteen bear potential guide regions to mature rRNAs suggesting that they are involved in 2'-O-ribose methylation. Indeed, eight ribose methylations have been mapped in the rRNA at sites predicted by the snoRNA sequences. Comparative genomics indicates that six of the seventeen are the first trypanosome homologs of known yeast and vertebrate methylation guide snoRNAs. Our results indicate that T. brucei has many fibrillarin-associated box C/D snoRNAs with roles in 2'-O-ribose methylation of rRNA and that the mechanism for targeting the nucleotide to be methylated at the fifth nucleotide upstream of box D or D' originated in early eukaryotes.


Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold.
Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.


Speech effects of a speaking valve versus external PEEP in tracheostomized ventilator-dependent neuromuscular patients.
Many patients with respiratory failure related to neuromuscular disease receive chronic invasive ventilation through a tracheostomy. Improving quality of life, of which speech is an important component, is a major goal in these patients. We compared the effects on breathing and speech of low-level positive end-expiratory pressure (PEEP, 5 cmH(2)O) and of a Passy-Muir speaking valve (PMV) during assist-control ventilation. We studied ten patients with neuromuscular disorders, between December 2008 and April 2009. Flow was measured using a pneumotachograph. Microphone speech recordings were subjected to both quantitative measurements and qualitative assessments; the latter consisted of both an intelligibility score (using a French adaptation of the Frenchay Dysarthria Assessment) and a perceptual score determined by two speech therapists. Text reading time, perceptive score, intelligibility score, speech comfort, and respiratory comfort were similar with PEEP and PMV. During speech with 5 cmH(2)O PEEP, six of the ten patients had no return of expiratory gas to the expiratory line and, therefore, had the entire insufflated volume available for speech, a condition met during PMV use in all patients. During speech, the respiratory rate increased by at least 3 cycles/min above the backup rate in seven patients with PEEP and in none of the patients with PMV. Low-level PEEP is as effective as PMV in ensuring good speech quality, which might be explained by sealed expiratory line with low-level PEEP and/or respiratory rate increase during speech with PEEP observed in most of the patients.


A new goatfish of the genus Upeneus (Mullidae) from Lombok, Indonesia and first verified record of U. asymmetricus for the Indian Ocean.
Upeneus lombok n. sp. is described from two specimens collected off Lombok, Indonesia, at depths of 54-76 m, and one subadult specimen from the local fish market at Tanjung Luar, Lombok. Four specimens of U. asymmetricus were collected at the same fish market representing the first record of the species since its description from two Philippine Islands in 1954. These two species are compared in detail and with five congeneric species that all share a 7-spined dorsal fin and a high gill-raker count. Upeneus lombok n. sp. differs from all other congeners in having a short snout (snout length 9.0-9.6% SL) combined with a low anal fin (anal-fin height 12-13% SL in adults, 15% in single subadult). The newly recorded U. asymmetricus specimens differ from their types only slightly and all eight specimens together differ from all congeneric species in the combination of 7 dorsal spines, 12-14 pectoral fin rays, 26-28 total gill rakers, short pectoral fins (pectoral-fin length 18-21% SL) and short jaws (upper jaw length 8.7-11% SL). In both species the caudal-fin colour patterns of fresh fish are of diagnostic significance, the only exception being a close similarity between Upeneus lombok n.sp., U. saiab, and U. seychellensis. Additional comparisons with 14 Upeneus species which overlap in distribution or occur in nearby areas are also made. Needs for further taxonomic exploration of the Indonesian-Philippine region and for enhanced attention to the economic and ecological importance of Upeneus species are discussed.


A comparison of outcomes of anterior cervical discectomy and fusion in patients with and without radicular symptoms.
Anterior cervical discectomy and fusion (ACDF) is commonly performed for degenerative conditions of the cervical spine with good to excellent results. There is controversy over the use of ACDF for patients with axial neck pain alone. A retrospective review of 202 patients from two private practice orthopaedic spine surgeons following ACDF with 39-month mean follow-up was performed. Patients completed pain drawings, pre- and postoperative visual analog pain scales (VAS), Oswestry functional capacity evaluations (OSW), and a postoperative neck disability index. Forty-one patients had axial neck pain alone, and 161 had radicular pain with or without neck pain. There were significant improvements in VAS and OSW scores following surgery for the combined study population as well as the neck pain only and radicular pain groups (p < .01). ACDF can be effectively used for treatment of patients with axial neck pain without radicular symptoms.


An intervention to decrease heavy episodic drinking in college students: the effect of executive function training.
To develop and test a planning-ability, executive function (EF) intervention to reduce heavy episodic drinking (HED). Fifty-five heavy-drinking, first-year college students, recruited from May to October 2012. Participants were randomly allocated to an experimental or active control group and then completed the Alcohol Use Disorders Identification Test-Consumption and demographic questions. Over 1 week, the experimental group completed 4 progressively harder planning tasks, whereas the control group completed 4 easier, consistent-difficulty planning tasks. Participants then recorded their daily alcohol consumption for 2 weeks. As hypothesized, both mean and maximum per-occasion alcohol consumption was significantly reduced in the experimental group compared with the control group. There were no significant differences in frequency of HED. These results provide initial support for the use of a planning-ability intervention in decreasing per-occasion alcohol consumption. Future researchers can examine the mechanism of effect, the long-term efficacy, and the specific EFs involved in other aspects of alcohol consumption.


The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x.
Schistosoma mansoni soluble egg antigens (SEAs) are crucially involved in modulating the host immune response to infection by S. mansoni. We report that human dendritic cells bind SEAs through the C-type lectin dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN). Monoclonal antibodies against the carbohydrate antigens Lewisx (Lex) and GalNAcbeta1-4(Fucalpha1-3)GlcNAc (LDNF) inhibit binding of DC-SIGN to SEAs, suggesting that these glycan antigens may be critically involved in binding. In a solid-phase adhesion assay, DC-SIGN-Fc binds polyvalent neoglycoconjugates that contain the Lex antigen, whereas no binding was observed to Galbeta1-4GlcNAc, and binding to neoglycoconjugates containing only alpha-fucose or oligosaccharides with a terminal alpha1-2-linked fucose is low. These data indicate that binding of DC-SIGN to Lex antigen is fucose-dependent and that adjacent monosaccharides and/or the anomeric linkage of the fucose are important for binding activity. Previous studies have shown that DC-SIGN binds HIV gp120 that contains high-mannose-type N-glycans. Site-directed mutagenesis within the carbohydrate recognition domain (CRD) of DC-SIGN demonstrates that amino acids E324 and E347 are involved in binding to HIV gp120, Lex, and SEAs. By contrast, mutation of amino acid Val351 abrogates binding to SEAs and Lex but not HIV gp120. These data suggest that DC-SIGN recognizes these ligands through different (but overlapping) regions within its CRD. Our data imply that DC-SIGN not only is a pathogen receptor for HIV gp120 but may also function in pathogen recognition by interaction with the carbohydrate antigens Lex and possibly LDNF, which are found on important human pathogens, such as schistosomes and the bacterium Helicobacter pylori.


Cerebrovascular responsiveness to hypercapnia in Alzheimer's dementia and vascular dementia of the Binswanger type.
Alzheimer's dementia is thought to be a primary degenerative dementia, whereas vascular dementia of the Binswanger type is an entity of vascular dementia. We evaluated the cerebrovascular responsiveness to hypercapnia to clarify the differences in the cerebral hemodynamics between two groups of patients. The subjects were eight younger control subjects, five age-matched control subjects, five Alzheimer's patients, and five patients with vascular dementia of the Binswanger type. In the resting state, the regional cerebral blood flow was low in both Alzheimer's dementia and vascular dementia of the Binswanger type. The responsiveness to hypercapnia was preserved in Alzheimer's dementia, whereas it was impaired in vascular dementia of the Binswanger type in the cerebral cortices and in the deep white matter. These results suggest that small vascular lesions exist in vascular dementia of the Binswanger type but not in Alzheimer's dementia, even though regional cerebral blood flow was thought to decrease by hypometabolism in both types of dementia.


Prostate needle biopsy: what we do and what should be improved.
Prostate cancer (PCa) is the cancer most frequently diagnosed in older men and the second most frequent for incidence of all tumors. With the widespread use of serum prostate-specific antigen (PSA), the detection rate as well as the incidence of localized tumors has been increasing, thus leading to a drop in PCa-related mortality. However, a corresponding estimated rate of overdiagnosis as high as 50% has been reported, and the adverse side effects related to unnecessary treatments make the overall benefit of PSA mass screening unclear. The lower PSA threshold and extended prostate biopsy protocols have led to a marked increase of small, low-grade tumors that will never threaten a patient's survival. Sextant biopsy technique, extended biopsy protocols (12-18 cores) and saturation prostate schemes are already familiar terms, together with quantitative histology in the pathology departments. This brief review will try to focus on what usually is done and what should be improved in prostate needle biopsy in order to answer many critical points such as the clinical implication of different modalities of prostate biopsy (transrectal, transperineal or even targeted), the use of quantitative histology and the importance of the new molecular findings in addition to conventional histological parameters in the era of the active surveillance protocols.


[Topical problems of occupational pathology of ENT organs].
This paper presents data on the prevalence of occupational diseases of ENT organs dominated by occupational neurosensory deafness (NSD). The prevalence of occupational NSD is highest among the personnel of civilian aviation and the workers employed in mining ore industry. The author emphasizes the utmost importance of timely and high-accuracy diagnostics of ENT organ pathology during prophylactic medical examinations of people exposed to occupational hazards. Information on the state of upper respiratory tracts affected by industrial aerosols that cause irritation and allergic reactions is considered. Special attention is given to the development of methods for diagnosis of occupational oncological diseases and voice disturbances in the voice-and-speech profession.


Permanent up-regulation of regulatory T-lymphocytes in patients with head and neck cancer.
Various immune functions of different types of immune cells are strongly impaired in patients with head and neck squamous cell carcinoma (HNSCC). Regulatory T-lymphocyte cells (Tregs) have been suggested to be involved in the immunomodulation of immune responses and contribute to HNSCC progression and immune escape. 'Naturally' occurring CD4+ CD25+ Tregs represent a small fraction within the different subsets of regulatory T cells, which are known to inhibit numerous immune functions of different types of immune cells. In this study, the cellular ratio of CD4+ CD25(high) Tregs to the entire population of CD4+ T-lymphocytes was analyzed with respect to different stages of tumor progression and disease. Our data indicate a significantly high increased abundance of CD4+ CD25(high) CD127(low) Tregs in the peripheral blood of patients with HNSCC, which in addition show modulated expression levels of various functional proteins. Surprisingly, increased Treg levels were found even in patients with no active disease several years after tumor resection, with no significant correlation to the individual tumor stage. Additionally, increased levels of chemokine CCL22, which mediates migration of Tregs to the tumor, and upregulation of the corresponding receptor protein CCR4 were observed in HNSCC. Our data strongly suggest that HNSCC leads to a permanent shift of Treg levels with hardly recognizable recovery rates.


A monoclonal antibody to tryptophan hydroxylase: applications and identification of the epitope.
Recombinant rabbit tryptophan hydroxylase (TPH) was expressed in Escherichia coli and purified from inclusion bodies by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). A mouse monoclonal antibody and rabbit and sheep polyclonal antibodies were generated. In immunohistochemical studies of formaldehyde-fixed primate brain, the monoclonal strongly labeled not only cell bodies in the raphe nuclei but also fibers in the cerebral cortex. Truncation mutants and peptide pre-competition were used to localize the epitope to E103SVPWFP109. Although the primary sequences of TPH encoded by mRNAs from brain and pineal gland are identical, differences in the immunoreactivity of TPH protein from these two sources were observed in blot immunolabeling studies. TPH immunoreactivity migrated as an M(r) approximately equal 56000 band in each of the tissues except human pineal glands, in which the TPH reactivity was approximately 3 kDa lower. In addition, the relative intensities of TPH immunolabeling across the four tissues differed among these antibodies and a previously described monoclonal antibody against phenylalanine hydroxylase (PH8), which cross-reacts with TPH. Whereas PH8 exhibited roughly equivalent TPH reactivity per protein in both tissues from both species, TPH from human and rat raphe nuclei was preferentially recognized by the present monoclonal. By contrast, the affinity-purified sheep polyclonal antibody reacted preferentially with TPH from human and rat pineal gland, and the affinity-purified rabbit polyclonal antibody appeared to selectively recognize TPH from human pineal gland.


Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis.
Oxidation of low-density lipoprotein (LDL) is considered to be the initial step in the atherosclerotic process. Autoantibodies to oxidized LDL (ox-LDL) have been detected in human serum. We used an enzyme-linked immunosorbent assay technique to measure autoantibody titers in 63 normal subjects and patients with coronary artery disease. Thirty-five patients underwent coronary angiography for suspected coronary artery disease. Patients were divided into the following categories: group 1, 20 healthy young volunteers; group 2, 8 patients age-matched to the catheterization patients; group 3, 10 patients with normal coronary angiograms; and group 4, 25 patients with angiographic coronary artery disease. Autoantibody titers to ox-LDL were group 1, 0.142 +/- 0.023; group 2, 0.197 +/- 0.039; group 3, 0.183 +/- 0.038; and group 4, 0.340 +/- 0.026. There was no statistical difference among groups 1, 2, and 3, but the difference between these groups and group 4 was highly significant (p < 0.05). This study demonstrates that (1) autoantibodies to ox-LDL can be detected in normal subjects and in patients with abnormal coronary angiograms and (2) significantly higher titers of autoantibodies to ox-LDL were seen in patients with angiographic evidence of coronary artery disease.


Cardiotrophin-1 is a key regulator of glucose and lipid metabolism.
Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity. Acute treatment with rCT-1 decreased blood glucose in an insulin-independent manner and increased insulin-stimulated AKT phosphorylation in muscle. These changes were associated with stimulation of fatty acid oxidation, an effect that was absent in AMPKα2(-/-) mice. Chronic rCT-1 treatment reduced food intake, enhanced energy expenditure, and induced white adipose tissue remodeling characterized by upregulation of genes implicated in the control of lipolysis, fatty acid oxidation, and mitochondrial biogenesis and genes typifying brown fat phenotype. Moreover, rCT-1 reduced body weight and corrected insulin resistance in ob/ob and in high-fat-fed obese mice. We conclude that CT-1 is a master regulator of fat and glucose metabolism with potential applications for treatment of obesity and insulin resistance.


Penetration depth method--novel real-time strategy for evaluating femoroacetabular impingement.
We introduce a new method for computerized real-time evaluation of femoroacetabular impingement (FAI). In contrast to previously presented stress analyses, this method is based on two types of predictions of penetration depths for two rotating bodies: curvilinear and radial penetration depth. This intuitive method allows the analysis of both bony and soft tissue structures (such as cartilage and acetabular labrum) in real time. Characteristic penetration depth patterns were found for different subtypes of FAI, such as cam and pincer pathologies. In addition, correlation between the penetration depths (estimated by applying this method) and the existing contact stresses (estimated by applying the finite element method) of various hip morphologies were found. A strong correlation with predicted stress values existed, with a mean correlation coefficient of 0.91 for the curvilinear and 0.80 for the radial penetration method. The results show that the penetration depth method is a promising, fast, and accurate method for quantification and diagnosis of FAI.


Deoxynivalenol Exposure Assessment for Pregnant Women in Bangladesh.
The trichothecene mycotoxin deoxynivalenol (DON) is a contaminant of crops worldwide and known to cause adverse health effects in exposed animals and humans. A small survey reported the presence of DON in maize samples in Bangladesh, but these data are insufficient to assess human exposure, and also, biomonitoring data are still scarce. The present study applied biomarker analysis to investigate the DON exposure of pregnant women in Bangladesh. Urine samples were collected from pregnant women living in a rural (n = 32) and in a suburban (n = 22) area of the country. Urines were subjected to enzymatic hydrolysis of glucuronic acid conjugates and to immunoaffinity column clean-up prior to LC-MS/MS analysis of DON and its de-epoxy metabolite DOM-1. The limits of detection (LOD) for DON and DOM-1 in urine were 0.16 ng/mL and 0.10 ng/mL, respectively. DOM-1 was not detected in any of the urines, whilst DON was detectable in 52% of the samples at levels ranging from 0.18-7.16 ng/mL and a mean DON concentration of 0.86 ± 1.57 ng/mL or 2.14 ± 4.74 ng/mg creatinine. A significant difference in mean urinary DON levels was found between the rural (0.47 ± 0.73 ng/mL) and suburban (1.44 ± 2.20 ng/mL) cohort, which may be related to different food habits in the two cohorts. Analysis of food consumption data for the participants did not show significant correlations between their intake of typical staple foods and DON levels in urine. The biomarker concentrations found and published urinary excretion rates for DON were used to estimate daily mycotoxin intake in the cohort: the mean DON intake was 0.05 µg/kg b.w., and the maximum intake was 0.46 µg/kg b.w., values lower than the tolerable daily intake of 1 µg/kg b.w. These first results indicate a low dietary exposure of pregnant women in Bangladesh to DON. Nonetheless, further biomonitoring studies in children and in adult cohorts from other parts of the country are of interest to gain more insight into DON exposure in the population of Bangladesh.


[Frozen shoulder].
Frozen shoulder, or adhesive capsulitis, is a painful inflammatory disorder with an unknown pathogenesis characterised by progressive fibrosis of the capsule. Frozen shoulder presents clinically with intense pain at rest and passive restricted motion. In general, treatment modalities seem to relieve pain and improve the range of movement, but no single treatment modality has been shown to affect the long-term outcome. Initially, a non-operative approach is traditionally recommended. Oral or intraarticular injection of cortisone relieves short-term pain. In refractory cases, arthroscopic capsular release is suggested.


[Lupus-nephritis--diagnosis and treatment].
Systemic lupus erythematosus (SLE) is an autoimmune, multiorgan disease that usually affects young women. The kidneys are affected (lupus nephritis) in close to one fifth of the patients. Over the past decade earlier diagnosis and improved treatment of lupus nephritis has resulted in substantial improvement of renal function and patient survival. Despite these advances, 10 - 15 % of SLE patients with lupus nephritis progress to end-stage renal disease, requiring dialysis or renal transplantation. The article outlines main principles for diagnosing and treating lupus nephritis, according to current practice at Oslo University Hospital. National and international guidelines (on treatment of lupus nephritis), literature identified through a non-systematic search in PubMed and our own clinical experience form the basis for the article. In lupus nephritis, low-dose cyclophosphamide and corticosteroids are topical treatment for induction therapy, and mycophenolate mofetil is an alternative treatment. We recommend maintenance treatment with azathioprine or mycophenolate mofetil for at least two years. Treatment with rituximab may be considered in patients with refractory lupus nephritis. Subtypes and activity of the renal disease are decisive for choice of treatment.


Differential processing of nociceptive input within upper limb muscles.
The cutaneous silent period is an inhibitory evoked response that demonstrates a wide variety of responses in muscles of the human upper limb. Classically, the cutaneous silent period results in a characteristic muscle pattern of extensor inhibition and flexor facilitation within the upper limb, in the presence of nociceptive input. The aims of the current study were: 1) to primarily investigate the presence and characteristics of the cutaneous silent period response across multiple extensor and flexor muscles of the upper limb, and 2) to secondarily investigate the influence of stimulation site on this nociceptive reflex response. It was hypothesized that the cutaneous silent period would be present in all muscles, regardless of role (flexion/extension) or the stimulation site. Twenty-two healthy, university-age adults (14 males; 8 females; 23 ± 5 yrs) participated in the study. Testing consisted of three different stimulation sites (Digit II, V, and II+III nociceptive stimulation) during a low intensity, sustained muscle contraction, in which, 7 upper limb muscles were monitored via surface EMG recording electrodes. Distal muscles of the upper limb presented with the earliest reflex onset times, longest reflex duration, and lowest level of EMG suppression when compared to the more proximal muscles, regardless of extensor/flexor role. Additionally, the greatest overall inhibitory influence was expressed within the distal muscles. In conclusion, the present study provides a new level of refinement within the current understanding of the spinal organization associated with nociceptive input processing and the associated motor control of the upper limb. Subsequently, these results have further implications on the impact of nociception on supraspinal processing.


Identification of a minimal promoter element of the mouse epidermal growth factor gene.
We have previously generated a transgenic mouse line (EGF/Tag) in which simian virus 40 (SV40) T-antigen expression is directed by the mouse epidermal growth factor (EGF) gene promoter. In these mice, cellular hyperproliferation is observed in the submaxillary gland associated with SV40 T-antigen expression. In addition, SV40 T-antigen-expressing tumours of prostatic origin are seen. We have now derived immortalized cell lines from these tissues and have used the cells to perform a functional analysis of the EGF gene promoter. Cells were transfected with EGF promoter/reporter constructs, and an element located between 51 and 35 bases upstream of the EGF mRNA start site required for basal activity of the promoter was identified. Electrophoretic mobility-shift analysis suggests that three proteins bind to this region, one of which is either Sp1 or a closely related protein.


Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis.
Hypertriglyceridemia (HTG) represents a major health problem with prevalence exceeding 30% in the U.S. The present study aims to assess the effect of elevated serum triglyceride (TG) levels on the severity of acute pancreatitis (AP). Prospectively enrolled AP patients were categorized into normal, mild, moderate, and severe/very severe categories based on their TG levels and compared in respect to demographics, comorbidities, and clinical outcomes. Multivariate analysis determined whether elevated TG levels were independently associated with persistent organ failure. Two hundred and one out of 400 AP patients had serum TGs measured within 72 h of presentation, of which 115 had normal TG levels and 86 HTG (20 mild, 41 moderate, and 25 severe/very severe). Patients with HTG were of younger age (44 vs. 52 years), predominantly male (65% vs. 45%), obese (57% vs. 34%), diabetic (38% vs. 17%), and developed more frequently persistent organ failure (40% vs. 17%) compared with those with normal TGs (P<0.02). The rate of persistent organ failure increased proportionally with HTG severity grades (17% when normal TGs, 30% in mild, 39% in moderate, and 48% in severe/very severe HTG, Ptrend<0.001). On multivariate analysis controlling for age, gender, body mass index, diabetes, and alcohol etiology, moderate HTG (odds ratio (OR), 2.6; P=0.04) and severe/very severe HTG (OR, 4.9; P=0.009) were independently associated with persistent organ failure. Elevated serum TGs in AP patients are independently and proportionally correlated with persistent organ failure regardless of etiology. TG-mediated lipotoxicity may be an attractive target to design novel interventions for severe AP.


Emerging Therapies for Breast Cancer.
The steady, incremental improvements in outcomes for both early-stage and advanced breast cancer patients are, in large part, attributable to the success of novel systemic therapies. In this review, we discuss key conceptual paradigms that have underpinned this success including (1) targeting the driver: the identification and targeting of major oncoproteins in breast cancers; (2) targeting the lineage pathway: inhibition of those pathways that drive normal mammary epithelial cell proliferation that retain importance in cancer; (3) targeting precisely: the application of molecular classifiers to refine therapy selection for specific cancers, and of antibody-drug conjugates to pinpoint tumor and tumor promoting cells for eradication; and (4) exploiting synthetic lethality: leveraging unique vulnerabilities that cancer-specific molecular alterations induce. We describe promising examples of novel therapies that have been discovered within each of these paradigms and suggest how future drug development efforts might benefit from the continued application of these principles.


Piezoelectric bimorphs' characteristics as in-socket sensors for transfemoral amputees.
Alternative sensory systems for the development of prosthetic knees are being increasingly highlighted nowadays, due to the rapid advancements in the field of lower limb prosthetics. This study presents the use of piezoelectric bimorphs as in-socket sensors for transfemoral amputees. An Instron machine was used in the calibration procedure and the corresponding output data were further analyzed to determine the static and dynamic characteristics of the piezoelectric bimorph. The piezoelectric bimorph showed appropriate static operating range, repeatability, hysteresis, and frequency response for application in lower prosthesis, with a force range of 0-100 N. To further validate this finding, an experiment was conducted with a single transfemoral amputee subject to measure the stump/socket pressure using the piezoelectric bimorph embedded inside the socket. The results showed that a maximum interface pressure of about 27 kPa occurred at the anterior proximal site compared to the anterior distal and posterior sites, consistent with values published in other studies. This paper highlighted the capacity of piezoelectric bimorphs to perform as in-socket sensors for transfemoral amputees. However, further experiments are recommended to be conducted with different amputees with different socket types.


[Resistance to azidothymidine in human immunodeficiency virus (HIV) infection].
The phenomenon of resistance to azidothymidine during the infection of human immunodeficiency virus (HIV) is reviewed. Different aspects of AZT resistance, including biological and virological characteristics of resistant HIV isolates, genetical mechanisms of resistance, cross-resistance to other nucleoside analogs and non-nucleoside inhibitors, are analyzed. The role of target cells in AZT resistance is also discussed.


Vulvodynia interventions--systematic review and evidence grading.
State of the art guidance exists for management of vulvodynia, but the scientific basis for interventions has not been well described. Although there are many interventional therapies, and their use is increasing, there is also uncertainty or controversy about their efficacy. To systematically assess benefits and harms of interventional therapies for vulvodynia and vestibulodynia. The following databases were searched, using MeSH terms for studies related to the treatment of vulvodynia or vulva pain/pruritus/dysesthesia/hyperesthesia/hypersensitivity: MEDLINE, PsycINFO, Scopus, Cochrane Library, EBSCO Academic, and Google Scholar. Using Medical Subject Reference sections of relevant original articles, reviews, and evidence-based guidelines were screened manually. Manual searching for indirect evidence supporting interventions was done whenever no direct evidence was found for a treatment described within a review or guideline. Each modality is assessed with a grading system similar to the Grades of Recommendation, Assessment, Development, and Evaluation system. The grading system assesses study quality, effect size, benefits, risks, burdens, and costs. For improvement of pain and/or function in women with vestibulodynia (provoked localized vulvodynia), there was fair evidence that vestibulectomy was of benefit, but the size of the effect cannot be determined with confidence. There was good evidence of a placebo effect from multiple studies of nonsurgical interventions. There was fair evidence of lack of efficacy for several nonsurgical interventions. There were several interventions for which there were insufficient evidence to reliably evaluate. There was insufficient evidence to judge harms or to judge long-term benefits. For clinically meaningful improvement of pain in women with generalized unprovoked vulvodynia, there was insufficient evidence for benefit of any intervention. There was fair evidence of a placebo effect in people with neuropathic pain and functional pain syndromes, from multiple studies of interventions. Based on indirect evidences from studies of patients with other pain disorders, interventions may be selected for future research. There is fair evidence for effectiveness of vestibulectomy for vestibulodynia; however, there is uncertainty about the size of the absolute effect, because of the risk of bias inherent in studies of pain interventions without a placebo control group. Providers and patients looking for evidence-based interventions for generalized unprovoked vulvodynia may need to rely on indirect evidences from studies of neuropathic pain and functional pain syndromes. Obstetricians & gynecologists, family physicians. After completion of this educational activity, the obstetrician/gynecologist should be better able to identify potential causes of vulvar pain to facilitate diagnosis of vulvodynia and vestibulodynia, distinguish between the symptoms of localized, provoked vulvodynia and generalized unprovoked vulvodynia to select the most appropriate therapies, evaluate the efficacy of surgical and nonsurgical interventions for the treatment of generalized unprovoked and localized, provoked vulvodynia. In addition, assess the benefits and risks of interventional therapies for vulvodynia and vestibulodynia to improve patient care.


Molecular Characterization of a DNA Polymerase from Thermus thermophilus MAT72 Phage vB_Tt72: A Novel Type-A Family Enzyme with Strong Proofreading Activity.
We present a structural and functional analysis of the DNA polymerase of thermophilic Thermus thermophilus MAT72 phage vB_Tt72. The enzyme shows low sequence identity (<30%) to the members of the type-A family of DNA polymerases, except for two yet uncharacterized DNA polymerases of T. thermophilus phages: φYS40 (91%) and φTMA (90%). The Tt72 polA gene does not complement the Escherichia colipolA− mutant in replicating polA-dependent plasmid replicons. It encodes a 703-aa protein with a predicted molecular weight of 80,490 and an isoelectric point of 5.49. The enzyme contains a nucleotidyltransferase domain and a 3′-5′ exonuclease domain that is engaged in proofreading. Recombinant enzyme with His-tag at the N-terminus was overproduced in E. coli, subsequently purified by immobilized metal affinity chromatography, and biochemically characterized. The enzyme exists in solution in monomeric form and shows optimum activity at pH 8.5, 25 mM KCl, and 0.5 mM Mg2+. Site-directed analysis proved that highly-conserved residues D15, E17, D78, D180, and D184 in 3′-5′ exonuclease and D384 and D615 in the nucleotidyltransferase domain are critical for the enzyme's activity. Despite the source of origin, the Tt72 DNA polymerase has not proven to be highly thermoresistant, with a temperature optimum at 55 °C. Above 60 °C, the rapid loss of function follows with no activity > 75 °C. However, during heat treatment (10 min at 75 °C), trehalose, trimethylamine N-oxide, and betaine protected the enzyme against thermal inactivation. A midpoint of thermal denaturation at Tm = 74.6 °C (ΔHcal = 2.05 × 104 cal mol−1) and circular dichroism spectra > 60 °C indicate the enzyme's moderate thermal stability.


Is alexithymia distinct from health locus of control?
Both locus of control and alexithymia have been considered personality factors fostering health concerns and behaviors. This study investigates the relationship between the health locus of control and alexithymia. Seventy-eight psychiatric outpatients were administered the Wallston Health Locus of Control Scale (HLC), the Toronto Alexithymia Scale (HLC), and the Five Factor Inventory, which measures neuroticism, extraversion, openness, agreeableness, and conscientiousness. Depressive and anxious affect was also measured. Regression models were developed to assess the influence of the above variables upon alexithymia. Although there was a significant bivariant correlation between an external locus of control and increased alexithymia, regression models found that HLC did not significantly predict TAS. Neuroticism, however, provided the most significant contribution to predict increased alexithymia. Neuroticism may link HLC and TAS due to the face validity of each construct. A sense of vulnerability is stated in each measure. This may foster somatic preoccupation. The data suggest HLC and TAS to be separate phenomena and further support the validity of alexithymia as a unique personality trait.


Structure and barrier properties of human embryonic stem cell-derived retinal pigment epithelial cells are affected by extracellular matrix protein coating.
Extracellular matrix (ECM) interactions play a vital role in cell morphology, migration, proliferation, and differentiation of cells. We investigated the role of ECM proteins on the structure and function of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells during their differentiation and maturation from hESCs into RPE cells in adherent differentiation cultures on several human ECM proteins found in native human Bruch's membrane, namely, collagen I, collagen IV, laminin, fibronectin, and vitronectin, as well as on commercial substrates of xeno-free CELLstart™ and Matrigel™. Cell pigmentation, expression of RPE-specific proteins, fine structure, as well as the production of basal lamina by hESC-RPE on different protein coatings were evaluated after 140 days of differentiation. The integrity of hESC-RPE epithelium and barrier properties on different coatings were investigated by measuring transepithelial resistance. All coatings supported the differentiation of hESC-RPE cells as demonstrated by early onset of cell pigmentation and further maturation to RPE monolayers after enrichment. Mature RPE phenotype was verified by RPE-specific gene and protein expression, correct epithelial polarization, and phagocytic activity. Significant differences were found in the degree of RPE cell pigmentation and tightness of epithelial barrier between different coatings. Further, the thickness of self-assembled basal lamina and secretion of the key ECM proteins found in the basement membrane of the native RPE varied between hESC-RPE cultured on compared protein coatings. In conclusion, this study shows that the cell culture substrate has a major effect on the structure and basal lamina production during the differentiation and maturation of hESC-RPE potentially influencing the success of cell integrations and survival after cell transplantation.


Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence.
The relationship between surgery and anesthetic-induced immunosuppression and cancer recurrence remains unresolved. Surgery and anesthesia stimulate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) to cause immunosuppression through several tumor-derived soluble factors. The potential impact of surgery and anesthesia on cancer recurrence was reviewed to provide guidance for cancer surgical treatment. PubMed was searched up to December 31, 2016 using search terms such as, "anesthetic technique and cancer recurrence," "regional anesthesia and cancer recurrence," "local anesthesia and cancer recurrence," "anesthetic technique and immunosuppression," and "anesthetic technique and oncologic surgery." Surgery-induced stress responses and surgical manipulation enhance tumor metastasis via release of angiogenic factors and suppression of natural killer (NK) cells and cell-mediated immunity. Intravenous agents such as ketamine and thiopental suppress NK cell activity, whereas propofol does not. Ketamine induces T-lymphocyte apoptosis but midazolam does not affect cytotoxic T-lymphocytes. Volatile anesthetics suppress NK cell activity, induce T-lymphocyte apoptosis, and enhance angiogenesis through hypoxia inducible factor-1α (HIF-1α) activity. Opioids suppress NK cell activity and increase regulatory T cells. Local anesthetics such as lidocaine increase NK cell activity. Anesthetics such as propofol and locoregional anesthesia, which decrease surgery-induced neuroendocrine responses through HPA-axis and SNS suppression, may cause less immunosuppression and recurrence of certain types of cancer compared to volatile anesthetics and opioids.


[What do we Mean by "Ideal" Blood Pressure Control?]
Arterial hypertension (AH) is one of the most important risk factors for development of myocardial infarction, chronic heart failure, stroke, cognitive disorders and dementia, and chronic kidney disease. Currently, special attention is paid to increased blood pressure variability (BPV) as a new risk factor for development of cardiovascular and cerebrovascular complications. The available evidence-based body of clinical studies demonstrates the importance of reducing not only the blood pressure itself but also the increased BPV to provide significant improvement of the prognosis and limits the risk of complications. This notion has been validated in consensus documents on the management of patients with AH. Among antihypertensive drugs, the fixed-dose combination (FC) amlodipine/perindopril has demonstrated a unique capability for reducing all types of BPV (visit-to-visit, day-to-day, during 24 h). According to current clinical guidelines, this combination belongs to first-line FCs indicated for most patients with AH. A distinctive feature of the FC amlodipine/perindopril is numerous data from real-life clinical practice, which support both its high antihypertensive efficacy and the ability to decrease high BPV. Therefore, the FC amlodipine/perindopril can be recommended for a broad range of AH patients to achieve BP control and to improve the prognosis.


[Urea treatment of Ménière's disease and other labyrinth disorders].
Urea (9 g a day) is a very useful drug in the treatment of Meniere's disease. Results are also effective in other labyrinthine disorders (sudden deafness, tinnitus) but less constant. The mechanism of the action of urea on the pathologic labyrinth is discussed.


Anti-cancer Effects of Polyphenolic Compounds in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer.
Polyphenolic phytochemicals are natural compounds, easily found in fruits and vegetables. Importantly, polyphenols have been intensively studied as excellent antioxidant activity which contributes to anticancer function of the natural compounds. Lung cancer has been reported to mainly account for cancer-related deaths in the world. Moreover, epidermal growth factor receptor tyrosine kinase inhibitor (TKI) resistance is one of the biggest issues in cancer treatment, especially in nonsmall cell lung cancer (NSCLC). Even though several studies both in preclinical and clinical trials have showed promising therapeutic effects of polyphenolic compounds in anticancer therapy, the function of the natural compounds in TKI-resistant (TKIR) lung cancer remains poorly studied. The aim of this study is to screen polyphenolic compounds as potential anticancer adjuvants which suppress TKIR lung cancer. Colony formation and thiazolyl blue tetrazolium blue assay were performed in the pair-matched TKI-sensitive (TKIS) versus TKIR tumor cell lines to investigate the therapeutic effect of polyphenolic compounds in TKIR NSCLC. Our data show that equol, kaempferol, resveratrol, and ellagic acid exhibit strong anticancer effect in HCC827 panel. Moreover, the inhibitory effect of most of tested polyphenolic compounds was highly selective for TKIR lung cancer cell line H1993 while sparing the TKIS one H2073. This study provides an important screening of potential polyphenolic compounds for drug development to overcome TKI resistance in advanced lung cancer. The study provides an important screening of potential polyphenolic compounds for drug development to overcome tyrosine kinase inhibitor (TKI) resistance in advance lung cancerEquol, kaempferol, resveratrol, and ellagic acid show strong anticancer effect in HCC827 panel, including TKI-sensitive (TKIS) and TKI-resistant clonesThe inhibitory effect of polyphenolic compounds such as equol, kaempferol, resveratrol, ellagic acid, gallic acid, p-Coumaric, and hesperidin is highly selective for TKI-resistant lung cancer cell line H1993 while sparing the TKIS one H2073. Abbreviations used: EGFR: Epidermal growth factor receptor, EMT: Epithelial-to-mesenchymal transition, GTP: Green tea polyphenols, IGF1R: Insulin-like growth factor 1 receptor, MET: Met proto-oncogene, MTT: Thiazolyl blue tetrazolium blue, NSCLC: Non-small cell lung cancer, ROS: Reactive oxygen species, RTK: Receptor tyrosine kinase, STAT3: Signal transducer and activator of transcription 3, TKIR: TKI-resistant, TKIs: Tyrosine kinase inhibitors, TKIS: TKI-sensitive.


Multiple hepatitis viruses in multiple attacks of acute viral hepatitis.
We evaluated the causes of 30 episodes of acute viral hepatitis in 13 patients who had multiple attacks. Two (seven per cent) of 30 bouts were caused by hepatitis A virus, and 12 (40%) by hepatitis B virus. No patient, however, had more than one attack with the serologic characteristics of Type A or Type B disease. Thus, there were 16 bouts (53 per cent) not attributable to either of the two recognized hepatitis viruses. None of these "non-A, non-B" episodes, evaluated for infectious mononucleosis and cytomegalovirus infection, could be ascribed to either. From this evidence, therefore, it appears that the clinical syndrome of viral hepatitis is produced not only by the two viruses (hepatitis A virus and hepatitis B virus) recognized since the 1940's but also, in all probability, by two non-A, non-B agents.


Genetics of ataxia telangiectasia in a highly consanguineous population.
Ataxia telangiectasia (AT) is a rare autosomal recessive multisystemic disorder. It usually presents in toddler years with progressive ataxia and oculomotor apraxia, or less commonly, in the late-first or early-second decade of life with mixed movement disorders. Biallelic mutations in ataxia telangiectasia mutated gene (ATM) cause AT phenotype, a disease not well documented in Saudi Arabia, a highly consanguineous society. We studied several Saudi AT patients, identified ATM variants, and investigated associated clinical features. We included 17 patients from 12 consanguineous families. All patients had comprehensive clinical and radiological assessment, and most were examined through whole-exome sequencing (WES). Selected individuals were analyzed using various genetic approaches. We identified five different ATM variants in our patients: three previously reported mutations, and two novel variants. Nearly all patients had classical AT presentation except for two patients with a milder phenotype. Among the three known variants, a deletion causing truncation (c.381delA resulting in p.(Val128Ter)) was identified in 13 patients. Two patients harboured the other two truncating variants, (c.9001_9002delAG resulting in p.Ser3001Phefs*6) and (c.9066delA resulting in p.Glu3023Alafs*10) and two patients had novel compound heterozygous variants (NM_000051.3:Paternal Allele:c.8762C > G;p.Thr2921Arg and Maternal Allele:c.1057T > C;p.Cys353Arg). We speculate that c.381delA is a founder mutation in our population. This study provides a genotype-phenotype relationship in a previously unstudied consanguineous population. Our findings contribute to improve local clinical care, therapy, and genetic counseling.


Intrauterine Fetal Growth Delay During Late Pregnancy After Maternal Gastric Bypass Surgery.
To investigate intrauterine fetal growth development and birth anthropometry of fetuses conceived after maternal gastric bypass surgery. Longitudinal cohort study describing longitudinal growth estimated by ultrasound on 43 singleton pregnancies after gastric bypass compared to 43 BMI-matched controls. In fetuses after maternal gastric bypass surgery, growth percentiles decreased markedly from the beginning of the second trimester until the end of the third trimester (decrease of 3.1 fetal abdomen circumference percentiles (95 %CI 0.9-5.3, p = 0.007) per four gestational weeks). While in the second trimester, fetal anthropometric measures did not differ between the groups, the mean abdomen circumference percentiles appeared significantly smaller during the third trimester in offspring of mothers after gastric bypass (mean difference 25.1 percentiles, p < 0.001). Similar tendencies have been observed in estimated fetal weight resulting in significantly more SGA offspring at delivery in the gastric bypass group. In children born after maternal gastric bypass surgery, weight percentiles (32.12th vs. 55.86th percentile, p < 0.001) as well as placental weight (525.2 g vs. 635.7 g, p < 0.001) were significantly reduced compared to controls. In fetuses conceived after maternal gastric bypass, intrauterine fetal growth distinctively declined in the second and third trimester, most prominently observed in fetal abdomen circumferences. Birth weight and placental weight at birth was significantly lower compared to BMI-matched controls, possibly due to altered maternal metabolic factors and comparable to mothers experiencing chronic hunger episodes.


Entanglement-Enhanced Radio-Frequency Field Detection and Waveform Sensing.
We demonstrate a new technique for detecting the amplitude of arbitrarily chosen components of radio-frequency waveforms based on stroboscopic backaction evading measurements. We combine quantum nondemolition measurements and stroboscopic probing to detect waveform components with magnetic sensitivity beyond the standard quantum limit. Using an ensemble of 1.5×10^{6} cold rubidium atoms, we demonstrate entanglement-enhanced sensing of sinusoidal and linearly chirped waveforms, with 1.0(2) and 0.8(3) dB metrologically relevant noise reduction, respectively. We achieve volume-adjusted sensitivity of δBsqrt[V]≈3.96 fTsqrt[cm^{3}/Hz], comparable to the best rf magnetometers.


Guideline adherence in management of stable chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is the only leading cause of death with rising morbidity and mortality. Clinical practice guidelines (CPGs) to optimize pharmacotherapy for patients with COPD have been updated based on promising results of randomized clinical trials. We examined the frequency of and factors associated with guideline adherence by physicians in clinical practice at an academic medical center. Patients with a clinical diagnosis of COPD, confirmed by spirometry, who presented to the ambulatory clinics, were enrolled. The primary outcome was provider's adherence to the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Subjects were categorized as guideline-concordant who received a rescue inhaler (all patients), or at least one long-acting bronchodilator (stage II), or at least one long-acting bronchodilator plus an inhaled corticosteroid (stage III-IV). Demographics, clinical information and type of provider were recorded. Provider type was classified as primary care physician (PCP), pulmonologist, or co-management by both. Among 450 subjects who met study criteria, 246 (54.7%) received guideline-concordant treatment. Age, sex, race, disease severity, and co-morbidities were not associated with guideline adherence. Multivariate analysis showed that patients co-managed by a PCP and pulmonologist had a higher likelihood of receiving guideline-concordant treatment than those managed by one or the other (Odds Ratio: 4.59; 95% Confidence Interval: 2.92, 7.22, p < 0.001). Just over half of stable COPD patients receive guideline-concordant care. Co-management by a PCP and pulmonologist increases the likelihood of receiving guideline-concordant inhaler therapy.


Photonic Torque Microscopy of the Nonconservative Force Field for Optically Trapped Silicon Nanowires.
We measure, by photonic torque microscopy, the nonconservative rotational motion arising from the transverse components of the radiation pressure on optically trapped, ultrathin silicon nanowires. Unlike spherical particles, we find that nonconservative effects have a significant influence on the nanowire dynamics in the trap. We show that the extreme shape of the trapped nanowires yields a transverse component of the radiation pressure that results in an orbital rotation of the nanowire about the trap axis. We study the resulting motion as a function of optical power and nanowire length, discussing its size-scaling behavior. These shape-dependent nonconservative effects have implications for optical force calibration and optomechanics with levitated nonspherical particles.


Rectal mucosal proliferation, dietary factors, and the risk of colorectal adenomas.
Colorectal cancer arises from a series of precursor stages, the so called adenoma-carcinoma sequence. Increased rectal mucosal proliferation may be an early step in this sequence. Because dietary factors are implicated in the etiology of colorectal cancer, one might predict that diet would also be associated with proliferation. We conducted this study to examine the association of diet with rectal mucosal proliferation. Rectal mucosal proliferation was measured in endoscopic biopsy specimens by proliferating cell nuclear antigen (PCNA) immunohistochemistry and whole crypt mitotic counts (WCMCs). Diet was evaluated using a validated quantitative food frequency questionnaire. The correlation between PCNA labeling index (LI) and WCMCs was determined using Kendall's tau, a nonparametric measure of correlation. Logistic regression was used to examine the effect of proliferation on adenoma status, controlling for confounders. The relationship between proliferation and dietary and demographic factors was examined using linear regression. There were 308 patients who had one or both measures of proliferation. There was no significant correlation between PCNA LI and WCMCs (Kendall's tau = 0.04; P = 0.35). Neither measure of proliferation was predictive of adenoma status, even after adjusting for potential confounders. Body mass index and calories per day were significant predictors of WCMC (P = 0.01 and P = 0.03, respectively). PCNA labeling index was not associated with any dietary variables, although its association with dietary fat nearly reached statistical significance (P = 0.09). The association between proliferation and diet were generally inconsistent. There appears to be no simple relationship between colorectal cancer risk factors, colorectal adenomas, and these two measures of rectal mucosal proliferation. We need simpler, more reliable intermediate markers for use in etiological and intervention studies.


Theory, experiment, and application of optical fiber etching.
Based on fiber Bragg grating (FBG), an online monitoring system for the etching process of optical fiber in a hydrofluoric (HF) acid solution has been designed. The variation curves of the wavelength shifts of FBGs with etching time at three different temperatures have been obtained and analyzed theoretically. The results show that the etching process of optical fiber in HF acid solution can be understood by the variation of the wavelength shift of FBG with etching time. Finally, required tapered fiber tips can be made by controlling the etching velocity and the pulling velocity of optical fiber from the etching solution.


α-Pinene-Derived Organic Coatings on Acidic Sulfate Aerosol Impacts Secondary Organic Aerosol Formation from Isoprene in a Box Model.
Fine particulate matter (PM2.5) is known to have an adverse impact on public health and is an important climate forcer. Secondary organic aerosol (SOA) contributes up to 80% of PM2.5 worldwide and multiphase reactions are an important pathway to form SOA. Aerosol-phase state is thought to influence the reactive uptake of gas-phase precursors to aerosol particles by altering diffusion rates within particles. Current air quality models do not include the impact of diffusion-limiting organic coatings on SOA formation. This work examines how α-pinene-derived organic coatings change the predicted formation of SOA from the acid-catalyzed multiphase reactions of isoprene epoxydiols (IEPOX). A box model, with inputs provided from field measurements taken at the Look Rock (LRK) site in Great Smokey Mountains National Park during the 2013 Southern Oxidant and Aerosol Study (SOAS), was modified to incorporate the latest laboratory-based kinetic data accounting for organic coating influences. Including an organic coating influence reduced the modeled reactive uptake when relative humidity was in the 55-80% range, with predicted IEPOX-derived SOA being reduced by up to 33%. Only sensitivity cases with a large increase in Henry's Law values of an order of magnitude or more or in particle reaction rates resulted in the large statistically significant differences form base model performance. These results suggest an organic coating layer could have an impact on IEPOX-derived SOA formation and warrant consideration in regional and global scale models.


[The functional status of the endocrine pancreas in patients with acute intestinal infections].
RIA was used to measure the content of insulin, C-peptide and glucagon in blood plasma of 84 patients with acute dysentery and food toxicoinfections. The studies were carried out in the acute disease period and before the discharge from hospital. The data obtained indicate that despite the appreciable differences in the disease pathogenesis, the pathophysiological mechanisms influencing pancreatic function are similar in many respects. The changes are characterized by an increase in plasma insulin and a reduction in C-peptide and glucagon. The content of hormones in the peripheral blood is dependent on the disease period. In the authors' opinion, despite the high insulin content, the reduced level of C-peptide attests to hypofunction of beta-cells in acute intestinal infection, since it reflects their function more precisely. The reduced content of plasma glucagon points to hypofunction of alpha-cells.


High prevalence of renal transplant recipients infected with more than one cytomegalovirus glycoprotein B genotype.
A prospective analysis of cytomegalovirus (CMV) glycoprotein B (gB) genotypes was conducted on 34 renal transplant recipients using peripheral blood leukocytes (PBLs) and urine specimens. The CMV gB genotypes were analyzed by polymerase chain reaction (PCR) followed by enzyme digestion. PBLs and urine samples showed almost equal proportions of the 4 known gB genotypes, as well as equal proportions of gB genotype mixtures. The gB genotypes 1, 2 and 3 were equally distributed in the patients. Twenty-four (70.6%) patients had more than one gB genotype during follow-up. There was no association of gB genotypes with the development of symptomatic CMV infection.


Attention-deficit/hyperactivity disorder: a plausible mouse model?
Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial and heterogeneous disorder, highly prevalent in children and characterized by three main components: inattention, lack of inhibitory control and hyperactivity. Epidemiological evidence reveals that ADHD is associated with nicotine exposure, mostly, with prenatal cigarette smoking. Mice deleted for the beta2-subunit gene of the neuronal nicotinic receptor are proposed as a simple and reliable animal model for ADHD. Nicotinic agonists targeting the alpha4beta2 nicotinic receptors alleviate ADHD symptoms and may possibly contribute to an efficient therapy of ADHD children.


Does FDG PET-assisted management of patients with left ventricular dysfunction improve quality of life? A substudy of the PARR-2 trial.
Patients with left ventricular dysfunction whose management is directed by F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may have a quality of life (QOL) benefit over standard care. Among 430 patients randomized in the PET and Recovery Following Revascularization (PARR)-2 trial to FDG PET-assisted management vs standard, QOL scores were obtained using the European Quality of Life-5 Dimensions (EQ-5D) in 427 patients at baseline (FDG PET n = 216; standard n = 211) and 355 patients at 12-month follow-up (FDG PET n = 184; standard n = 171). EQ-5D scores between FDG PET and standard arms were compared using mixed model repeated measures (MMRM). Subgroup analysis compared EQ-5D scores between patients in FDG PET who adhered to PET recommendations (Adherence) vs standard using MMRM. Interaction of revascularization with management was assessed using a general linear model. A trend toward higher EQ-5D scores in FDG PET was observed (P = 0.056). Subgroup analysis showed a significant difference favouring adherence (P = 0.04). Higher QOL at 6 months for FDG PET (P = 0.02) and Adherence (P = 0.02) were observed. For revascularization, an interaction with management (FDG PET vs standard) for QOL was observed (6 months: P = 0.01; 12 months: P = 0.1); Adherence (6 months: P = 0.01; 12 months: P = 0.1). FDG PET-directed management improves QOL, at least in the short-term and with adherence to recommendations. This may relate to revascularization, and may indicate better treatment selection using FDG PET.


Equal North: how can we reduce health inequalities in the North of England? A prioritization exercise with researchers, policymakers and practitioners.
The Equal North network was developed to take forward the implications of the Due North report of the Independent Inquiry into Health Equity. The aim of this exercise was to identify how to reduce health inequalities in the north of England. Workshops (15 groups) and a Delphi survey (3 rounds, 368 members) were used to consult expert opinion and achieve consensus. Round 1 answered open questions around priorities for action; Round 2 used a 5-point Likert scale to rate items; Round 3 responses were re-rated alongside a median response to each item. In total, 10 workshops were conducted after the Delphi survey to triangulate the data. In Round 1, responses from 253 participants generated 39 items used in Round 2 (rated by 144 participants). Results from Round 3 (76 participants) indicate that poverty/implications of austerity (4.87 m, IQR 0) remained the priority issue, with long-term unemployment (4.8 m, IQR 0) and mental health (4.7 m, IQR 1) second and third priorities. Workshop 3 did not diverge from findings in Round 1. Practice professionals and academics agreed that reducing health inequalities in the North of England requires prioritizing research that tackles structural determinants concerning poverty, the implications of austerity measures and unemployment.


Corticotropin releasing hormone and the skin.
Cotricotropin-releasing hormone (CRH) and related peptides are produced in skin that is dependent on species and anatomical location. Local peptide production is regulated by ultraviolet radiation (UVR), glucocorticoids and phase of the hair cycle. The skin also expresses the corresponding receptors (CRH-R1 and CRH-R2), with CRH-R1 being the major receptor in humans. CRH-R1 is expressed in epidermal and dermal compartments, and CRH-R2 predominantly in dermal structures. The gene coding for CRH-R1 generates multiple isoforms through a process modulated by UVR, cyclic adenosine monophosphate (cAMP) and phorbol 12-myristate 13-acetate. The phenotypic effects of CRH in human skin cells are largely mediated by CRH-R1alpha through increases in concentrations of cAMP, inositol triphosphate (IP3), or Ca2+ with subsequent activation of protein kinases A (PKA) and C (PKC) dependent pathways. CRH also modulates the activity of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB), activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB). The cellular functions affected by CRH depend on cell type and nutritional status and include modulation of differentiation program(s), proliferation, viability and immune activity. The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis.


Haem synthesis during mitochondrogenesis in yeast.
The activities of delta-aminolaevulate synthetase and delta-aminolaevulate dehydratase have been assayed in Saccharomyces cerevisiae during glucose repression and de-repression. delta-Aminolaevulate dehydratase increased concomitantly with the increase in oxygen uptake during the de-repression phase caused by the depletion of glucose in the medium. delta-Aminolaevulate synthetase showed an oscillatory behaviour and a spurt in its activity always preceded the increase in oxygen uptake. The activity of both the enzymes was lowered if the cells were incubated with glucose or cycloheximide, but not with chloramphenicol.


Modulation of fibroblast proliferation by oxygen free radicals.
The major unexplained phenomenon in fibrotic conditions is an increase in replicating fibroblasts. In this report we present evidence that oxygen free radicals can both stimulate and inhibit proliferation of cultured human fibroblasts, and that fibroblasts themselves release superoxide (O2.-) free radicals. Fibroblasts released O2.- in concentrations which stimulated proliferation, a finding confirmed by a dose-dependent inhibition of proliferation by free radical scavengers. Oxygen free radicals released by a host of agents may thus provide a very fast, specific and sensitive trigger for fibroblast proliferation. Prolonged stimulation may result in fibrosis, and agents which inhibit free radical release may have a role in the prevention of fibrosis.


Hemorrhagic shock in rats.
Rats are commonly used as models of hemorrhagic shock. Both constant-pressure and constant-volume protocols have been used, although the latter is considered by some to be a better model of human shock. However, differences in survival have been reported when the same experiment is done by different investigators. Changes in oxygen consumption have been reported to correlate with mortality after shock, and these changes may be implicated in the variability seen in different experimental studies. Using the constant-volume model, in which a given percentage of the animal's estimated blood volume is withdrawn, we have determined oxygen consumption rates before and after hemorrhage in Sprague Dawley rats. Our results indicate that specific oxygen consumption rates decrease once rats reach a certain weight, but removing a given percentage of blood reduces the rate by a constant amount regardless of the weight of the animal. In addition, there appears to be a "critical" level of oxygen consumption needed for survival. Thus use of a constant-volume protocol could result in survival for smaller but not larger rats. It is suggested that rat weights must be the same to compare results from different investigators.