Treatment Outcomes for Isolated Maxillary Complex Fractures with Maxillomandibular Screws.
Intermaxillary fixation (IMF) is a basic and fundamental principle in the management of patients with fractures of the maxillomandibular complex. There are several shortcomings related to the conventionally recommended tooth-mounted devices that are used to achieve IMF. To circumvent these, the use of bone-borne screws has been advocated. We present a series of maxillary fractures treated with IMF screws. Over a 12-month period, 15 cases of maxillary fracture were managed with open reduction and bone plate fixation. IMF screws were used to achieve IMF intraoperatively and for a short duration postoperatively. Eight cortical titanium screws were inserted transmucosally, two for each quadrant at the junction of the attached and mobile mucosa. Satisfactory occlusion was achieved in all the patients with few complications. IMF screw fixation was observed to be a safe and quick method for open reduction of maxillary fractures. Tooth-borne devices are associated with problems such as poor oral hygiene and periodontal health, extrusion of teeth, loss of tooth vitality, traumatic ulcers of buccal and labial mucosa, and needle stick injury to the operator. These procedures are also time consuming. The use of cortical bone screws is a quicker and safe alternative for achieving satisfactory IMF.


Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer.
Extracellular vesicles (EVs) are released by nearly all cell types as part of normal cell physiology, transporting biological cargo, including nucleic acids and proteins, across the cell membrane. In pathological states such as cancer, EV-derived cargo may mirror the altered state of the cell of origin. Exosomes are the smaller, 50-150 nanometer-sized EVs released from fusion of multivesicular endosomes with the plasma membrane. Exosomes play important roles in cell-cell communication and participate in multiple cancer processes, including invasion and metastasis. Therefore, proteomic analysis of exosomes is a promising approach to discover potential cancer biomarkers, even though it is still at an early stage. Herein, we critically review the advances in exosome isolation methods and their compatibility with mass spectrometry (MS)-based proteomic analysis, as well as studies of exosomes in pathogenesis and progression of prostate and bladder cancer, two common urologic cancers whose incidence rates continue to rise annually. As urological tumors, both urine and blood samples are feasible for noninvasive or minimally invasive analysis. A better understanding of the biological cargo and functions of exosomes via high-throughput proteomics will help provide new insights into complex alterations in cancer and provide potential therapeutic targets and personalized treatment for patients.


COVID-19 and Pregnancy: A Prospective Descriptive Study from a Tertiary Hospital in Nigeria.
It is known that pregnant women are more susceptible to viral infectious diseases, with an attendant risk of adverse foetal and maternal outcomes. The objective of this descriptive study is to evaluate the epidemiologic and clinical pattern, as well as the obstetric and COVID-19 outcome among pregnant women seen at a tertiary hospital in Southern, Nigeria. This was a descriptive prospective study of all pregnant women seen and diagnosed with COVID-19 based on positive RT-PCR for SARS-COV-2, at the University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria from March 2020 to August 2020. Seven (5.2%) pregnant patients were diagnosed with COVID-19 out of 134 patients. The common presenting symptoms were fever 4(57.1%), Productive cough 3 (42.9%), shortness of breath 3 (42.9%), myalgia 3 (42.9%), rhinorrhoea 3 (42.9%), and anosmia 3 (42.9%). The majority (85.7%) of patients were in the second and third trimesters at diagnosis. All deliveries occurred at term, with a mean gestational age of 38±0.82 weeks. Four patients (57.1%) had caesarean section (CS) deliveries for obstetric indications. No adverse outcomes were recorded for mothers and babies with birth weight ranging from 2.5 to 3.5 Kg. No case fatality was recorded. In this study, pregnant women with COVID-19 did not have adverse maternal and foetal outcome. The pattern of symptoms and the presence of severe disease also did not differ from what is observed in the general non-pregnant population. The impact of COVID-19 on pregnancy is less severe when compared to other high consequence viral infectious diseases.


Full genome sequencing of archived wild type and vaccine rinderpest virus isolates prior to their destruction.
When rinderpest virus (RPV) was declared eradicated in 2011, the only remaining samples of this once much-feared livestock virus were those held in various laboratories. In order to allow the destruction of our institute's stocks of RPV while maintaining the ability to recover the various viruses if ever required, we have determined the full genome sequence of all our distinct samples of RPV, including 51 wild type viruses and examples of three different types of vaccine strain. Examination of the sequences of these virus isolates has shown that the African isolates form a single disparate clade, rather than two separate clades, which is more in accord with the known history of the virus in Africa. We have also identified two groups of goat-passaged viruses which have acquired an extra 6 bases in the long untranslated region between the M and F protein coding sequences, and shown that, for more than half the genomes sequenced, translation of the F protein requires translational frameshift or non-standard translation initiation. Curiously, the clade containing the lapinised vaccine viruses that were developed originally in Korea appears to be more similar to the known African viruses than to any other Asian viruses.


BRD4 as a Therapeutic Target in Pulmonary Diseases.
Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET proteins have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative and redox balance, and immune responses. As a result, BET proteins have been found to be actively involved in a broad range of human lung diseases including acute lung inflammation, asthma, pulmonary arterial hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Due to the identification of specific small molecular inhibitors of BET proteins, targeting BET in these lung diseases has become an area of increasing interest. Emerging evidence has demonstrated the beneficial effects of BET inhibitors in preclinical models of various human lung diseases. This is, in general, largely related to the ability of BET proteins to bind to promoters of genes that are critical for inflammation, differentiation, and beyond. By modulating these critical genes, BET proteins are integrated into the pathogenesis of disease progression. The intrinsic histone acetyltransferase activity of bromodomain-containing protein 4 (BRD4) is of particular interest, seems to act independently of its bromodomain binding activity, and has implication in some contexts. In this review, we provide a brief overview of the research on BET proteins with a focus on BRD4 in several major human lung diseases, the underlying molecular mechanisms, as well as findings of targeting BET proteins using pharmaceutical inhibitors in different lung diseases preclinically.


Evidence for compounds hydrolyzable to amino acids in aqueous extracts of apollo 11 and apollo 12 lunar fines.
Hydrolyzates of aqueous extracts of Apollo 11 fines, an Apollo 12 trench sample, and an Apollo 12 surface sample have been analyzed on an ultrasensitive amino acid analyzer. The total content of amino acids recovered ranged from 20 to 70 parts per billion of lunar soil. Amino acids are not recovered by the direct hydrolysis of lunar fines, presumably because of decomposition in the presence of the large excess of lunar mineral. As judged by retention time, glycine is the dominant amino acid found; alanine is secondarily present in each case in the profile. Only a few amino acids have been recorded in each analysis. The pattern is relatively consistent in the samples from the three locations; the pattern from either hydrolyzed or unhydrolyzed extracts differs markedly from that of hydrolyzed or unhydrolyzed handprints. The evidence is not consistent with contamination of the kind expected by many investigators.


Regulation of UDP-Glucuronosyltransferases UGT2B4 and UGT2B7 by MicroRNAs in Liver Cancer Cells.
The transcriptional regulation of UDP-glucuronosyltransferases UGT2B4 and UGT2B7 has been well studied using liver cancer cell lines, and post-transcriptional regulation of these two UGTs by microRNA (miRNA/miR) miR-216b-5p was recently reported. This study describes novel miRNA-mediated regulation of UGT2B4 and UGT2B7 in liver cancer cells. Bioinformatic analyses identified a putative miR-3664-3p binding site in the UGT2B7 3'-untranslated region (UTR) and binding sites for both miR-135a-5p and miR-410-3p in the UGT2B4 3'-UTR. These sites were functionally characterized using miRNA mimics and reporter constructs. A miR-3664-3p mimic induced repression of a luciferase reporter carrying the UGT2B7 3'-UTR in liver cancer cell lines; mutation of the miR-3664-3p site abrogated the response of the reporter to the mimic. Similarly, mutation of the miR-135a-5p site or miR-410-3p site in a luciferase reporter bearing UGT2B4 3'-UTR abrogated the ability of miR-135a-5p or miR-410-3p mimics to reduce reporter activity. Transfection of miR-3664-3p mimics in HepG2 liver cancer cells significantly reduced mRNA and protein levels of UGT2B7, and this led to reduced enzymatic activity. Transfection of miR-135a-5p or miR-410-3p mimics significantly decreased UGT2B4 mRNA levels in Huh7 liver cancer cells. The expression levels of miR-410-3p were inversely correlated with UGT2B4 mRNA levels in The Cancer Genome Atlas cohort of liver hepatocellular carcinoma (371 specimens) and a panel of ten normal human tissues. Similarly, there was an inverse correlation between miR-135a and UGT2B4 mRNA levels in a panel of 18 normal human liver tissues. Together, these data suggest that miR-135a and miR-410 control UGT2B4 and that miR-3664 controls UGT2B7 expression in liver cancer and/or normal liver cells.


A chip-scale second-harmonic source via self-injection-locked all-optical poling.
Second-harmonic generation allows for coherently bridging distant regions of the optical spectrum, with applications ranging from laser technology to self-referencing of frequency combs. However, accessing the nonlinear response of a medium typically requires high-power bulk sources, specific nonlinear crystals, and complex optical setups, hindering the path toward large-scale integration. Here we address all of these issues by engineering a chip-scale second-harmonic (SH) source based on the frequency doubling of a semiconductor laser self-injection-locked to a silicon nitride microresonator. The injection-locking mechanism, combined with a high-Q microresonator, results in an ultra-narrow intrinsic linewidth at the fundamental harmonic frequency as small as 41 Hz. Owing to the extreme resonant field enhancement, quasi-phase-matched second-order nonlinearity is photoinduced through the coherent photogalvanic effect and the high coherence is mapped on the generated SH field. We show how such optical poling technique can be engineered to provide efficient SH generation across the whole C and L telecom bands, in a reconfigurable fashion, overcoming the need for poling electrodes. Our device operates with milliwatt-level pumping and outputs SH power exceeding 2 mW, for an efficiency as high as 280%/W under electrical driving. Our findings suggest that standalone, highly-coherent, and efficient SH sources can be integrated in current silicon nitride photonics, unlocking the potential of χ(2) processes in the next generation of integrated photonic devices.


[Depot fluphenazine as a means of stabilizing remission in cases of schizophrenia].
(1) The use of compounds with a prolonged effect completely does away with the uncontrolled intake of drugs, which leads to a considerable reduction in the number of relapses and exacerbations. (2) It allows a diminution of the maintenance dosage and thereby reduces the occurrence of side-effects and furthermore the danger of the chemo-toxic damaging of a series of inner organs and systems. (3) It facilitates the organisation of the treatment of patients in the hospital, so that a more frequent daily administration of drugs is unnecessary. (4) On the side of the patients, the feeling that their condition is constantly dependent of the intake of drugs is reduced and the notion that they suffer from a chronic incurable disease is weakened.


Strategies for development of novel antithrombotics: modulating thrombin's procoagulant and anticoagulant properties.
Thrombin is a serine proteinase that can interact with a large number of diverse macromolecular substrates, which results in either a procoagulant or anticoagulant effect. These divergent properties are physiologically regulated by the endogenous protein thrombomodulin. This review summarizes recent work on a variety of methods used to exploit the allosteric nature of the enzyme. The procoagulant and anticoagulant functions of thrombin can be modulated by sodium binding, site-directed mutagenesis, and a small synthetic molecule. Modulation of thrombin's intrinsic properties represents a novel approach to the development of unique antithrombotic agents.


Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy.
Overuse tendinopathy is problematic to manage clinically. People of different ages with tendons under diverse loads present with varying degrees of pain, irritability, and capacity to function. Recovery is similarly variable; some tendons recover with simple interventions, some remain resistant to all treatments. The pathology of tendinopathy has been described as degenerative or failed healing. Neither of these descriptions fully explains the heterogeneity of presentation. This review proposes, and provides evidence for, a continuum of pathology. This model of pathology allows rational placement of treatments along the continuum. A new model of tendinopathy and thoughtful treatment implementation may improve outcomes for those with tendinopathy. This model is presented for evaluation by clinicians and researchers.


How to Study Protein-protein Interactions.
Physical and functional interactions between molecules in living systems are central to all biological processes. Identification of protein complexes therefore is becoming increasingly important to gain a molecular understanding of cells and organisms. Several powerful methodologies and techniques have been developed to study molecular interactions and thus help elucidate their nature and role in biology as well as potential ways how to interfere with them. All different techniques used in these studies have their strengths and weaknesses and since they are mostly employed in in vitro conditions, a single approach can hardly accurately reproduce interactions that happen under physiological conditions. However, complementary usage of as many as possible available techniques can lead to relatively realistic picture of the biological process. Here we describe several proteomic, biophysical and structural tools that help us understand the nature and mechanism of these interactions.


Topology of the network integrating salicylate and jasmonate signal transduction derived from global expression phenotyping.
The signal transduction network controlling plant responses to pathogens includes pathways requiring the signal molecules salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). The network topology was explored using global expression phenotyping of wild-type and signaling-defective mutant plants, including eds3, eds4, eds5, eds8, pad1, pad2, pad4, NahG, npr1, sid2, ein2, and coi1. Hierarchical clustering was used to define groups of mutations with similar effects on gene expression and groups of similarly regulated genes. Mutations affecting SA signaling formed two groups: one comprised of eds4, eds5, sid2, and npr1-3 affecting only SA signaling; and the other comprised of pad2, eds3, npr1-1, pad4, and NahG affecting SA signaling as well as another unknown process. Major differences between the expression patterns in NahG and the SA biosynthetic mutant sid2 suggest that NahG has pleiotropic effects beyond elimination of SA. A third group of mutants comprised of eds8, pad1, ein2, and coi1 affected ethylene and jasmonate signaling. Expression patterns of some genes revealed mutual inhibition between SA- and JA-dependent signaling, while other genes required JA and ET signaling as well as the unknown signaling process for full expression. Global expression phenotype similarities among mutants suggested, and experiments confirmed, that EDS3 affects SA signaling while EDS8 and PAD1 affect JA signaling. This work allowed modeling of network topology, definition of co-regulated genes, and placement of previously uncharacterized regulatory genes in the network.


Polyvalent lactose-quantum dot conjugate for fluorescent labeling of live leukocytes.
Oligosaccharides play crucial roles in many biorecognition processes by the so-called "cluster glycosidic effect". We here report a facile synthesis of lactose-CdSeS/ZnS quantum dot conjugate (Lac-QDs) by use of 1-thiol-beta-D-lactose via ligand exchange, which exhibits significantly high affinity and specificity to leukocytes in contrast to the monovalent lactose. Structural analyses indicate that there are about 132 lactosyl molecules assembled on single QDs and the hydrodynamic diameter is small, close to 8.2 nm. Further, Lac-QDs display good fluorescence and physicochemical stability in physiological conditions, as well as extremely low cytotoxicity. These properties facilitate the use of Lac-QDs in fluorescent labeling of live leukocytes.


Structure of Ribosomal Subunits of M. vannielii: Ribosomal Morphology as a Phylogenetic Marker.
On the basis of ribosomal morphology, it has been proposed that the sulfur-metabolizing archaebacteria constitute a group (the eocytes) with a phylogenetic importance equal to that of the eubacteria, archaebacteria, and eukaryotes. It has been further proposed that eocytes should be given kingdom status. Ribosomal subunits from the methanogenic archaebacterium Methanococcus vannielii were examined by electron microscopy, and their structures were compared to those of other archaebacterial, eubacterial, and eukaryotic ribosomes. 30S subunits from M. vannielii showed the elongated contour and the one-third to two-thirds partition characteristic of such subunits. In addition, the angled asymmetric projections of those subunits showed a squarish base and a beak on the head. 50S subunits from M. vannielii were seen in both crown and kidney views. In crown views, the L1 protuberance was frequently pronounced and split; an incision below this protuberance and a protrusion at the base of the particle were also observed. Although previous studies suggested that certain of these structural features were found exclusively in ribosomes from sulfur-metabolizing archaebacteria, these new results indicate that such features also occur in ribosomes from a typical methanogenic archaebacterium and thus may not be reliable phylogenetic markers.


Impact of recent legislative bills regarding clinical research on Italian ethics committee activity.
The present work assessed the impact of two decrees on ethics committees in Italy, aimed at bringing the national laws on the conduct of clinical trials into line with the rest of the EC, and regulating and facilitating not-for-profit research. Prospectively collected data from an Italian multicentre study were examined with respect to the ethics review process. Administrative and time elements of the review process were audited. Main outcome measures were time between the application submission and the ethics committee definitive opinion, type and number of application submission forms, number of ethics committees that refused fee exemption, and time between the ethics committee approval and the administrative authorisation. A total of 134 local research ethics committees (LRECs) were approached. Application submission procedures and application forms varied greatly; paper submission was mandatory. The median time from submission to approval was 72 days. Only two LRECs refused the fee exemption. The median time from LREC approval to administrative agreement was 50 days and only 9.6% of local authorities came to a verbal agreement with the sponsor. Italian LRECs are still not sufficiently efficient in complying with the Directive 2001/20/EC requirement (60 days). Better coordination of LRECs work is needed although the optimal level of coordination between them is still not known. In the meantime, national guidelines are needed concerning the application of Directive 2001/20/EC. The behaviour of Italian LRECs towards not-for-profit research was excellent although only the fee exemption was requested.


Idealized analysis of SAW longitudinally coupled resonator filters.
A surface acoustic wave (SAW) longitudinally coupled resonator (LCR) filter consists of either two or three interdigital transducers located between two strongly reflecting gratings. The behavior of this structure is, in general, very complex because the transducers are of the single-electrode type, which gives strong electrode reflections. It is shown here that, for the filter passband, a number of realistic assumptions can be used to derive a very simple set of approximate relations for the device Y-matrix. The simplifications involve reciprocity, symmetry, and power conservation. The theory also uses the necessary fact that each grating, combined with its adjacent transducer, must have high directivity so that application of a voltage results in wave generation primarily toward the center of the device. For a three-transducer device, it is shown using symmetry that the central transducer behaves as if it were transparent, despite having strong electrode reflections. Hence, the device behaves as a single resonant cavity. The simple Y-matrix formulae are shown to agree very well with accurate results obtained by a coupling-of-modes (COM) analysis for both types of device. They also lead to simple formulae for the electrical loading required to obtain a flat, low-loss filter response. Equivalent circuits also are discussed.


The DEAD-box RNA helicase Vasa functions in embryonic mitotic progression in the sea urchin.
Vasa is a broadly conserved ATP-dependent RNA helicase that functions in the germ line of organisms from cnidarians to mammals. Curiously, Vasa is also present in the somatic cells of many animals and functions as a regulator of multipotent cells. Here, we report a mitotic function of Vasa revealed in the sea urchin embryo. We found that Vasa protein is present in all blastomeres of the early embryo and that its abundance oscillates with the cell cycle. Vasa associates with the spindle and the separating sister chromatids at metaphase, and then quickly disappears after telophase. Inhibition of Vasa protein synthesis interferes with proper chromosome segregation, arrests cells at M-phase, and delays overall cell cycle progression. Cdk activity is necessary for the proper localization of Vasa, implying that Vasa is involved in the cyclin-dependent cell cycle network, and Vasa is required for the efficient translation of cyclinB mRNA. Our results suggest an evolutionarily conserved role of Vasa that is independent of its function in germ line determination.


Psychosocial risk factors for depressive symptoms after the AZF chemical factory explosion in Toulouse, France.
On 21 September 2001, a huge explosion occurred in a chemical plant in Toulouse. The hypothesis of the study was that the level of depressive symptoms after an industrial disaster would be related to the intensity of exposure and the characteristics of the exposed population, as well as to the consequences of the disaster during the following months. A random sample of the population living close to the plant at the time of the explosion was included in a cross-sectional study, and 811 persons aged > 18 years were interviewed at home. The depressive symptoms score was analysed by gender in relation to characteristics of the population before the explosion, immediate exposure to the explosion and post-trauma factors. The mean depressive symptoms scores (± SD) 18 months after the explosion were 17.8 (± 1) in women and 13.5 (± 1) in men. Age > 45 years and psychiatric treatment in the previous year; high immediate exposure (proximity to the site at the time of the explosion < 2500 m); and post-trauma factors such as financial difficulties or physical sequelae during the months after the disaster were related to a higher depressive symptoms score in both men and women. In the population living near the site of an industrial explosion, individual vulnerability, exposure and post-trauma factors were associated with depressive symptoms. All three sets of factors need to be taken into account when planning a response to a disaster and reducing the psychological aftermath.


Towards Quantifying Stress in Patients with a History of Myocardial Infarction: Validating ECG-Derived Patch Features.
Patients with prior myocardial infarction (MI) have an increased risk of experiencing a secondary event which is exacerbated by mental stress. Our team has developed a miniaturized patch with the capability to capture electrocardiogram (ECG), seismocardiogram (SCG) and photoplethysmogram (PPG) signals which may provide multimodal information to characterize stress responses within the post-MI population in ambulatory settings. As ECG-derived features have been shown to be informative in assessing the risk of MI, a critical first step is to ensure that the patch ECG features agree with gold-standard devices, such as the Biopac. However, this is yet to be done in this population. We, thus, performed a comparative analysis between ECG-derived features (heart rate (HR) and heart rate variability (HRV)) of the patch and Biopac in the context of stress. Our dataset contained post-MI and healthy control subjects who participated in a public speaking challenge. Regression analyses for patch and Biopac HR and HRV features (RMSSD, pNN50, SD1/SD2, and LF/HF) were all significant (p<0.001) and had strong positive correlations (r>0.9). Additionally, Bland-Altman analyses for most features showed tight limits of agreement: 0.999 bpm (HR), 11.341 ms (RMSSD), 0.07% (pNN50), 0.146 ratio difference (SD1/SD2), 0.750 ratio difference (LF/HF).Clinical relevance- This work demonstrates that ECG-derived features obtained from the patch and Biopac are in agreement, suggesting the clinical utility of the patch in deriving quantitative metrics of physiology during stress in post-MI patients. This has the potential to improve post-MI patients' outcomes, but needs to be further evaluated.


Catch-up growth in females born short for gestational age reduces the risk of giving birth to short-for-gestational-age infants.
The aim of the present study was to study the effect of catch-up growth on the offspring's length at birth among females born short for gestational age. Data of 1,363 females born short for gestational age (<-2 standard deviation scores) were obtained from the Swedish Birth Register. The females were included in the register both as babies and mothers. The effect of catch-up growth on the offspring's birth length was studied. Short adult stature was associated with a threefold increase in the risk of giving birth to a short infant [OR 3.08 (CI 1.73-5.50)] and smoking increased the risk in a dose-dependent manner. Overweight was associated with a reduced risk [OR 0.46 (CI 0.22-0.96)] of giving birth to a short infant. Catch-up growth to normal adult stature among women born short for gestational age is associated with a reduced risk of giving birth to a short-for-gestational-age infant.


Light-dependent magnetoreception: quantum catches and opponency mechanisms of possible photosensitive molecules.
Dozens of experiments on magnetosensitive, migratory birds have shown that their magnetic orientation behavior depends on the spectrum of light under which they are tested. However, it is not certain whether this is due to a direct effect on the magnetoreceptive system and which photosensitive molecules may be involved. We examined 62 experiments of light-dependent magnetoreception in three crepuscular and nocturnal migrants (48 for the European robin Erithacus rubecula, ten for the silvereye Zosterops lateralis, and four on the garden warbler Sylvia borin). For each experiment, we calculated the relative quantum catches of seven of the eight known photosensitive molecules found in the eyes of passerine birds: a short- (SW), medium- (MW) and long-wavelength (LW) cone pigment, rhodopsin, melanopsin, and cryptochrome in its fully-oxidized and semiquinone state. The following five opponency processes were also calculated: LW-SW, LW-MW, MW-SW, LW-(MW+SW), and cryptochrome-semiquinone. While the results do not clearly show which receptor system may be responsible for magnetoreception, it suggests several candidates that may inhibit the process. The two significant inhibitors of magnetoreceptive behavior were overall irradiances (from 400 to 700 nm) higher than those found at sunset and high quantum catch by the LW receptor. The results were also consistent with the hypothesis that high quantum catch by the semiquinone form of cryptochrome inhibits magnetoreception. The opponency mechanism that best separated oriented from non-oriented behavior was LW-MW, where a difference above a certain level inhibited orientation. Certain regions of experimental spectral space have been over-sampled, while large regions have not been sampled at all, including: (1) from 440 to 500 nm at all irradiance levels, (2) for wavelengths longer than 570 nm from 10(12) to 3x10(12) photons s(-1) cm(-2) and (3) for wavelengths less than 560 nm from 10(12) to 3x10(12) photons s(-1) cm(-2) and below 5x10(11) photons s(-1) cm(-2). Experiments under these conditions are needed to draw further conclusions.


Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: cellular mechanisms of input selection.
Inputs from multiple sites in the telencephalon, including the hippocampus and basolateral amygdala (BLA), converge on neurons in the nucleus accumbens (NAc), and dopamine (DA) is believed to play an essential role in the amplification and gating of these different limbic inputs. The present study used extracellular single-unit recordings of NAc neurons in combination with chronoamperometric sampling of mesoaccumbens DA efflux to assess the importance of DA in the integration of different limbic inputs to the NAc. Tetanic stimulation of the fimbria potentiated hippocampal-evoked firing activity of NAc neurons and increased DA extracellular levels. Systemic administration of the D(1) receptor antagonist SCH23390 or the NMDA receptor antagonist CPP abolished the potentiation of hippocampal-evoked activity and produced a D(2) receptor-mediated suppression of evoked firing. In neurons that received converging input from the hippocampus and BLA, fimbria tetanus potentiated hippocampal-evoked firing activity and suppressed BLA-evoked activity in the same neurons. Both D(1) and NMDA receptors participated in the potentiation of fimbria-evoked activity, whereas the suppression of BLA-evoked activity was blocked by either D(1) receptor antagonism with SCH23390 or the adenosine A(1) antagonist 8-cyclopentyl-1,2-dimethylxanthine. Coincidental tetanus of both the fimbria and BLA resulted in potentiation of both inputs, indicating that DA and adenosine-mediated suppression of BLA-evoked firing was activity-dependent. These data suggest that increases in mesoaccumbens DA efflux by hippocampal afferents to the NAc play a critical role in an input selection mechanism, which can ensure preferential responding to the information conveyed from the hippocampus to the ventral striatum.


The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking.
Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. rLTL was measured by qPCR in a Swedish population-based glioma case-control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02-1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. In this Swedish glioma case-control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.


RNA-Seq analysis of long non-coding RNA in human intestinal epithelial cells infected by Shiga toxin-producing Escherichia coli.
The Shiga toxin-producing Escherichia coli (STEC) infects animals and induces acute intestinal inflammation. Long non-coding RNAs (lncRNAs) are known to play crucial roles in modulating inflammation response. However, it is not clear whether lncRNAs are involved in STEC-induced inflammation. To understand the association of lncRNAs with STEC infection, we used RNA-seq technology to analyze the profiles of lncRNAs in Mock-infected and STEC-infected human intestinal epithelial cells (HIECs). We detected a total of 702 lncRNAs differentially expressed by STEC infection. 583 differentially expressed lncRNAs acted as competitive microRNAs (miRNAs) binding elements in regulating the gene expression involved in TNF signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, and apoptosis pathways. We analyzed 3 targeted genes, TRADD, TRAF1 and TGFB2, which were differentially regulated by mRNA-miRNA-lncRNA interaction network, potentially involved in the inflammatory and apoptotic response to STEC infection. Functional analysis of up/downstream genes associated with differentially expressed lncRNAs revealed their role in adheres junction and endocytosis. We also used the qRT-PCR technique to validate 8 randomly selected differentially expressed lncRNAs and mRNAs in STEC-infected HIECs. Our results, for the first time, revealed differentially expressed lncRNAs induced by STEC infection of HIECs. The results will help investigate the molecular mechanisms for the inflammatory responses induced by STEC.


Neurogenesis in the neocortex of adult primates.
In primates, prefrontal, inferior temporal, and posterior parietal cortex are important for cognitive function. It is shown that in adult macaques, new neurons are added to these three neocortical association areas, but not to a primary sensory area (striate cortex). The new neurons appeared to originate in the subventricular zone and to migrate through the white matter to the neocortex, where they extended axons. These new neurons, which are continually added in adulthood, may play a role in the functions of association neocortex.


Immunohistochemical analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice.
Dioxins are widespread persistent environmental contaminants with adverse impacts on humans and experimental animals. Behavioral and cognitive functions are impaired by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. TCDD exerts its toxicity via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. The hippocampus, which plays important roles in episodic memory and spatial function, is considered vulnerable to TCDD-induced neurotoxicity, because it contains the AhR. We herein investigated the effects of TCDD toxicity on hippocampal development in embryonic mice. TCDD was administered to dams at 8.5 days postcoitum with a single dose of 20, 200, 2,000 and 5,000 ng/kg body weight (groups T20, T200, T2000 and T5000, respectively), and the brains were dissected from their pups at embryonic day 18.5. Immunohistochemical analysis demonstrated that the Glial Fibrillary Acidic Protein (GFAP) immunoreactivities in the dentate gyrus (DG) were reduced in the T5000 group. Granular GFAP immunoreactivity was observed in the hippocampal fimbria, and the number of immunoreactive fimbria was significantly decreased in the T5000 group. The number of Proliferating Cell Nuclear Antigen (PCNA)-positive cells was decreased in all TCDD-exposed groups and significantly reduced in the T20, T200 and T5000 groups. Together, these results demonstrate that maternal TCDD exposure has adverse impacts on neural stem cells (NSCs), neural precursor cells (NPCs) and granular cells in the DG and disrupts the NSC maintenance and timing of differentiation in the hippocampal fimbria, which in turn interrupt neuronal development in future generations of mice.


Control of soliton self-frequency shift dynamics via Airy soliton interaction.
We investigate Airy-soliton interaction in a nonlinear fiber with Raman effect. We find that Airy solitons may fuse upon interaction at a position that can be controlled by a proper engineering of the Airy tail direction. This control allows us to generate Airy solitons with varying deceleration. At variance with the case of two solitons interaction, Raman-induced soliton self-frequency shift (SSFS) is strongly enhanced when the leading soliton is replaced with the accelerating Airy pulse and slightly suppressed for the decelerating one. These notable features are ascribed to the unique properties of asymmetrical Airy pulses with a switchable direction of the oscillatory tails. We show the way these processes are uncovered unambiguously by cross-correlation frequency resolved optical gating. We also investigate the impact of chirp imposed on the input pulse on the SSFS dynamics. Our results not only provide a new way to manipulate the SSFS, but may help to improve the control of soliton fusion events during supercontinuum generation, optical rogue waves and giant dispersive waves formation.


Aging Affects Bone Marrow Macrophage Polarization: Relevance to Bone Healing.
Macrophages are an important component of the inflammatory cascade by initiating and modulating the processes leading to tissue regeneration and bone healing. Depending on the local environment, macrophages can be polarized into M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. In order to assess the effects of aging on macrophage function, bone marrow macrophage polarization using primary bone marrow macrophages (BMMs) from young (8 weeks old) and aged (72 weeks old) wild-type male C57BL/6J mice was analyzed. Fluorescence-activated cell sorting (FACS) analysis (CD11b, iNOS, CD206), qRT-PCR (iNOS, TNF-α, CD206, Arginase 1), and ELISA (TNF-α, IL-1ra) were performed to compare the M1 and M2 phenotypic markers in young and aged mouse macrophages. Once M1 and M2 macrophage phenotypes were confirmed, the results showed that TNF-α mRNA was significantly upregulated in aged M1s after interferon gamma (INF-γ) exposure. Arginase 1 and CD206 mRNA expression were still upregulated with IL4 stimulation in aged macrophages, but to a lesser extend than those from younger animals. TNF-α secretion was also significantly increased in aged M1s compared to young M1s, following lipopolysaccharide (LPS) exposure. However, the IL-1ra secretion did not increase accordingly in aged mice. The results demonstrate that, compared to younger animals, aging of bone marrow derived macrophages increases the resting levels of oxidative stress, and the ratios of pro- to anti-inflammatory markers. These age-related changes in macrophage polarization may explain in part the attenuated response to adverse stimuli and delay in processes such as fracture healing seen in the elderly. Bone healing is a complex process that involves both biological and mechanical factors. Macrophages are key cells that regulate the events involved in bone healing, especially the initial inflammatory phase. In this biological cascade of events, macrophages present as different functional phenotypes including uncommitted (M0), pro-inflammatory (M1), and anti-inflammatory (M2), a process called macrophage polarization. A clear understanding of the effects of aging on macrophage polarization is critical to modulating adverse events such as fractures, atraumatic bone loss, and tissue regeneration in an aging population.


Computed tomographic angiography as a screening modality for blunt cervical arterial injuries: preliminary results.
The diagnosis of blunt cervical arterial injury (CAI) is made difficult by its infrequent occurrence and delayed presentation. Beginning in January of 1995, we used computed tomographic angiography (CTA) of the neck to screen for CAI. We hypothesized that CTA could be incorporated into the workup of patients sustaining blunt neck injury as a screening modality for CAI and that CTA would increase the early detection of CAI. Retrospective review of all CAI for the years January of 1988 to June of 1997 at a Level I trauma center. CAI diagnosed before introduction of CTA (pre-CTA; January of 1988 to December of 1994) were compared with those after (post-CTA; January of 1995 to June of 1997). The overall incidence of CAI for the entire time period was 0.11%. Motor vehicle crash (53%) was the most common mechanism, with focal neurologic deficit (23%) or seizures (17.6%) the most common presenting clinical symptoms. CTA added only a few additional minutes to the time required for the workup of patients sustaining blunt neck injury in whom CAI was suspected. The incidence of CAI increased from 0.06% pre-CTA to 0.19% post-CTA (p = 0.02; Fisher exact test). CTA was associated with a decrease in mean time to make the diagnosis of CAI (156 hours pre-CTA vs. 5.9 hours post-CTA). In addition, CTA was associated with a decrease in the incidence of permanent neurologic sequelae from CAI (50% pre-CTA vs. 0% post-CTA; p = 0.07; Fisher exact test). We conclude that CTA does not significantly increase the time of the diagnostic workup of the patient with injuries caused by blunt trauma. The introduction of CTA at our institution was associated with an increase in the detection rate of CAI. Earlier detection of CAI may allow for more timely therapeutic intervention and potentially prevent permanent neurologic sequelae.


RISK FACTORS ASSOCIATED WITH HEPATIC ARTERY THROMBOSIS: ANALYSIS OF 1050 LIVER TRANSPLANTS.
Hepatic artery thrombosis is an important cause of graft loss and ischemic biliary complications. The risk factors have been related to technical aspects of arterial anastomosis and non-surgical ones. To evaluate the risk factors for the development of hepatic artery thrombosis. The sample consisted of 1050 cases of liver transplant. A retrospective and cross-sectional study was carried out, and the variables studied in both donor and recipient. Univariate analysis indicated that the variables related to hepatic artery thrombosis are: MELD (p=0.04) and warm time ischemia (p=0.005). In the multivariate analysis MELD=14.5 and warm ischemia time =35 min were independent risk factors for hepatic artery thrombosis. In the prevalence ratio test for analysis of the anastomosis as a variable, it was observed that patients with continuous suture had an increase in thrombosis when compared to interrupted suture. Prolonged warm ischemia time, calculated MELD and recipient age were independent risk factors for hepatic artery thrombosis after liver transplantation in adults. Transplanted patients with continuous suture had an increase in thrombosis when compared to interrupted suture. Re-transplantation due to hepatic artery thrombosis was associated with higher recipient mortality.


Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution.
Five sequence-related genes encoding four adrenergic receptors and a serotonin receptor were localized to specific regions of four mouse chromosomes with respect to 11 other genetic markers. Linkage was established by the analysis of the haplotypes of 114 interspecific backcross mice. Adra2r (alpha 2-C10) and Adrb1r (beta 1) receptors mapped to the distal region of mouse chromosome 19. These genes were separated by 2.6 +/- 1.5 cM in a segment of mouse chromosome 19 that has a similar organization of these genes on the long arm of human chromosome 10. The Adra1r (alpha 1B), Adrb2r (beta 2), and Htra1 (5HT1A) genes mapped to proximal mouse chromosome 11, proximal mouse chromosome 18, and distal mouse chromosome 13, respectively. The organization of genes linked to these loci on regions of the three mouse chromosomes is consistent with the organization of homologous human genes on human chromosome 5. These findings further define the relationship of linkage groups conserved during the evolution of the mouse and human genomes. We have identified a region that may have been translocated during evolution and suggest that the human genomic organization of adrenergic receptors more closely resembles that of a putative primordial ancestor.


Reconstruction of large diaphyseal defects, without free fibular transfer, in Grade-IIIB tibial fractures.
Eight Grade-IIIB tibial fractures that were associated with large soft-tissue and segmental diaphyseal defects, averaging ten centimeters in length, were successfully reconstructed without the use of a free fibular transfer. A free tissue flap was the preferred form of soft-tissue coverage. The osseous reconstruction was accomplished by using a massive amount of autogenous cancellous bone graft. Beads that were made from polymethylmethacrylate and impregnated with two antibiotics at the time of operation were used as soft-tissue spacers to preserve the volume of the diaphyseal defect for later receipt of the cancellous bone graft. The beads prevented the soft-tissue flap from collapsing into and adhering to the site of the tibial defect. The beads also served as vehicles for local delivery of the antibiotics that they contained. When the soft-tissue flap had healed, the beads were replaced with cancellous graft. All of the tibiae healed. The time to healing averaged nine months. The average duration of external fixation was 5.5 months. One deep infection developed, but resolved after debridement and antibiotic therapy. This conservative technique is safe and reliable for patients who have sustained a high-energy tibial fracture and a large segmental diaphyseal defect.


Teaching the Rational Use of Medicines to medical students: a qualitative research.
Prescribing is a complex and challenging task that must be part of a logical deductive process based on accurate and objective information and not an automated action, without critical thinking or a response to commercial pressure. The objectives of this study were 1) develop and implement a discipline based on the WHO's Guide to Good Prescribing; 2) evaluate the course acceptance by students; 3) assess the impact that the Rational Use of Medicines (RUM) knowledge had on the students habits of prescribing medication in the University Hospital. In 2003, the RUM principal, based in the WHO's Guide to Good Prescribing, was included in the official curriculum of the Botucatu School of Medicine, Brazil, to be taught over a total of 24 hours to students in the 4th year. We analyzed the students' feedback forms about content and teaching methodology filled out immediately after the end of the discipline from 2003 to 2010. In 2010, the use of RUM by past students in their medical practice was assessed through a qualitative approach by a questionnaire with closed-ended rank scaling questions distributed at random and a single semistructured interview for content analysis. The discipline teaches future prescribers to use a logical deductive process, based on accurate and objective information, to adopt strict criteria (efficacy, safety, convenience and cost) on selecting drugs and to write a complete prescription. At the end of it, most students considered the discipline very good due to the opportunity to reflect on different actions involved in the prescribing process and liked the teaching methodology. However, former students report that although they are aware of the RUM concepts they cannot regularly use this knowledge in their daily practice because they are not stimulated or even allowed to do so by neither older residents nor senior medical staff. This discipline is useful to teach RUM to medical students who become aware of the importance of this subject, but the assimilation of the RUM principles in the institution seems to be a long-term process which requires the involvement of a greater number of the academic members.


Comparative effectiveness of post-discharge strategies for hospitalized smokers: Study protocol for the Helping HAND 4 randomized controlled trial.
Tobacco smoking remains the leading preventable cause of death in the US. A hospital admission provides smokers with a unique opportunity to stop smoking because it requires temporary tobacco abstinence while illness may enhance motivation to quit. Hospital interventions must continue post-discharge to increase tobacco abstinence long-term, but how best to accomplish this remains unclear. Building on two previous randomized controlled trials, each of which tested smoking cessation interventions that began in hospital and continued after discharge, this trial compares two interventions that provide sustained smoking cessation treatment after hospital discharge with the goal of improving long-term smoking cessation rates among hospitalized smokers. Helping HAND 4 is a three-site randomized controlled trial that compares the effectiveness of two active interventions for producing validated past 7-day tobacco abstinence 6 months after hospital discharge. Smokers who are admitted to three hospitals receive a standard in-hospital smoking intervention, and those who plan to quit smoking after discharge are recruited and randomly assigned to two interventions that begin at discharge, Personalized Tobacco Care Management (PTCM) or Quitline eReferral. Each lasts 3 months. At discharge, PTCM provides 8 weeks of free nicotine replacement (NRT; a participant's choice of patch, gum, lozenge, or a combination) and then proactive smoking cessation support using an automated communication platform and live contact with a tobacco treatment specialist who is based in the health care system. In the eReferral condition, a direct referral is made from the hospital electronic health record to a community-based resource, the state's telephone quitline. The quitline provides up to 8 weeks of free NRT and offers behavioral support via a series of phone calls from a trained coach. Outcomes are assessed at 1, 3, and 6 months after discharge. The study hypothesis is that PTCM will produce higher quit rates than eReferral. Helping HAND 4 is a pragmatic trial that aims to evaluate interventions in real-world conditions. This project will give hospital systems critical evidence-based tools for meeting National Hospital Quality Measures for tobacco treatment and maximizing their ability to improve cessation rates and overall health for the millions of smokers hospitalized annually in the US. Prospectively registered prior to start of enrollment at Clinicaltrials.gov, NCT03603496 (July 27, 2018). https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S00084MJ&selectaction=Edit&uid=U00002G7&ts=2&cx=ff0oxn.


Representations of influenza and influenza-like illness in the community--a qualitative study.
There is little information regarding lay-people's representations of influenza and influenza-like illness in their day-to-day lives. An insight into these views may aid our understanding of community attitudes regarding official recommendations for its prevention. This was a qualitative research. Semi-structured face-to-face interviews were conducted with 40 French participants from the community, and from five different locations. Questions elicited the participants' representations of onset of flu and influenza-like illness, as well as their views on what can/should be done to deal with symptoms and their personal experience with flu and flu-like symptoms. Thematic content analyses allowed us to identify five main themes: the presence of a clear continuum between influenza-like illness and flu; a description of flu as a very contagious disease; flu as being benign, except in "frail people", which the respondents never considered themselves to be; interruption of daily activities, which could be considered pathognomonic for influenza for most subjects; self-medication as the main current practice, and requests for healthcare mainly to confirm an auto-diagnosis. There was a large homogeneity in the representation of flu. There was also a gap between people's representations (i.e., a continuum from having a "cold" to having "influenza") and scientific knowledge (i.e., a distinction between "true" influenza and influenza-like illnesses based on the existence of a confirmatory virological diagnosis). This gap raises issues for current campaigns for flu prevention, as these may not be congruent with the representation of flu being responsible for interrupting daily activities while also being seen as a non-severe disease, as well as the perception that flu is only a risk to "frail people" though no participants considered themselves to be "frail".


Bias-corrected paralinear and LogDet distances and tests of molecular clocks and phylogenies under nonstationary nucleotide frequencies.
The statistical properties of the paralinear and LogDet distances under nonstationary nucleotide frequencies were studied. First, we developed formulas for correcting the estimation biases of the paralinear and LogDet distances, i.e., the bias-corrected distance is estimated by dc = d - 2var(d), where d and var(d) are the estimated distance and sampling variance, respectively. The performances of these formulas and the formulas for sampling variances were examined by computer simulation. Second, we developed a method for estimating the variance-covariance matrix of paralinear distances, so that statistical tests of DNA phylogenies can be conducted in the nonstationary case. Third, a new LogDet-based method for testing the molecular clock hypothesis was developed under nonstationary nucleotide frequencies.


Accessibility and use of primary healthcare for immigrants living in the Niagara Region.
Although the challenges of accessing and using primary healthcare for new immigrants to Canada have been fairly well documented, the focus has primarily been on large cities with significant immigrant populations. The experiences of immigrants living in smaller, less diverse urban centres remain largely unknown. The purpose of this study was to examine the lived experiences of immigrants living in a small urban centre with regards to the primary healthcare system. A total of 13 immigrants living in the Greater Niagara Region participated in semi-structured interviews. All interviews were recorded, transcribed, and then coded and analyzed for emergent themes using NVivo. Five factors were found to impact primary care access and use: lack of social contacts, lack of universal healthcare coverage during their initial arrival, language as a barrier, treatment preferences, and geographic distance to primary care. Overall findings suggest that immigrants moving to smaller areas such as the Niagara Region face similar barriers to primary care as those moving into large cities. Some barriers, however, appear to be specific to the context of smaller urban centres, further exacerbated by living in a small city due to a smaller immigrant population, fewer services for immigrants, and less diversity in practicing physicians. More research is required to understand the contextual factors inhibiting primary care access and use among immigrants moving to smaller urban centres, and determine effective strategies to overcome these barriers.


Rapid and selective enzymatic debridement of porcine comb burns with bromelain-derived Debrase: acute-phase preservation of noninjured tissue and zone of stasis.
Deep burns are associated with the formation of an eschar, which delays healing and increases the risk of infection. Surgical debridement of the eschar is, at present, the fastest means to achieve an eschar-free bed, but the process can not differentiate between the viable tissue and the eschar and follow the minute irregularities of the interface between the two. We evaluated the efficacy and selectivity of a novel enzymatic bromelain-based debriding agent, Debrase Gel Dressing (Debrase), in a porcine comb burn model. We hypothesized that Debrase would result in rapid debridement of the eschar without adverse effects on the surrounding uninjured skin. This is a prospective, controlled, animal experiment. Five domestic pigs (20-25 kg) were used in this study. Sixteen burns were created on each animal's dorsum using a brass comb with four rectangular prongs preheated in boiling water and applied for 30 seconds, resulting in four rectangular 10 x 20 mm full-thickness burns and separated by three 5 x 20 mm unburned interspaces representing the zone of stasis. The burned keratin layer (blisters) was removed, and the burns were treated with a single, topical, Debrase or control vehicle application for 4 hours. The Debrase/control was then wiped off using a metal forceps handle, and the burns were treated with a topical silver sulfadiazine (SSD). The wounds were observed, and full-thickness biopsies were obtained at 4 and 48 hours for evidence of dermal thickness, vascular thrombosis, and burn depth, both within the comb burns and the unburned interspaces in between them. Chi-square and t tests are used for data analysis. A single 4-hour topical application of Debrase resulted in rapid and complete eschar dissolution of all the burns in which the keratin layer was removed. The remaining dermis was thinner (1.1 +/- 0.7 mm) than in the control burns (2.1 +/- 0.3 mm; difference 0.9 mm [95% confidence interval: 0.3-1.4]) and was viable with no injury to the normal surrounding skin or to the unburned interspaces between the burns, which represents the zone of stasis. In control burns, the entire thickness of the dermis was necrotic. At 48 hours, Debrase-treated areas were found partially desiccated under SSD treatment. The unburned interspaces demonstrated partial-thickness necrosis in two third and full-thickness necrosis in one third of wounds. In contrast, full-thickness necrosis was noted in all control interspaces (P = .05). In a porcine comb burn model, a single, 4-hour topical application of Debrase resulted in rapid removal of the necrotic layer of the dermis with preservation of unburned tissues. At 48 hours, SSD treatment resulted in superficial tissue damage and partial preservation of the unburned interspaces.


The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care.
NAFLD is common in primary care. Liver fibrosis stage 2 or higher (≥F2) increases future risk of morbidity and mortality. We developed and validated a score to aid in the initial assessment of liver fibrosis for NAFLD in primary care. Data from patients with biopsy-proven NAFLD were extracted from the NASH Clinical Research Network observational study ( n = 676). Using logistic regression and machine-learning methods, we constructed prediction models to distinguish ≥F2 from F0/1. The models were tested in participants in a trial ("FLINT," n = 280) and local patients with NAFLD with magnetic resonance elastography data ( n = 130). The final model was applied to examinees in the National Health and Nutrition Examination Survey (NHANES) III ( n = 11,953) to correlate with long-term mortality. A multivariable logistic regression model was selected as the Steatosis-Associated Fibrosis Estimator (SAFE) score, which consists of age, body mass index, diabetes, platelets, aspartate and alanine aminotransferases, and globulins (total serum protein minus albumin). The model yielded areas under receiver operating characteristic curves ≥0.80 in distinguishing F0/1 from ≥F2 in testing data sets, consistently higher than those of Fibrosis-4 and NAFLD Fibrosis Scores. The negative predictive values in ruling out ≥F2 at SAFE of 0 were 88% and 92% in the two testing sets. In the NHANES III set, survival up to 25 years of subjects with SAFE < 0 was comparable to that of those without steatosis ( p = 0.34), whereas increasing SAFE scores correlated with shorter survival with an adjusted HR of 1.53 ( p < 0.01) for subjects with SAFE > 100. The SAFE score, which uses widely available variables to estimate liver fibrosis in patients diagnosed with NAFLD, may be used in primary care to recognize low-risk NAFLD.


Limited preoperative knee extension in anterior cruciate ligament reconstruction using a hamstring tendon affects improvement of postoperative knee extensor strength.
This study aimed to determine the factors affecting knee extensor strength 6 months after anterior cruciate ligament (ACL) reconstruction using autograft hamstring tendon. 144 patients who could undergo regular follow-up after ACL reconstruction were divided into 2 groups: those with greater than 90% (Group A: n = 95) and less than 85% (Group B: n = 49) isokinetic knee contraction at 60°/s 6 months post-ACL reconstruction. Basic information, injury status, limited preoperative knee extension, and knee extensor strength at 3 and 6 months postoperatively were compared between the groups. Multivariate logistic analysis was performed and included variables that showed statistically significant differences between the groups in the univariate analysis. In addition, the cut-off value for the limb symmetry index (LSI) at 3 months postoperatively needed to exceed an LSI of 90% at 6 months postoperatively was calculated using the receiver operating characteristics curve. Age, preoperative waiting period, limited preoperative knee extension, and knee extensor strength at 3 months postoperatively were significantly different between the two groups. The multivariate logistic analysis showed that all the variables affected the improvement in knee extensor strength at 6 months postoperatively. Limited preoperative knee extension was the most significant factor (odds ratio: 15.1, 95% confidence interval: 2.57-118.56, p < 0.01). The LSI cut-off value at 3 months postoperatively was 72.0%. Key factors in achieving the necessary knee extensor strength criteria for return to sports at 6 months post-ACL reconstruction include addressing limited preoperative knee extension and achieving an LSI ≥ 72% in knee extensor strength at 3 months postoperatively. Level III.


Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide.
Cancer maintenance, metastatic dissemination and drug resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest number of CSCs and the poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. The anti-CSC efficacy of up to 17 small drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness features were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes after 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on CSC proliferation and stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSC-enriched mammospheres. Finally, the efficacy of NCS in combination with PTX was analyzed in vivo using an orthotopic mouse model of MDA-MB-231 cells. Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The sole use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination of 8Q and NCS counteracted this pro-CSC activity of PTX while significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth and limited the dissemination of the disease by reducing circulating tumor cells and the incidence of lung metastasis. The combination of 8Q and NCS with PTX at established ratios inhibits both the proliferation of differentiated cancer cells and the viability of CSCs, paving the way for more efficacious TNBC treatments.


Tuning the magnetic anisotropy energy by external electric fields of CoPt dimers deposited on graphene.
In the framework of first-principles calculations, we comprehensively investigate the external electric-field (EF) manipulation of the magnetic anisotropy energy (MAE) of alloyed CoPt dimers deposited on graphene. In particular, we focus on the possibility of tuning the MAE barriers under the action of external EFs and on the effects of Co-substitution. Among the various considered structures, the lowest-energy configurations were the hollow-upright and top-upright, having the Co-atom closest to the graphene layer. The optimal and higher energy configurations were related to the electronic structure through the local density of states and hybridizations between the transition-metal (TM) atoms of the dimer and graphene. In contrast to Co2/graphene [M. Tanveer, J. Dorantes-Dávila and G. M. Pastor, Phys. Rev. B, 2017, 96(22), 224413.], the CoPt dimer having the hollow-upright ground-state configuration, exhibits a much lower value of the MAE (about |ΔE| ≃ 4.5 meV per atom) and the direction of the magnetization lies in the graphene layer. Moreover, we observe a spin-reorientation transition occurring at εz ≃ 0.5 V Å-1, which opens the possibility of inducing magnetization switching by external electric fields. The microscopic origin of the changes of the MAE associated with changes in the EF has been qualitatively related to the details of the electronic structure by analyzing the local density of states and to the spin-dependent electronic densities close to the Fermi energy. Finally, the role of local environment was quantified by performing electronic structure and magnetic calculations on several higher-energy structure configurations.


The New Surgical Technique for Improving Total Knee and Hip Arthroplasty Outcomes: Patient Selection.
Inclusion of patient satisfaction scores in setting reimbursements has been suggested by health care policy makers to contain cost and improve outcomes. The Short Form 36 Health Survey (SF-36) score provides a health-related quality of life (HRQoL) measure of arthroplasty outcome. Although previous work identified factors that influence this score for hip and knee arthroplasty patients, they did not focus on how a surgeon might use this information in a clinical setting. The present study examined whether relatively simple criteria might identify patients more likely to experience minimal HRQoL improvement. "Improvements" in SF-36 composite physical scores and subscales were calculated from the difference between initial (preoperative) and SF-36 scores at 1 year. The rates of achieving a clinically significant improvement were compared between patient groups. After knee arthroplasty, women and younger patients achieved a clinically significant improvement in physical function more frequently than men and older patients (P = .04 and .02, respectively). The largest differences in improvement occurred between the diabetic and nondiabetic groups (P = .001), where the diabetic patients with ≥2 additional comorbidities demonstrated the lowest rate of achieving a clinically significant improvement in physical function and bodily pain. In comparison, in hip patients only age had significant influence on gains in physical function, but this did not alter the rate at which patients achieved a clinically significant improvement. These data indicate simple screening criteria can identify patients where arthroplasty might provide marginal HRQoL improvement. They suggest HRQoL-based reimbursement incentives will favor practices with younger, healthier patient populations.


Critically timed ethanol exposure reduces GABAAR function on septal neurons developing in vivo but not in vitro.
Six-day 'binge' ethanol intoxication postnatal days (PD) 4-9 delays up-regulation of gamma-aminobutyric acid type A receptors (GABAARs) in developing rat septal neurons [Dev. Brain Res. 130 (2001) 25]. This distortion occurs during synaptogenesis and could contribute to cognitive dysfunction in fetal alcohol syndrome (FAS). Here, we asked two questions concerning requirements for vulnerability to GABAAR blunting by ethanol. First, we asked whether receptor blunting required PD 4-9 ethanol exposure in rat pups and found that just a brief 2-day exposure (PD 8-9) was as effective as all 6 days. However, 2-day exposure on PD 4-5 was ineffective, showing that 'binge' timing was important. We also asked whether 'binge' exposure directly inhibited intrinsic processes of septal neurons and could blunt GABAARs on cells maturing outside the brain. Embryonic septal neurons grown in serum-free dispersed culture developed extensive dendritic arborizations, spontaneous synaptic activity and robust whole-cell GABAAR function, but surprisingly, did not show developmental up-regulation of GABAARs like septal neurons maturing in vivo [Brain Res. 810 (1998) 100]. Furthermore, age-matched 6-day 'binge' ethanol exposure did not blunt GABAAR function in septal neurons in vitro. These results suggest developmental mechanisms driving up-regulation of GABAAR function in septal neurons in vivo briefly becomes vulnerable to ethanol insult in early postnatal life. While septal neurons express comparable functional GABAARs whether maturing in vivo or in vitro, vulnerability to ethanol-induced receptor blunting requires elements of an intact brain environment not replicated in culture.


Sulfate-reducing bacteria in marine sediment (Aarhus Bay, Denmark): abundance and diversity related to geochemical zonation.
In order to better understand the main factors that influence the distribution of sulfate-reducing bacteria (SRB), their population size and their metabolic activity in high- and low-sulfate zones, we studied the SRB diversity in 3- to 5-m-deep sediment cores, which comprised the entire sulfate reduction zone and the upper methanogenic zone. By combining EMA (ethidium monoazide that can only enter damaged/dead cells and may also bind to free DNA) treatment with real-time PCR, we determined the distributions of total intact bacteria (16S rDNA genes) and intact SRB (dsrAB gene), their relative population sizes, and the proportion of dead cells or free DNA with depth. The abundance of SRB corresponded in average to 13% of the total bacterial community in the sulfate zone, 22% in the sulfate-methane transition zone and 8% in the methane zone. Compared with the total bacterial community, there were relatively less dead/damaged cells and free DNA present than among the SRB and this fraction did not change systematically with depth. By DGGE analysis, based on the amplification of the dsrA gene (400 bp), we found that the richness of SRB did not change with depth through the geochemical zones; but the clustering was related to the chemical zonation. A full-length clone library of the dsrAB gene (1900 bp) was constructed from four different depths (20, 110, 280 and 500 cm), and showed that the dsrAB genes in the near-surface sediment (20 cm) was mainly composed of sequences close to the Desulfobacteraceae, including marine complete and incomplete oxidizers such as Desulfosarcina, Desulfobacterium and Desulfococcus. The three other libraries were predominantly composed of Gram-positive SRB.


The determination of magnesium in biological materials by flame photometry.
A method is described for the measurement of magnesium in biological materials and has been applied to the Unicam flame spectrophotometer SP 900. Samples were diluted in 10 mM strontium ethylenedinitrolo tetraacetate (EDTASr), 10 mM potassium carbonate, giving final magnesium concentrations of about 0.1 to 0.2 mM. The EDTASr almost eliminated the depression of magnesium emission by interfering anions. The potassium carbonate slightly depressed both magnesium emission and flame background, which were then virtually unaffected by further addition of cations. Spectral interference by sodium was controlled by including 14 mM sodium chloride in the plasma standards and making small corrections (usually under 2%) on the basis of the plasma sodium level. The urine standards contained no sodium, but a small correction (usually about 2%) was made on the basis of the urine sodium level. There was insufficient sodium in faeces to cause spectral interference. Using the diluent described, added magnesium was satisfactorily recovered from plasma deproteinized with perchloric acid, urine, and faeces. When different volumes of identical samples of plasma and urine were analysed, the magnesium found was proportional to the volume of sample diluted. The plasma magnesium levels reported for a small group of healthy people were similar to those found by previous workers.


Diosmin ameliorates LPS-induced depression-like behaviors in mice: inhibition of inflammation and oxidative stress in the prefrontal cortex.
Diosmin is a flavone glycoside with a confirmed therapeutic effectiveness on the chronic venous disorders. In this paper, the classical mouse depression model induced by LPS was established to explore the effect of Diosmin on depression. Firstly, we found that Diosmin could inhibit the inflammation and neuronal damage in the prefrontal cortex (PFC) of mice, and thus alleviating the LPS-induced depressive-like behaviors. Specifically, Diosmin treatment significantly suppressed the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), reduced the activation of microglia, and inhibited the expression of NLRP3 inflammasome and its downstream effector caspase-1 in both PFC of mice and BV2 microglial cells exposed to LPS. Then, we demonstrated that pretreatment with Diosmin dramatically suppressed the LPS-induced oxidative stress in the PFC of mice, manifested in the decrease of reactive oxygen species and malondialdehyde while increase of catalase activity. Consistently, Diosmin also alleviated the oxidative stress in BV2 cells exposed to LPS. Finally, we confirmed that Diosmin effectively suppressed the activation of NF-κB signaling pathway in the PFC of LPS-treated mice. Further in vitro experiments also verified that Diosmin could prevent the p65 transposition to nucleus in LPS-treated BV2 cells, suggesting that the antidepressant effects of Diosmin are partially mediated by blocking of NF-κB signaling. Taken together, this study proposes the potential antidepressant effect of Diosmin, which provides useful support to the development of new therapies for depression.


Feasibility of Dose-reduced Chest CT with Photon-counting Detectors: Initial Results in Humans.
Purpose To investigate whether photon-counting detector (PCD) technology can improve dose-reduced chest computed tomography (CT) image quality compared with that attained with conventional energy-integrating detector (EID) technology in vivo. Materials and Methods This was a HIPAA-compliant institutional review board-approved study, with informed consent from patients. Dose-reduced spiral unenhanced lung EID and PCD CT examinations were performed in 30 asymptomatic volunteers in accordance with manufacturer-recommended guidelines for CT lung cancer screening (120-kVp tube voltage, 20-mAs reference tube current-time product for both detectors). Quantitative analysis of images included measurement of mean attenuation, noise power spectrum (NPS), and lung nodule contrast-to-noise ratio (CNR). Images were qualitatively analyzed by three radiologists blinded to detector type. Reproducibility was assessed with the intraclass correlation coefficient (ICC). McNemar, paired t, and Wilcoxon signed-rank tests were used to compare image quality. Results Thirty study subjects were evaluated (mean age, 55.0 years ± 8.7 [standard deviation]; 14 men). Of these patients, 10 had a normal body mass index (BMI) (BMI range, 18.5-24.9 kg/m2; group 1), 10 were overweight (BMI range, 25.0-29.9 kg/m2; group 2), and 10 were obese (BMI ≥30.0 kg/m2, group 3). PCD diagnostic quality was higher than EID diagnostic quality (P = .016, P = .016, and P = .013 for readers 1, 2, and 3, respectively), with significantly better NPS and image quality scores for lung, soft tissue, and bone and with fewer beam-hardening artifacts (all P < .001). Image noise was significantly lower for PCD images in all BMI groups (P < .001 for groups 1 and 3, P < .01 for group 2), with higher CNR for lung nodule detection (12.1 ± 1.7 vs 10.0 ± 1.8, P < .001). Inter- and intrareader reproducibility were good (all ICC > 0.800). Conclusion Initial human experience with dose-reduced PCD chest CT demonstrated lower image noise compared with conventional EID CT, with better diagnostic quality and lung nodule CNR. © RSNA, 2017 Online supplemental material is available for this article.


Laminar differences in the spatiotemporal structure of simple cell receptive fields in cat area 17.
Previous studies of cat visual cortex have shown that the spatiotemporal (S-T) structure of simple cell receptive fields correlates with direction selectivity. However, great heterogeneity exists in the relationship and this has implications for models. Here we report a laminar basis for some of the heterogeneity. S-T structure and direction selectivity were measured in 101 cells using stationary counterphasing and drifting gratings, respectively. Two procedures were used to assess S-T structure and its relation to direction selectivity. In the first, the S-T orientations of receptive fields were quantified by fitting response temporal phase versus stimulus spatial phase data. In the second procedure, conventional linear predictions of direction selectivity were computed from the amplitudes and phases of responses to stationary gratings. Extracellular recording locations were reconstructed histologically. Among direction-selective cells, S-T orientation was greatest in layer 4B and it correlated well (r = 0.76) with direction selectivity. In layer 6, S-T orientation was uniformly low, overlapping little with layer 4B, and it was not correlated with directional tuning. Layer 4A was intermediate in S-T orientation and its relation (r = 0.46) to direction selectivity. The same laminar patterns were observed using conventional linear predictions. The patterns do not reflect laminar differences in direction selectivity since the layers were equivalent in directional tuning. We also evaluated a model of linear spatiotemporal summation followed by a static nonlinear amplification (exponent model) to account for direction selectivity. The values of the exponents were estimated from differences between linearly predicted and actual amplitude modulations to counterphasing gratings. Comparing these exponents with another exponent--that required to obtain perfect matches between linearly predicted and measured directional tuning--indicates that an exponent model largely accounts for direction selectivity in most cells in layer 4, particularly layer 4B, but not in layer 6. Dynamic nonlinearities seem essential for cells in layer 6. We suggest that these laminar differences may partly reflect the differential involvement of geniculocortical and intracortical mechanisms.


Multi-omics reveals the protective effects of curcumin against AFB1-induced oxidative stress and inflammatory damage in duckling intestines.
Aflatoxin B1 (AFB1) is the most prevalent and toxic class of aflatoxins, which is considered a significant risk factor for food safety. Curcumin, a phytoconstituent with anti-inflammatory and antioxidant properties, has potential therapeutic value for intestinal inflammatory diseases. In this study, the duckling model susceptible to AFB1 was selected for toxicity testing, aiming to explore the effect of curcumin on AFB1 enterotoxicity and its possible mechanism of action. The results showed that curcumin promoted the growth and development of ducklings and mitigated the changes in morphology and permeability serological index (DAO and D-LA) after AFB1 exposure. Curcumin also mitigated AFB1-induced oxidative stress by activating the Nrf2 pathway, and ameliorated intestinal inflammation by inhibiting the NF-κB/IκB signaling pathway and boosting intestinal autophagy. In terms of gut flora and their metabolites, we found that curcumin supplementation significantly increased the intestinal flora's abundance index and diversity index compared to the AFB1 group, mitigating the decline in the abundance of Actinobacteria and the rise in that of harmful bacteria Clostridia. Furthermore, untargeted metabolomic analysis revealed that the protective effect of curcumin on the intestine was mainly through the regulation of AFB1-induced disorders of lipid metabolism, involving linoleic acid metabolism, α-linolenic acid metabolism, and glycerolipid metabolism. Overall, the enteroprotective effects of curcumin may be of significant value in the future for treating chronic AFB1 poisoning and also provide new therapeutic ideas for other mycotoxicosis.


Farmer attitudes to vaccination and culling of badgers in controlling bovine tuberculosis.
Controversy persists in England, Wales and Northern Ireland concerning methods of controlling the transmission of bovine tuberculosis (bTB) between badgers and cattle. The National Trust, a major land-owning heritage organisation, in 2011, began a programme of vaccinating badgers against bTB on its Killerton Estate in Devon. Most of the estate is farmed by 18 tenant farmers, who thus have a strong interest in the Trust's approach, particularly as all have felt the effects of the disease. This article reports on a study of the attitudes to vaccination of badgers and to the alternative of a culling programme, using face-to-face interviews with 14 of the tenants. The results indicated first that the views of the respondents were more nuanced than the contemporary public debate about badger control would suggest. Secondly, the attitude of the interviewees to vaccination of badgers against bTB was generally one of resigned acceptance. Thirdly, most respondents would prefer a combination of an effective vaccination programme with an effective culling programme, the latter reducing population of density sufficiently (and preferably targeting the badgers most likely to be diseased) for vaccination to have a reasonable chance of success. While based on a small sample, these results will contribute to the vigorous debate concerning contrasting policy approaches to bTB control in England, Wales and Northern Ireland.


All-trans-retinoic acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells.
Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of certain malignancies. Loss of retinoic acid (RA) receptor-beta function may be an important event in mammary carcinogenesis, because the majority of breast cancers, in contrast to normal mammary epithelial cells, fail to express this receptor. We previously reported that all-trans-RA mediates G1 arrest as well as apoptosis in certain RAR beta-transduced breast cancer cell lines. We now report the effect of RA on normal human mammary epithelial cells (HMECs), which express functionally active retinoid receptors. We observe that RA induces growth suppression and G1 arrest of these HMECs but find no evidence that RA mediates apoptosis in these normal cell strains. This RA-induced G1 arrest is temporally associated with decreased levels of hyperphosphorylated retinoblastoma protein without any significant changes in c-myc, p53, p21, or p27 expression. Expression of cyclin D1, cyclin-dependent kinase 4, and cyclin E proteins, however, decreased in association with RA-mediated G1 arrest. Our studies suggest that growth inhibition, rather than apoptosis, may be a mechanism by which RA and RA receptors act to prevent the malignant transformation of normal mammary epithelial cells. The molecular target(s) of the activated RA receptors that mediate this G1 arrest in HMECs appear to be associated with a retinoblastoma-dependent pathway.


Selection criteria for combined resection of synchronous colorectal cancer hepatic metastases: a cautionary note.
Combined resection of primary colorectal cancer and synchronous hepatic metastases has been shown to be safe and associated with acceptable oncologic outcomes in selected patients. The purpose of this study was to determine if selection criteria for combined resection could be identified using major morbidity or mortality as an avoidable outcome. We queried the American College of Surgeons National Surgery Quality Improvement Program dataset from 2005 to 2010 for combined liver and colorectal resections for colorectal cancer using procedure and diagnosis codes. These patients were compared to colorectal cancer patients receiving colectomy alone and patients receiving liver-directed surgery for secondary liver cancer. During the study period, 1,641 (53.1 %) of patients underwent colectomy alone, 1,113 (36 %) underwent liver-directed surgery alone, and 334 (10.9 %) underwent combined colectomy and liver-directed surgery for colorectal cancer. The combined patient population had statistically significant increases in American Society of Anesthesiologists class, preoperative ascites, preoperative systemic inflammatory response syndrome/sepsis, weight loss, functional dependence, and decreased serum albumin compared to the other cohorts. While major hepatectomy was less frequent in the combined cohort, the rate of rectal resection was similar to the colectomy-alone cohort. These selection disparities resulted in a subsequent increase in composite major morbidity, return to operating room, infectious complications, and length of stay in combined patients. While combined resection in patients with synchronous colorectal cancer hepatic metastases may be feasible, it is associated with considerable increase in morbidity without application of stringent selection criteria. We recommend only patients without known risk factors for perioperative morbidity and infectious complications be considered for this approach.


Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies.
Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A-class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg(2.39), His(2.43) and Glu(3.46), which makes a polar lock with T(6.37). These alignments and models provide useful tools for understanding class B GPCR function.


Reliability and Fall Risk Detection for the BESTest and Mini-BESTest in Older Adults.
Test stability and test-retest reliability have not previously been reported for either the Balance Evaluation Systems Test (BESTest) or mini-BESTest (mBEST) in a population of older adults with nonspecific balance limitations. Furthermore, no criterion for identifying change greater than chance has been reported in older adults with nonspecific balance problems using either BESTest or mBEST scores. The purposes of this study were to determine test stability over time, test-retest reliability, to identify minimum detectable change for the BESTest and mBEST in a population of older adults with nonspecific balance problems. In addition, the ability of the BESTest and mBEST to identify past fallers was characterized. This was an observational study with 58 adults 65 years or older with a history of falls or self-reported balance problem. The BESTest and mBEST were administered to all participants at the beginning and end of 4 weeks. Test-retest reliability was calculated with intraclass correlations, and minimum detectable change was calculated at the 95% confidence level (MDC95). Receiver operating characteristics were used to characterize the sensitivity and specificity of the BESTest and mBEST to identify older adults who had previously fallen. Balance scores did not significantly change over a 4-week period. Test-retest reliability for the BESTest (0.86) and mBEST (0.84) was good to excellent. MDC95 scores were identified for the BESTest (8.9) and mBEST (4). The BESTest and mBEST scores were stable and reliable over a period of 4 weeks for a population of older adults with self-reported balance problems or a history of falling. MDC95 scores allow interpretation of change in BESTest and mBEST scores following rehabilitation.


[Legal liability in drug trials].
Studies on humans are carried out in all nations with scientific trials. These studies are concerned with all kinds of goals, i.e. pharmacological treatment procedures. This necessitates clinical and pharmaceutical testing on healthy volunteers or patients. Lawyers watch over the activities of the clinical drug testing. The participation on human tests requires voluntariness and information. The documentation of the voluntariness and the information about goals, methods, and risks are very important.


Unexpected bleeding disorders: Algorithm for approach to therapy.
The management of unexpected bleeding must be directed at the specific abnormality identified, as there is no universally effective and safe procoagulant product. Where practical, a purely pharmaceutical approach obviates the residual risks of exposure to plasma-derived products. Desmopressin is often effective in bleeding due to mild haemophilia A, Type I von Willebrand's disease and some platelet function disorders. Where replacement therapy is necessary, it should be as specific as possible, preferably using purified components singly or in combination. Recombinant proteins provide the greatest margin of safety, but it must be borne in mind that these are biologicals, and that they may contain human and animal plasma-derived proteins. Where specific replacement is unavailable or impractical, plasma or crudely fractionated plasma derivatives may be used. In the case of inhibitor antibodies to factor VIII, high dose human factor VIII or porcine factor VIII may be used. Where replacement therapy is impossible due to a high inhibitory titre, it may be necessary to bypass the specific haemostatic defect using activated prothrombin complex concentrates or recombinant activated factor VIIa. The latter product is being studied in patients with various disorders of platelet function, and in the more global haemostatic failure that accompanies end-stage liver disease. Ancillary methods are often of great value in securing haemostasis. These may be derived from pharmacological or biological sources, and their sites of action may be systemic or topical. Examples include antifibrinolytic lysine analogues, corticosteroids where inflammation accompanies bleeding, and the topical application of fibrin sealants or thrombin. Simple physical measures such as pressure, ice, or splinting are also valuable adjunctive measures. Finally, it must be emphasized that the ultimate control of bleeding often depends upon effective management of the inciting cause, such as eliminating the trigger for DIC, or suppressing the causative antibody of ITP. These principles will be presented using a practical algorithmic approach. The initial question when considering treatment should be whether or not the patient is acutely unstable. Instability may be due to one of two causes: the volume of blood loss leading to a compromised cardio-vascular status, or the site of the bleed. The relevance of the site of the bleed is independent of the volume of blood loss, so for example, a closed bleed into CNS will cause critical functional compromise even though the volume of bleeding may be minimal. Similarly bleeding into a compartment, such as into a forearm or a calf will cause critical functional compromise irrespective of the volume of bleeding.


Outlier Practice Patterns in Mohs Micrographic Surgery: Defining the Problem and a Proposed Solution.
Outlier physician practices in health care can represent a significant burden to patients and the health system. To study outlier physician practices in Mohs micrographic surgery (MMS) and the associated factors. This retrospective analysis of publicly available Medicare Part B claims data from January 2012 to December 2014 includes all physicians who received Medicare payments for MMS from any practice performing MMS on the head and neck, genitalia, hands, and feet region of Medicare Part B patients. Characteristics of outlier physicians, defined as those whose mean number of stages for MMS was 2 standard deviations greater than the mean number for all physicians billing MMS. Logistic regression was used to study the physician characteristics associated with outlier status. Our analysis included 2305 individual billing physicians performing MMS. The mean number of stages per MMS case for all physicians practicing from January 2012 to December 2014 was 1.74, the median was 1.69, and the range was 1.09 to 4.11. Overall, 137 physicians who perform Mohs surgery were greater than 2 standard deviations above the mean (2 standard deviations above the mean = 2.41 stages per case) in at least 1 of the 3 examined years, and 49 physicians (35.8%) were persistent high outliers in all 3 years. Persistent high outlier status was associated with performing Mohs surgery in a solo practice (odds ratio, 2.35; 95% CI, 1.25-4.35). Volume of cases per year, practice experience, and geographic location were not associated with persistent high outlier status. Marked variation exists in the number of stages per case for MMS for head and neck, genitalia, hands, and feet skin cancers, which may represent an additional financial burden and unnecessary surgery on individual patients. Providing feedback to physicians may reduce unwarranted variation on this metric of quality.


Synthesis, characterization, and electrochemical and electrochromic properties of sandwich dilutetium tetraphthalocyanine.
A new sandwich-tpype dilutetium tetraphthalocyanine 4 has been synthesized by the reaction of dimeric lutetium(III) phthalocyanine 3 with two equiv. of dilithium octakishexylthiophthalocyanine in amyl alcohol. Compound 3 was prepared from 4',5',4",5"-tetraiminoisoindoline(1,4,7,10-tetrathia-12-crown-4) 1, 4,5-bis(hexylthio)-1,2-diiminoisoindoline and lutetium acetate in amyl alcohol. Compounds 3 and 4 were characterized by elemental analysis, UV/visible, IR, (1)H NMR and ESR spectroscopy. The electrochemical and electrochromic properties of 3 and 4 have been examined by cyclic voltammetry. Both 3 and 4 displayed well-defined electrochromic behavior.


Graphene oxide/black phosphorus nanoflake aerogels with robust thermo-stability and significantly enhanced photothermal properties in air.
Here we report a new kind of three-dimensional (3D) hybrid aerogels, based on graphene oxide (GO) and black phosphorus nanoflakes (BPNFs), for the first time. Our results demonstrate that the as-prepared GO/BPNF hybrid aerogels exhibited significantly enhanced photothermal as well as electrical properties of GO aerogels due to the addition of BP. Moreover, they also possessed excellent photothermal stability under ambient conditions without any protection, which can be ascribed to the coverage of BPNFs with GO nanosheets in these aerogels. This exceptional photothermal property along with robust stability renders GO/BPNF aerogels with promising bio-related applications, such as photothermal therapy for cancer treatment.