Leptomeningeal metastases in high-grade adult glioma: development, diagnosis, management, and outcomes in a series of 34 patients.
Leptomeningeal metastases (LM) in the setting of glioma have often been thought to carry a particularly poor prognosis. We sought to better characterize this phenomenon through a review of patients with glioma seen in our institution over the preceding 10 years. We focus here on 34 cases with LM due to grade III or IV glioma. Over the period in question, we estimate a prevalence of almost 4% in those affected by grade IV tumors. Leptomeningeal spread was present at the time of initial diagnosis in 4 patients. Among the others, LM occurred at the time of first progression of disease in 17. The median time to development of LM (excluding those where it was present at initial diagnosis) was 16.4 months [95% confidence interval (CI) 8.2-43.9]. The median time to further progression of disease following LM was 4.9 months (95% CI 3.1-6.9). Twenty-five patients were known to have died at the time of writing. Thus, median overall survival (OS) was 10.2 months (95% CI 8.8-14.7) following LM. At the time of diagnosis of LM, some form of treatment (chemotherapy and/or radiation vs. no treatment) increased OS (median 11.7 vs. 3.3 months, p < 0.001 by log-rank test). Use of radiation therapy (vs. no radiation) also increased OS, although the effect was more modest (7.8 vs. 16.8 months, p = 0.07). Higher Karnofsky Performance Status (KPS) at the time of diagnosis of LM was associated with OS (p = 0.007, median OS for KPS ≥90 19 months vs. 7.8 for KPS <90). In a two-variable model incorporating the use any treatment (vs. none) and KPS, the latter tended to be a more significant predictor of survival (p = 0.22 vs. p = 0.06 by likelihood-ratio test). This was also true for radiation (vs. none) and KPS (p = 0.27 vs. p = 0.02). No significant benefit could be demonstrated for the use of chemotherapy considered alone, either systemic or intrathecal. It should be noted that 4 of 9 patients receiving intrathecal chemotherapy had a ventriculo-peritoneal shunt in place during these injections, which may have reduced its effectiveness. Overall, treatment appears to improve outcomes. We favor maximal treatment, as tolerated, particularly with a KPS of ≥70. Such treatment would typically include radiation to the maximum tolerated dose, concurrent, and adjuvant chemotherapy (preferably with an alkyating agent), in addition to intrathecal treatment.


Genetics and evolution of the Salmonella galactose-initiated set of o antigens.
This paper covers eight Salmonella serogroups, that are defined by O antigens with related structures and gene clusters. They include the serovars that are now most frequently isolated. Serogroups A, B1, B2, C2-C3, D1, D2, D3 and E have O antigens that are distinguished by having galactose as first sugar, and not N-acetyl glucosamine or N-acetyl galactosamine as in the other 38 serogroups, and indeed in most Enterobacteriaceae. The gene clusters for these galactose-initiated appear to have entered S. enterica since its divergence from E. coli, but sequence comparisons show that much of the diversification occurred long before this. We conclude that the gene clusters must have entered S. enterica in a series of parallel events. The individual gene clusters are discussed, followed by analysis of the divergence for those genes shared by two or more gene clusters, and a putative phylogenic tree for the gene clusters is presented. This set of O antigens provides a rare case where it is possible to examine in detail the relationships of a significant number of O antigens. In contrast the more common pattern of O-antigen diversity within a species is for there to be only a few cases of strains having related gene clusters, suggesting that diversity arose through gain of individual O-antigen gene clusters by lateral gene transfer, and under these circumstances the evolution of the diversity is not accessible. This paper on the galactose-initiated set of gene clusters gives new insights into the origins of O-antigen diversity generally.


Liquid microjunction surface sampling of acetaminophen, terfenadine and their metabolites in thin tissue sections.
The aim of this work was to evaluate the analytical performance of a fully automated droplet-based surface-sampling system for determining the distribution of the drugs acetaminophen and terfenadine, and their metabolites, in rat thin tissue sections. The rank order of acetaminophen concentration observed in tissues was stomach > small intestine > liver, while the concentrations of its glucuronide and sulfate metabolites were greatest in the liver and small intestine. Terfenadine was most concentrated in the liver and kidney, while its major metabolite, fexofenadine, was found in the liver and small intestine. The spatial distributions of both drugs and their respective metabolites observed in this work were consistent with previous studies using radiolabeled drugs.


Temporal population genetic structure of Phormia regina (Diptera: Calliphoridae).
The genetic structure of forensically important blow fly (Brauer & Bergenstamm) (Diptera: Calliphoridae) populations has remained elusive despite high relatedness within wild-caught samples. This research aimed to determine if the implementation of a high-resolution spatiotemporal sampling design would reveal latent genetic structure among blow fly populations and to elucidate any environmental impacts on observed patterns of genetic structure. Adult females of the black blow fly, Phormia regina (Meigen) (Diptera: Calliphoridae), were collected from 9 urban parks in Indiana, USA over 3 yr and genotyped at 6 polymorphic microsatellite loci. The data analysis involved 3 clustering methods: principal coordinate analysis (PCoA), discriminant analysis of principal components (DAPC), and STRUCTURE. While the PCoA did not uncover any discernible clustering patterns, the DAPC and STRUCTURE analyses yielded significant results, with 9 and 4 genetic clusters, respectively. Visualization of the STRUCTURE bar plot revealed N = 11 temporal demarcations indicating barriers to gene flow. An analysis of molecular variance of these STRUCTURE-inferred populations supported strong temporally driven genetic differentiation (FST = 0.048, F'ST = 0.664) relative to geographic differentiation (FST = 0.009, F'ST = 0.241). Integrated Nested Laplace Approximation and Boosted Regression Tree analyses revealed that collection timepoint and 4 main abiotic factors (temperature, humidity, precipitation, and wind speed) were associated with the genetic subdivisions observed for P. regina. A complex interplay between environmental conditions, the unique reproductive strategies of the blow fly, and the extensive dispersal abilities of these organisms likely drives the strong genetic structure of P. regina in the Midwestern US.


Nonlinear optical chromophores based on Dewar's rules: enhancement of electro-optic activity by introducing heteroatoms into the donor or bridge.
In this work, we investigated the enhancement of the electro-optic response by introducing electron-rich heteroatoms as additional donors into the donor or bridge of a conventional second-order nonlinear optical chromophore. A series of chromophores C2-C4 based on the same tricyanofuran acceptor (TCF) but with different heteroatoms in the alkylamino phenyl donor (C2 or C3) or thiophene bridge (C4) have been synthesized and systematically investigated. Density functional theory calculations suggested that chromophores C2-C4 had a smaller energy gap and larger first-order hyperpolarizability (β) than traditional chromophore C1 due to the additional heteroatoms. Single crystal structure analyses and optimized configurations indicate that the rationally introduced heteroatom group would bring larger β and weaker intermolecular interactions which were beneficial for translating molecular β into macro-electro-optic activity in electric field poled films. The electro-optic coefficient of poled films containing 25 wt% of these new chromophores doped in amorphous poly-carbonate afforded values of 83 and 91 pm V(-1) at 1310 nm for chromophores C3 and C4, respectively, which are two times higher than that of the traditional chromophore C1 (39 pm V(-1)). High r33 values indicated that introducing heteroatoms to the donor and bridge of a conventional molecular structure can efficiently improve the electron-donating ability, which improves the β. The long-chain on the donor or bridge part, acting as the isolation group, may reduce inter-molecular electrostatic interactions, thus enhancing the macroscopic EO activity. These results, together with good solubility and compatibility with the polymer, show the new chromophore's potential application in electro-optic devices.


A mechanistic investigation of the C-terminal redox motif of thioredoxin reductase from Plasmodium falciparum.
High-molecular mass thioredoxin reductases (TRs) are pyridine nucleotide disulfide oxidoreductases that catalyze the reduction of the disulfide bond of thioredoxin (Trx). Trx is responsible for reducing multiple protein disulfide targets in the cell. TRs utilize reduced β-nicotinamide adenine dinucleotide phosphate to reduce a bound flavin prosthetic group, which in turn reduces an N-terminal redox center that has the conserved sequence CICVNVGCCT, where CIC is denoted as the interchange thiol while the thiol involved in charge-transfer complexation is denoted as CCT. The reduced N-terminal redox center reduces a C-terminal redox center on the opposite subunit of the head-to-tail homodimer, the C-terminal redox center that catalyzes the reduction of the Trx-disulfide. Variations in the amino acid sequence of the C-terminal redox center differentiate high-molecular mass TRs into different types. Type Ia TRs have tetrapeptide C-terminal redox centers of with a GCUG sequence, where U is the rare amino acid selenocysteine (Sec), while the tetrapeptide sequence in type Ib TRs has its Sec residue replaced with a conventional cysteine (Cys) residue and can use small polar amino acids such as serine and threonine in place of the flanking glycine residues. The TR from Plasmodium falciparum (PfTR) is similar in structure and mechanism to type Ia and type Ib TRs except that the C-terminal redox center is different in its amino acid sequence. The C-terminal redox center of PfTR has the sequence G534CGGGKCG541, and we classify it as a type II high-molecular mass TR. The oxidized type II redox motif will form a 20-membered disulfide ring, whereas the absence of spacer amino acids in the type I motif results in the formation of a rare eight-membered ring. We used site-directed mutagenesis and protein semisynthesis to investigate features of the distinctive type II C-terminal redox motif that help it perform catalysis. Deletion of Gly541 reduces thioredoxin reductase activity by ∼50-fold, most likely because of disruption of an important hydrogen bond between the amide NH group of Gly541 and the carbonyl of Gly534 that helps to stabilize the β-turn-β motif. Alterations of the 20-membered disulfide ring either by amino acid deletion or by substitution resulted in impaired catalytic activity. Subtle changes in the ring structure and size caused by using semisynthesis to substitute homocysteine for cysteine also caused significant reductions in catalytic activity, demonstrating the importance of the disulfide ring's geometry in making the C-terminal redox center reactive for thiol-disulfide exchange. The data suggested to us that the transfer of electrons from the N-terminal redox center to the C-terminal redox center may be rate-limiting. We propose that the transfer of electrons from the N-terminal redox center in PfTR to the type II C-terminal disulfide is accelerated by the use of an "electrophilic activation" mechanism. In this mechanism, the type II C-terminal disulfide is polarized, making the sulfur atom of Cys540 electron deficient, highly electrophilic, and activated for thiol-disulfide exchange with the N-terminal redox center. This hypothesis was investigated by constructing chimeric PfTR mutant enzymes containing C-terminal type I sequences GCCG and GCUG, respectively. The PfTR-GCCG chimera had 500-fold less thioredoxin reductase activity than the native enzyme but still reduced selenocystine and lipoic acid efficiently. The PfTR-GCUG chimera had higher catalytic activity than the native enzyme with Trx, selenocystine, and lipoic acid as substrates. The results suggested to us that (i) Sec in the mutant enzyme accelerated the rate of thiol-disulfide exchange between the N- and C-terminal redox centers, (ii) the type II redox center evolved for efficient catalysis utilizing Cys instead of Sec, and (iii) the type II redox center of PfTR is partly responsible for substrate recognition of the cognate PfTrx substrate relative to noncognate thioredoxins.


Renal denervation for the treatment of hypertension: the Dutch consensus.
Since 2010, renal denervation (RDN) is being performed in the Netherlands. To make sure RDN is implemented with care and caution in the Netherlands, a multidisciplinary Working Group has been set up by the Dutch Society of Cardiology (NVVC). The main aim of this Working Group was to establish a consensus document that can be used as a guide for implementation of RDN in the Netherlands. This consensus document was prepared in consultation with the Dutch Association of Internal Medicine (NIV) and the Dutch Society of Radiology (NVVR).


Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1alpha, and C/EBPalpha.
Hypoxia, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. Plasminogen activator inhibitor-1 (PAI-1) is an important factor suppressing fibrinolysis under conditions of low oxygen tension. We previously reported that hypoxia induced PAI-1 mRNA and antigen expression in murine macrophages secondary to increased de novo transcription as well as increased mRNA stability. We now show in RAW264.7 murine macrophages that the transcription factors early growth response gene-1 (Egr-1), hypoxia-inducible factor-1alpha (HIF-1alpha), and CCAAT/enhancer binding protein alpha (C/EBPalpha) are quickly activated in hypoxia and are responsible for transcription and expression of PAI-1. Murine PAI-1 promoter constructs, including Egr, HIF-1alpha, and/or C/EBPalpha binding sites, were transfected into RAW 264.7 murine macrophages. To identify the relative importance of each of these putative hypoxia-responsive elements, cells were exposed to normobaric hypoxia, and transcriptional activity was recorded. At 16 h of hypoxic exposure, murine PAI-1 promoter deletion constructs that included Egr, HIF-1alpha, and/or C/EBPalpha binding sites demonstrated increased transcriptional activity. Mutation of each of these three murine PAI-1 promoter sites (or a combination of them) resulted in a marked reduction in hypoxia sensitivity as detected by transcriptional analysis. Functional data obtained using 32P-labeled Egr, HIF-1alpha response element (HRE), and C/EBPalpha oligonucleotides revealed induction of DNA binding activity in nuclear extracts from hypoxic RAW cells, with supershift analysis confirming activation of Egr-1, HIF-1alpha, or C/EBPalpha. ChIP analysis confirmed the authenticity of these interactions as each of these transcription factors binds to chromatin under hypoxic conditions. Further, the induction of PAI-1 by Egr-1, HIF-1alpha, or C/EBPalpha was replicated in primary peritoneal macrophages. These data suggest that although HIF-1alpha appears to dominate the PAI-1 transcriptional response in hypoxia, Egr-1 and C/EBPalpha greatly augment this response and can do so independent of HIF-1alpha or each other. These studies are relevant to ischemic up-regulation of the PAI-1 gene and consequent accrual of microvascular thrombus under ischemic conditions.


[NONINVASIVE BRAIN STIMULATION IN NEUROPSYCHIATRIC DISORDERS].
Noninvasive brain stimulation is a growing field of treatment for many neuropsychiatric problems. In this review, several of the more common brain stimulation devices are presented. Specifically, we will review Transcranial Magnetic Stimulation (TMS), Transcranial Direct Current Stimulation (tDCS), Alternating Current Stimulation (ACS), Infrared Stimulation, Electroencephalography Neurofeedback (EEG-NF) and functional Magnetic Resonance Imagining Neurofeedback (fMRI-NF). We will outline some of the properties of these devices including the mechanism, side effect profile, using sham for research and major future developments.


Epidemiology of Airmen Treated with Immunosuppressive Drugs and Vaccination Concerns.
Immunosuppressive treatments are increasingly prescribed in a variety of diseases. This issue concerns airmen. To assess the problem, we conducted an observational retrospective study in the aircrew population examined in 2014 at the Aeromedical Center of Percy Military Hospital. Airmen treated with immunosuppressive drugs accounted for 0.5% of the total population (N = 13,326). Rheumatic and digestive diseases were the main etiologies, respectively 43% and 35% of cases. One-third of airmen took such medications during at least 3 yr and three-quarters of airmen were declared fit to fly, with some limitations. Due to their working conditions, airmen are exposed to a real infectious risk, which is, however, difficult to evaluate. The risk is obviously increased by immunosuppressive drugs and may affect flight safety. Aeromedical evaluation should consider this problem. Vaccination plays a central role in the prevention of infectious risk. Based on French recommendations, we propose a vaccination schedule for these particular patients.Guiu G, Monin J, Hamm-Hornez A-P, Manen O, Perrier E. Epidemiology of airmen treated with immunosuppressive drugs and vaccination concerns. Aerosp Med Hum Perform. 2018; 89(4):377-382.


Inhibitory mechanisms in motor imagery: disentangling different forms of inhibition using action mode switching.
In motor imagery, probably several inhibitory mechanisms prevent actual movements: global inhibition, effector-specific inhibition, and inhibition retrieved during target processing. We investigated factors that may influence those mechanisms. In an action mode switching paradigm, participants imagined and executed movements from home buttons to target buttons. We analysed sequential effects. Activation (due to execution) or inhibition (due to imagination) in the previous trial should affect performance in the subsequent trial, enabling conclusions about inhibitory mechanisms in motor imagery. In Experiment 1, evidence for global and effector-specific inhibition was observed. Evidence for inhibition retrieved during target processing was inconclusive. Data patterns were similar when start and end of the imagined movements were indicated with an effector that was part of the imagined movement (hand) and with a different effector (feet). In Experiment 2, we ruled out that the use of biological stimuli (left/right hands in Experiment 1) to indicate the effector causes sequential effects attributed to effector-specific inhibition, by using uppercase letters (R, L). As in Experiment 1, evidence for effector-specific inhibition was observed. In conclusion, we could reliably disentangle several inhibitory mechanisms in motor imagery.


The neurobiological mechanism underlying hypothalamic GnRH pulse generation: the role of kisspeptin neurons in the arcuate nucleus.
This review recounts the origins and development of the concept of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator. It starts in the late 1960s when striking rhythmic episodes of luteinizing hormone secretion, as reflected by circulating concentrations of this gonadotropin, were first observed in monkeys and ends in the present day. It is currently an exciting time witnessing the application, primarily to the mouse, of contemporary neurobiological approaches to delineate the mechanisms whereby Kiss1/NKB/Dyn (KNDy) neurons in the arcuate nucleus of the hypothalamus generate and time the pulsatile output of kisspeptin from their terminals in the median eminence that in turn dictates intermittent GnRH release and entry of this decapeptide into the primary plexus of the hypophysial portal circulation. The review concludes with an examination of questions that remain to be addressed.


Personality, depression and anxiety in primary Sjogren's syndrome - Association with sociodemographic factors and comorbidity.
Patients with primary Sjögren's Syndrome (pSS) have diminished health quality and fatigue, arthralgia along with dryness of the mouth and eyes have major impact on their psychological and social aspects of life. The purpose of this study was to determine psychological features of patients with pSS. We analyzed personality, depression and anxiety of patients with primary Sjögren's Syndrome (pSS) in comparison with patients with rheumatoid arthritis (RA) and healthy controls (HC) and assessed their association with sociodemographic factors and comorbidity. In 105 pSS patients (mean age 51.34 years, mean disease duration 5.98 years), 52 RA patients (mean age 51.37 years, mean disease duration 8.10 years) and 54 HC (mean age 51.35 years) clinical and sociodemographic characteristics were determined and results analyzed. At enrollment patients and controls completed the Revisited NEO Personality Inventory Five-Factor model (NEO-PI-R), the Zung Self-Rating Depression Scale and the Zung Self-Rating Anxiety Scale. Statistical analyses were performed using SPSS [Version 16.0]. The relative size of the effect was assessed based on standardized estimates of effect size (d). Patients with pSS, similarly to RA patients had higher scores of Neuroticism (d = 0.46, p = 0.007) and lower scores of Extraversion (d = 0.51, p = 0.001) and Openness for experience (d = 0.65, p = 0.013) compared to HC. There was no significant differences between pSS group and HC in the depression (d = 0.171, p>0.05). However, patients with pSS had higher anxiety in comparison to HC (p<0.0001). In multivariate models, education and satisfaction with family relationships were significant predictors for psychological characteristics of patients, independently of clinical diagnosis. Our study is the first to show that patients with pSS scored high on neuroticism and anxiety and low on sociability. Education and satisfaction with family relationships predisposed to their psychological profile. Psychological assessment of patients with pSS may improve understanding and treatment of this clinical condition.


Heterogeneity of Powdery Mildew Resistance Revealed in Accessions of the ICARDA Wild Barley Collection.
The primary genepool of barley comprises two subspecies - wild barley (Hordeum vulgare subsp. spontaneum) and cultivated barley H. vulgare. subsp. vulgare. The former originated 5.5 million years ago in southwest Asia and is the immediate ancestor of cultivated barley, which arose around 10,000 years ago. In this study, the specific resistance of a set of 146 wild barley accessions, maintained by the International Center for Agriculture Research in the Dry Areas (ICARDA), to 32 isolates of barley powdery mildew caused by Blumeria graminis f. sp. hordei was evaluated. The set comprised 146 heterogeneous accessions of a previously tested collection. Seed was obtained by single seed descent and each accession was usually represented by five single plant progenies. In total, 687 plant progenies were tested. There were 211 phenotypes of resistance among the accessions, 87 of which were found in single plants, while 202 plants contained the eight most common phenotypes. The most frequent phenotype was found in 56 plants that were susceptible to all pathogen isolates, whereas the second most frequent phenotype, which occurred in 46 plants, was resistant to all isolates. The broad resistance diversity that was revealed is of practical importance and is an aid to determining the extent and role of resistance in natural ecosystems.


Burst of virus infection and a possibly largest epidemic threshold of non-Markovian susceptible-infected-susceptible processes on networks.
Since a real epidemic process is not necessarily Markovian, the epidemic threshold obtained under the Markovian assumption may be not realistic. To understand general non-Markovian epidemic processes on networks, we study the Weibullian susceptible-infected-susceptible (SIS) process in which the infection process is a renewal process with a Weibull time distribution. We find that, if the infection rate exceeds 1/ln(λ_{1}+1), where λ_{1} is the largest eigenvalue of the network's adjacency matrix, then the infection will persist on the network under the mean-field approximation. Thus, 1/ln(λ_{1}+1) is possibly the largest epidemic threshold for a general non-Markovian SIS process with a Poisson curing process under the mean-field approximation. Furthermore, non-Markovian SIS processes may result in a multimodal prevalence. As a byproduct, we show that a limiting Weibullian SIS process has the potential to model bursts of a synchronized infection.


Interaction between Antibiotic Resistance, Resistance Genes, and Treatment Response for Urinary Tract Infections in Primary Care.
Given increasing antimicrobial resistance, we aimed to determine antibiotic susceptibility and presence of resistance genes in uropathogens in primary care, factors associated with resistance to commonly prescribed antibiotics, and effect of treatment on early symptom resolution. We conducted a prospective study of primary care patients with urinary tract infection (UTI) symptoms and culture-confirmed UTI in Singapore from 2015 to 2016. Cohort characteristics and antimicrobial susceptibility of cultured isolates were analyzed. Among Enterobacteriaceae isolates, early symptom resolution (within 3 days) according to antibiotic prescribed and isolate susceptibility and factors associated with antibiotic resistance were evaluated. Of 695 symptomatic patients, 299 were urine culture positive; of these 299 patients, 259 (87%) were female. Escherichia coli was the most common uropathogen (76%). Enterobacteriaceae isolates (n = 283) were highly susceptible to amoxicillin-clavulanate (86%), nitrofurantoin (87%), and fosfomycin (98%), but >20% were resistant to ciprofloxacin and co-trimoxazole. Isolates resistant to appropriate indicator antibiotics were further tested to determine proportions positive for blaCTX-M (14/26, 54%), plasmid-mediated ampC (12/24, 50%), qnr (7/69, 10%), and fos (1/6, 17%) resistance genes. A total of 67% of patients given antibiotics with susceptible isolates reported early resolution versus 45% given antibiotics with nonsusceptible isolates (P = 0.001) and 27% not treated (P = 0.018). On multivariable analysis, Indian ethnicity and diabetes mellitus were associated with amoxicillin-clavulanate resistance. Genitourinary abnormalities, UTI in the past 12 months, and hospitalization in the past 6 months were associated with ciprofloxacin and co-trimoxazole resistance. Patients given active empirical antibiotics were most likely to report early symptom resolution, but correlation with in vitro susceptibility was imperfect. Factors associated with resistance may guide the decision to obtain initial urine culture.


The relationship of cervicothoracic mobility restrictions to fall risk and fear of falling in ankylosing spondylitis.
The objective of this study is to determine whether restricted cervical mobility in ankylosing spondylitis (AS) is associated with increased fall frequency or fear of falling. A total of 134 AS patients and 199 age- and gender-matched control subjects (CS) with soft-tissue cervicothoracic pain were prospectively evaluated for fall risk. Subjects were divided into non-fallers, single fallers, and multiple fallers. Dynamic cervical rotations and static cervicothoracic axial measurements were compared between the groups. In total, 88 AS patients were reviewed more than once; Kaplan-Meier plots were constructed for fall risk as a function of cervical rotation amplitudes. Falls Efficacy Scale-International (FES-I) questionnaire measured the fear of falling. In total, 34% of AS patients and 29% of CS fell (p = 0.271) in the year prior to evaluation. In AS, static anatomical measurements were unrelated to fall occurrence. The trends of multiple AS fallers to greater flexed forward postures and reduced dynamic cervical rotations were not statistically significant. Cervicothoracic pain (p = 0.0459), BASDAI (p = 0.002), and BASFI (p = 0.003) scores were greater in multiple fallers. FES-I scores were greater in fallers (p = 0.004). Of the 88 AS patients reviewed (or seen) on more than one occasion, 46.5% fell over the 9-year observation period, including all multiple fallers and 71.4% of single fallers. Survival curves showed increased fall risk as cervical rotational amplitudes decreased. In AS, decreased cervical rotations increase fall risk and fear of falling. In multiple fallers, falls were associated with greater disease activity. Cervical muscle stiffness in AS may cause non-veridical proprioceptive inputs and contribute to increased fall frequency similar to individuals with soft-tissue cervicothoracic pain.


Digital health RCT interventions for cardiovascular disease risk reduction: a systematic review and meta-analysis.
Heart disease is a leading cause of UK mortality. Evidence suggests digital health interventions (DHIs), such as smartphone applications, may reduce cardiovascular risk, but no recent reviews are available. This review examined the effect of DHIs on cardiovascular disease (CVD) risk scores in patients with increased CVD risk, compared to usual care alone. PubMed, Cochrane Database, Medline, and Google Scholar were searched for eligible trials published after 01/01/2010, involving populations with at least one CVD risk factor. Primary outcome was change in CVD risk score (e.g. QRISK3) between baseline and follow-up. Meta-analysis was undertaken using Revman5/STATA using random-effects modelling. Cochrane RoB-2 tool determined risk-of-bias. 6 randomised controlled trials from 36 retrieved articles (16.7%) met inclusion criteria, involving 1,157 patients treated with DHIs alongside usual care, and 1,127 patients offered usual care only (control group). Meta-analysis using random-effects model in STATA showed an inconclusive effect for DHIs as effective compared to usual care (Mean Difference, MD -0.76, 95% CI -1.72, 0.20), with moderate certainty (GRADEpro). Sensitivity analysis by DHI modality suggested automated email messaging was the most effective DHI (MD -1.09, 95% Cl -2.15, -0.03), with moderate certainty (GRADEpro). However, substantial study heterogeneity was noted in main and sensitivity analyses (I2 = 66% and 64% respectively). Quality assessment identified risk-of-bias concerns, particularly for outcome measurement. Findings suggest specific DHIs such as automated email messaging may improve CVD risk outcomes, but were inconclusive for DHIs overall. Further research into specific DHI modalities is required, with longer follow-up. The online version contains supplementary material available at 10.1007/s12553-022-00651-0.


Platinum trans-Bis(borirene) complexes displaying coplanarity and communication across a platinum metal center.
Ambient-temperature photolysis of the aminoborylene complex [(OC)5 Cr=B=N(SiMe3 )2 ] in the presence of a series of trans-bis(alkynyl)platinum(II) precursors of the type trans-[Pt(CCAr)2 (PEt3 )2 ] (Ar=Ph, p-C6 H4 OMe, and p-C6 H4 CF3 ) successfully leads to twofold transfer of the borylene moiety [:B=N(SiMe3 )2 ] onto the alkyne functionalities. The alkynyl precursors and resultant bis(borirene)platinum(II) complexes formed are of the type trans-[Pt(B{=N(SiMe3 )2 }C=CAr)2 (PEt3 )2 ] (Ar=Ph, p-C6 H4 OMe, and p-C6 H4 CF3 ). These species have all been successfully characterized by NMR, IR, and UV/Vis spectroscopy as well as by elemental analysis. Single-crystal X-ray diffraction has verified that these trans-bis(borirene)platinum(II) complexes display coplanarity between the twin three-membered rings across the platinum core in the solid state and stand as the first examples of coplanar conformations of twin borirene systems. These complexes were modeled using density functional theory (DFT), providing information helpful in determining the ability of the transition metal core to interact with each individual borirene ring system and allowing for the observed coplanarity of these rings in the solid state. This proposed transition metal interaction with the twin borirene systems is manifested in the electronic characterization of these borirene species, which display divergent photophysical UV/Vis spectroscopic profiles compared to a previously published mono(borirene)platinum(II) complex.


Polymorphism of conventional genetic markers and HLA system in Turkey.
This study is part of a general survey in which the regional variability of various genetic markers in Turkey will be analyzed with special regard to its application in forensic medicine. Blood samples from 3173 unrelated healthy individuals of both sexes and from different regions of Turkey have been sampled and were typed for the blood group polymorphisms AB0, MNSs, Kell, Duffy, Kidd, P, Lutheran and Lewis, for the red cell enzyme polymorphisms adenylate kinase (AK), glyoxalase (GLO), phosphoglucomutase (PGM), esterase D (ESD), red cell acid phosphatase (aP), and for the serum protein polymorphisms group specific component (vitamin D binding protein, GC) and transferrin (TF). In addition to this the HLA-A and HLA-B antigens of the major histocompatibility complex (HLA) were also typed in 973 individuals. The blood group polymorphisms were typed by the classical haemagglutination methods. Serum protein and red cell enzyme polymorphisms were determined by conventional cellulose acetate electrophoresis. HLA antigens were typed by the standard two stage microlymphocytotoxicity technique. Genetic equilibrium can be assumed for all polymorphic systems under study. The results indicate some regional differences in the distribution of allele frequencies.


Psychiatric Hospital of Leros: a portrayal of the current situation.
The purpose of this study was to describe the demographic and clinical features of the inpatients currently residing at the Psychiatric Hospital of Leros. The present systematic documentation and presentation aimed to demonstrate the standard of living and healthcare conditions provided today, after the implementation of the State's "Psychargos" program; this is the main Greek Psychiatric reform program, adhering to the principles of deinstitutionalization and community psychiatry, in accordance with the current international guidelines. In addition, we discussed the current relationship between the psychiatric departments of the hospital and the other departments and clinics in terms of providing healthcare services to chronic psychiatric inpatients in full compliance with the biopsychosocial model and its application to the unique case of Leros. The implemented patient profiles incorporated both subjective and objective factors, such as compliance with rules and treatment, self-injury, and harm to others. Furthermore, we quantified and categorized the level of care required for each patient in terms of personnel-reported activities. This parameter was assessed through the Greek version of Katz's Index of Independence in Activities of Daily Living. Simultaneously, the fundamental actions provided to inpatients by the social care and support services of the hospital were also depicted and categorized, in terms of connection to State social services, communication with the patient's families, and cooperation between the families and the hospital for the patient's healthcare needs. Furthermore, we analyzed and presented all statistically significant correlations found in our patients' characteristics. Briefly, the main results of our study show that the mean age of the 212 patients was 62.4 years old (with a standard deviation of ±13.6 years and the longest hospitalization of 62 consecutive years) including patients from the institution's asylum period. Since 1989, the year when the psychiatric reform began in our hospital, 87 new patients were admitted, 85.1% of whom were from the southern Aegean, thus following the principle of naiveness. Intellectual disabilities and psychotic spectrum disorders were the most common disorders among the total number of hospitalized patients, accounting for 40% in each category. Regarding the 87 patients hospitalized after 1989, psychotic spectrum disorders were diagnosed in the vast majority (58 patients, 66.7%) followed by organic mental disorders (10 patients, 11.5%). The rest were diagnosed with other disorders. Somatic comorbidity and the need for care and services, especially for patients with intellectual disabilities, demonstrate how the Institution now mainly offers psychogeriatric healthcare services. In conclusion, the purpose of this study was to highlight the Psychiatric Hospital of Leros as it stands today, in stark contrast to the long-established, stereotypical depiction of asylums in the scientific and public communities.


Pityriacitrin -- an ultraviolet-absorbing indole alkaloid from the yeast Malassezia furfur.
As the main nitrogen source in Malassezia furfur, tryptophan induces the formation of fluorochromes and pigments, which make the yeast less sensitive to UV light. To detect a chemical UV filter, M. furfur (CBS 1878) was incubated at 30 degrees C for 14 days on a pigment-inducing medium and agar extracts were purified by column chromatography, preparative TLC and HPLC. Structural analysis of the pure metabolites was performed by mass spectroscopy and NMR. A yellow compound eluting from the column with 64% acetonitrile was found to be a potential UV filter because of its broad UV absorption (lambda(max) 389, 315, 289, 212 nm). It was an indole derivative (C(20)H(13)N(3)O; pityriacitrin) which had recently been shown to be a potent UV filter in bacteria. Its UV protective properties were confirmed in a yeast model and also in humans. Pityriasis versicolor induced by Malassezia yeasts is characterized by depigmented skin areas showing reduced melanin synthesis but no increased UV sensitivity. This UV protection might be explained by the presence of pityriacitrin which is produced by M. furfur.


[The helium-3 MRT of pulmonary ventilation: the initial clinical applications].
of the study is the visualisation of normal pulmonary ventilation in healthy volunteers and the evaluation of abnormalities in patients with different lung diseases using 3He magnetic resonance imaging (3He-MRI). Hyperpolarized 3He gas (V = 300 ml, p = 3 x 10(5) Pa, polarised to 35-45% by optical pumping, provided in special glass cells) was inhaled by eight healthy volunteers and ten patients with different lung diseases. A 3D FLASH sequence (TR = 11.8 ms; TE = 5 ms; matrix 144 x 256, FOV 350 mm, section thickness 7-10 mm, coronal orientation) was performed in a single breath-hold (22-42 s). Clinical and radiological examinations were available for correlation. The studies were successfully carried out in 8/8 volunteers and in 8/10 patients. The central airways were constantly visualised with intermediate to high signal intensity. The lung parenchyma of volunteers with normal ventilatory function showed rather homogeneous intermediate to high signal, whereas patients with chronic obstructive lung disease and/or pneumonia presented severe signal inhomogeneities. Space-occupying lesions and pleural effusion caused large areas with little or no signal. The represented the lesion and adjacent ventilatory disturbances whose extent had not been presumed from chest x-ray or CT. The spatial resolution was higher than in ventilation scintigraphy. 3He MRI is a promising new modality for the assessment of pulmonary ventilation and its anomalies.


Impact of Prolonged Absence of Low Temperature on Adult Eclosion Patterns of Western Cherry Fruit Fly (Diptera: Tephritidae).
Western cherry fruit fly, Rhagoletis indifferens (Curran) (Diptera: Tephritidae), is a serious pest of cherries (Prunus spp.) in the Pacific Northwest of the United States. Previous research suggests that R. indifferens is unlikely to establish in commercial cherry production areas in California and in tropical export markets because cold temperatures, below 5 °C, in those regions appear insufficient to complete diapause. However, it is unclear how prolonged absence of cold exposure affects diapause termination in R. indifferens. Here, we examined this question by exposing R. indifferens pupae for 40 wk to simulated temperate and tropical conditions of 23 or 26 °C, 40 or 80% RH, and a photoperiod of 16:8 or 12:12 (L:D) h. Eclosion patterns among fly groups in the four conditions did not differ. For all groups, fly eclosion from pupae not exposed to cold exhibited a bimodal distribution. The first major peak, comprising 3.2% of the total fly emergence, occurred at 1-10 wk. The second major peak, comprising the remaining 96.8%, occurred at a mode of ∼30 wk. Based on responses to no cold and cold (3 ± 1.5 °C) exposures, there were three distinct pupal diapause groups: the first eclosion group was likely nondiapausing pupae; the second eclosion group was likely diapausing pupae; a third group that remained viable but did not produce adults after 40 wk may represent prolonged dormancy pupae. We suggest that eclosion of adults after prolonged absence of cold exposure needs to be incorporated into models for potential fly establishment in warm climates.


Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work.
We assessed whether pregnancy results in enhanced nitric oxide (NO)-mediated control of myocardial oxygen consumption. Rats were studied before (C), at 1 wk (1w) or 2 wk (2w) of pregnancy, and at 4 days after giving birth (-4d). Left ventricular endothelial NO synthase (eNOS) protein expression was determined by immunoblotting. Oxygen consumption of left ventricular tissue samples was measured in vitro in response to increasing doses of bradykinin with or without addition of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Echocardiography indicated an increased cardiac output during pregnancy. Myocardial eNOS protein expression significantly increased by 46 +/- 9 and 39 +/- 8% at 1w and 2w, respectively, and returned to control levels at -4d. Bradykinin (10(-4) M) decreased cardiac oxygen consumption in a NO-dependent manner by 17 +/- 2% at C, by 21 +/- 2% at 1w, by 24 +/- 2% at 2w (P < 0.05 vs. C and -4d), and by 18 +/- 1% at -4d. Myocardial eNOS protein expression is transiently increased during pregnancy in rats, and this increase is associated with enhanced NO-dependent control of myocardial oxygen consumption at a time when cardiac output is increased.


Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy.
Diabetic nephropathy is a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function remains unclear, although several hypotheses have been postulated. The cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through the polyol pathway and formation of advanced glycation end-products. The renal effects in vivo of each and every one of these mechanisms are even less clear. However, there is growing evidence that hyperglycaemia results in altered renal oxygen metabolism and decreased renal oxygen tension and that these changes are linked to altered kidney function. Clinical data regarding renal oxygen metabolism and oxygen tension are currently rudimentary and our present understanding regarding renal oxygenation during diabetes is predominantly derived from data obtained from animal models of experimental diabetic nephropathy. This review will present recent findings regarding the link between hyperglycaemia and diabetes-induced alterations in renal oxygen metabolism and renal oxygen availability. A possible link between reduced renal oxygen tension and the development of diabetic nephropathy includes increased polyol pathway activity and oxidative stress, which result in decreased renal oxygenation and subsequent activation of hypoxia-inducible factors. This initiates increased gene expression of numerous genes known to be involved in development of diabetic nephropathy.


Correlation between ECG changes and early left ventricular remodeling in preadolescent footballers.
The aim of this study was to assess the early electrocardiogram (ECG) changes induced by physical training in preadolescent elite footballers. This study included 94 preadolescent highly trained male footballers (FG) competing in Serbian Football League (minimum of 7 training hours/week) and 47 age-matched healthy male controls (less than 2 training hours/week) (CG). They were screened by ECG and echocardiography at a tertiary referral cardio center. Sokolow-Lyon index was used as a voltage electrocardiographic criterion for left ventricular hypertrophy diagnosis. Characteristic ECG intervals and voltage were compared and reference range was given for preadolescent footballers. Highly significant differences between FG and CG were registered in all ECG parameters: P-wave voltage (p < 0.001), S-wave (V1 or V2 lead) voltage (p < 0.001), R-wave (V5 and V6 lead) voltage (p < 0.001), ECG sum of S V1-2 + R V5-6 (p < 0.001), T-wave voltage (p < 0.001), QRS complex duration (p < 0.001), T-wave duration (p < 0.001), QTc interval duration (p < 0.001), and R/T ratio (p < 0.001). No differences were found in PQ interval duration between these two groups (p > 0.05). During 6-year follow-up period, there was no adverse cardiac event in these footballers. None of them expressed pathological ECG changes. Benign ECG changes are presented in the early stage of athlete's heart remodeling, but they are not related to pathological ECG changes and they should be regarded as ECG pattern of LV remodeling.


DOES INTERFERENCE COMPETITION AMONG POLLEN GRAINS OCCUR IN WILD RADISH?
Interest in the possibility of sexual selection in plants has focused primarily on competition among pollen donors based on the speed of pollen-tube growth. However, when pollen arrives on stigmas, there is the opportunity for both races for access to ovules (exploitation competition) and interference with the germination and growth of pollen from other donors (interference competition). We considered whether this second form of competition might occur among pollen grains of wild radish in two experiments. In the first, interference likely occurred because the amount of pollen germination was less in mixed-donor than in single-donor pollinations. This result was duplicated in a second experiment, which also showed that interference occurred only when pollen grains from different donors were in direct contact with each other. In addition, in the second experiment, the opportunity for interference affected the frequency of seeds sired by different pollen donors. Because pollen loads are often mixed in nature, interference competition among pollen grains may be important in the ecology and evolution of plant reproduction.


Social capital: its constructs and survey development.
This article reports on experiences and methods of adapting a valid adult social capital assessment to youth audiences in order to measure social capital and sense of place. The authors outline the process of adapting, revising, prepiloting, piloting, and administering a youth survey exploring young people's sense of community, involvement in the community, and the development of social capital. They then discuss the trade-offs of defining the often amorphous concepts included in social capital as they select measurement scales. The constructs used in the survey are agency, belonging, engagement, and trust for bonding, bridging, and linking forms of social capital.


Solvent-free, under air selective synthesis of α-glycosides adopting glycosyl chlorides as donors.
α-Glycosides are highly relevant synthetic targets due to their abundance in natural oligosaccharides involved in many biological processes. Nevertheless their preparation is hampered by several issues, due to both the strictly anhydrous conditions typically required in glycosylation procedures and the non-trivial achievement of high α-stereoselectivity, one of the major challenges in oligosaccharide synthesis. In this paper we report a novel and efficient approach for the highly stereoselective synthesis of α-glycosides. This is based on the unprecedented solvent-free combination of triethylphosphite, tetrabutylammonium bromide and N,N-diisopropylethylamine for the activation of glycosyl chlorides under air. Despite the relative stability of glycosyl chlorides with respect to more reactive halide donors, the solvent-free procedure allowed a wide set of α-glycosides, including biorelevant fragments, to be obtained in much shorter times compared with similar glycosylation approaches in solution. The presented method features a wide target scope and functional group compatibility, also serving with partially disarmed substrates, and it does not require a high stoichiometric excess of reagents nor the preparation of expensive precursors. The solvent-free glycosylation can be even directly performed from 1-hydroxy sugars without purification of the in situ generated chloride, providing an especially useful opportunity in the case of highly reactive and labile glycosyl donors.


Psychological construing and meaningfulness in schizophrenia.
The ratings of schizophrenic and non-schizophrenic in-patients on a Semantic Differential were compared. Those schizophrenic patients who obtained low scores on a test of psychological construing (the Grid Test) made less use than other schizophrenics of extreme ratings on psychological scales on the Semantic Differential. The two groups of schizophrenics did not differ on their use of non-psychological scales. This indicates that the psychological scales are relatively meaningless to this group of subjects. The findings may explain the presentation of symptoms in schizophrenic patients.


Evaluation of Thompson's quadricepsplasty results in patients with knee stiffness resulted from femoral fracture.
Posttraumatic and/or postsurgical knee stiffness is one of the orthopedic complications which is difficult to be treated and can affect individual's life negatively. The aim of this study is to investigate the results of quadricepsplasty in patients with knee stiffness resulted from femoral fracture. This is a cross-sectional study on all patients with femoral fracture which has caused knee flexion limitation referred to Kashani and Al-Zahra Hospitals in Isfahan from January 2010 to March 2013. The type and site of fracture, joint extension, and fracture fixation technique were recorded. Moreover, the range of motion (ROM) before surgery, under general anesthesia, and 3- and 6-month postoperation were measured. Among the patients, 13 had a simple fracture (48%) and 14 had a segmental fracture (51.9%). Considering the fracture site, 11, 10, and 6 patients had femoral (40.74%), supracondylar (37.3%), and femoral supracondylar (22.2%) fractures, respectively. The fracture fixation was performed by the plate, external, and Wagner fixation techniques for 24 (88.9%), 2 (7.4%), and 1 (3.7%) patients, respectively. The mean ROM before operation, under general anesthesia, and 3- and 6-month postoperation were determined to be 33.15° ± 24.73°, 122.60° ± 10.22°, 99.63° ± 16.52°, and 100.74° ± 15.67°, respectively. The mean ROM value at various stages was not similar (P < 0.001). The mean changes in the ROM were 79.2° ± 24.6° and 62.1° ± 19.7° in the cases with simple and segmental fractures, respectively. The mean changes in the knee ROM were significantly higher in simple fractures in comparison with the segmental femoral fracture (P = 0.03). We found Thompson's quadricepsplasty may successfully increase the range of knee flexion in knee fracture and also regardless of quadriceps time.


Cyanidin 3-glucoside improves diet-induced metabolic syndrome in rats.
Increased consumption of dark-coloured fruits and vegetables may mitigate metabolic syndrome. This study has determined the changes in metabolic parameters, and in cardiovascular and liver structure and function, following chronic administration of either cyanidin 3-glucoside (CG) or Queen Garnet plum juice (QG) containing cyanidin glycosides to rats fed either a corn starch (C) or a high-carbohydrate, high-fat (H) diet. Eight to nine-week-old male Wistar rats were randomly divided into six groups for 16-week feeding with C, C with CG or QG, H or H with CG or QG. C or H were supplemented with CG or QG at a dose of ∼ 8 mg/kg/day cyanidin glycosides from week 8 to 16. H rats developed signs of metabolic syndrome including visceral adiposity, impaired glucose tolerance, hypertension, cardiovascular remodelling, increased collagen deposition in left ventricle, non-alcoholic fatty liver disease, increased plasma liver enzymes and increased inflammatory cell infiltration in the heart and liver. Both CG and QG reversed these cardiovascular, liver and metabolic signs. However, no intact anthocyanins or common methylated/conjugated metabolites could be detected in the plasma samples and plasma hippuric acid concentrations were unchanged. Our results suggest CG is the most likely mediator of the responses to QG but that further investigation of the pharmacokinetics of oral CG in rats is required.


Association Between Mast Cells and Collagen Maturation in Chronic Periodontitis in Humans.
Mast cells (MCs) can influence the maturation of collagen fibers. This study evaluated the relationship between the distribution and degranulation of MCs and collagen maturation in human gingival tissue in chronic periodontitis. A total of 16 specimens of patients clinically diagnosed as periodontitis and 18 controls clinically diagnosed as healthy or gingivitis were included. Immunohistochemistry and Picrosirius staining were performed to identify MCs and assess collagen fibers, respectively. Chi-square, t test, and Pearson's correlation test ( p<0.05) were used. In control specimens, there was a positive association between MCs in the connective tissue and the presence of immature collagen ( p=0.001); in periodontitis samples, this association was not confirmed ( p≥0.12). There was no significant relationship between periodontal diagnosis and collagen maturation or MC degranulation ( p≥0.35). MC density was significantly higher ( p=0.04) in periodontitis tissue (339.01 ± 188.94 MCs/mm2) than in control tissue (211.14 ± 131.13 MCs/mm2) in the area of connective tissue containing inflammatory infiltrate. There was a correlation between the number of MCs and probing depth ( r = 0.34, p=0.04). MCs are involved in the pathogenesis of periodontal diseases and might be associated with collagen maturation in periodontal tissue during the early stages of periodontal disease pathogenesis.


Fabrication of solid-state nanopores.
Nanopores are valuable single-molecule sensing tools that have been widely applied to the detection of DNA, RNA, proteins, viruses, glycans, etc. The prominent sensing platform is helping to improve our health-related quality of life and accelerate the rapid realization of precision medicine. Solid-state nanopores have made rapid progress in the past decades due to their flexible size, structure and compatibility with semiconductor fabrication processes. With the development of semiconductor fabrication techniques, materials science and surface chemistry, nanopore preparation and modification technologies have made great breakthroughs. To date, various solid-state nanopore materials, processing technologies, and modification methods are available to us. In the review, we outline the recent advances in nanopores fabrication and analyze the virtues and limitations of various membrane materials and nanopores drilling techniques.


A framework for managing risk.
Supervision aims to maintain standards, thereby reducing clinical risk. Katrina Neal warns that supervision records could be used in a court of law, so should not be written simply to let off steam.


Inhibitory effect on nitric oxide production and free radical scavenging activity of Thai medicinal plants in osteoarthritic knee treatment.
Thai medicine plants used for Osteoarthritis of knee (OA) treatment consist of twelve plants such as Crinumn asiaticum, Cleome viscosa, Drypetes roxburghii, Piper longum, Piper nigrum, Plumbago indica, Alpinia galanga, Curcuma aromatica, Globba malaccensis, Zingiber montanum, Zingiber officinale andZingiberzerumbet. They showedhighfrequency in OA formula. To investigate inhibitory effect on LPS-induced nitric oxide (NO) release from RAW264. 7 cell and free radical scavenging activity usingDPPH assay of these ethanolic plant extracts. Plant materials were extracted by maceration in 95% ethanol. Anti-inflammatory activity were tested on LPS-induced NO production. Free radical scavenging activity was performed by DPPH assay. All of ethanolic extracts exhibited potent inhibitory effect on NO release. The ethanolic extract of Z. zerumbet exhibited the highest inhibitory effect followed by Z. montanum and G. malaccensis, respectively. Except A. galanga and C. viscosa, all extracts possessed more influential than indomethacin (IC50 = 20.32±3.23 μLg/ml), a positive control. The investigation on antioxidant activity suggested that the ethanolic extracts of D. roxburghii, Z. officinale, Z. montanum, C. aromatic, A. galanga, P indica, G malaccensis, P nigrum exhibited antioxidant activity. By means ofD. roxburghii had the highest electron donating activity,followed by Z. officinale. Moreover both extracts were more effective than BHT apositive control (EC50 = 14.04±1.95 μg/ml). Thai medicinal plants had anti-inflammatory activity and could inhibit destruction of articular cartilage that corresponded to the traditional medicine and supported using these medicinal plants for OA treatment.


Histopathological effects of short and long-term treatment of Orchis antolica crude root extract on female albino rats fertility and pregnancy.
The present study has investigated the effects of Orchis antolica (dose of 400 mg/kg/Body Wight) on female rats reproductive system for two time periods 4 and 12 weeks. Forty adult female Sprague-Dawley rats were divided into two treatment and two control groups of 10 rats each. The two treated groups received 400 mg/kg/body weight of Orchis antolica for two periods of 4 and 12 weeks. Female rats were allowed mating with untreated males when treatment ended. Pregnancy parameters such as: total number of pregnancy, body weight, reproductive organ weight, number of implantation sites, number of resorption sites and number of viable fetuses. The significance of these results was calculated using student's "t" and Chi- square tests. Treatment with Orchis antolica for 4 weeks did not have any significant effects on most parameters investigated except for a slight increase in the relative ovarian and embryo weights. Orchis antolica for 12 weeks induces a significant increased in the percentage of pregnancies and the number of implantation sites when compared with controls. Further, an increase in ovarian weights and in viable fetuses count was also observed. Histological sections of treated female ovaries were found to have an empty blood vessels within the cortical and modularly regions. We also noted an increased in the developing follicles at primary and secondary stages in addition to an absence of degenerative areas and increased cellularity in medulla. Long-term treatment with Orchis antolica might lead to diversified positive effects on fertility and pregnancy in female rats.


Importance of coronoidotomy and masticatory muscle myotomy in surgical release of trismus caused by submucous fibrosis.
Thirty patients with trismus resulting from betel nut chewing-induced oral submucous fibrosis were treated with either fibrotic tissue release only (group I) or fibrotic tissue release in combination with masticatory muscle myotomy and coronoidotomy (group II). The latter procedures were only performed in patients whose intraoperative interincisal distance remained less than 35 mm immediately after submucous fibrous tissue release. There were eight and 22 patients in groups I and II, respectively. In group I patients, the average intraoperative interincisal distance improved from 19.5 mm to 42 mm. In group II patients, the average intraoperative interincisal distance improved from 13.5 mm to 27 mm after fibrotic tissue release and further improved to 40 mm after masticatory muscle myotomy and coronoidotomy. At an average follow-up of 22.1 months (range, 7 to 70 months), the group I and II patients had an average interincisal distance of 41.5 mm (range, 35 to 50 mm) and 32.9 mm (range, 20 to 42 mm), respectively. These results demonstrate the efficacy of submucous fibrotic tissue release in treating trismus resulting from betel nut chewing-induced submucous fibrosis and confirm the role of additional masticatory muscle and coronoidotomy in treating its severe forms.


D5 dopamine receptors are required for dopaminergic activation of phospholipase C.
Dopamine activates phospholipase C in discrete regions of the mammalian brain, and this action is believed to be mediated through a D(1)-like receptor. Although multiple lines of evidence exclude a role for the D(1) subtype of D(1)-like receptors in the phosphoinositide response, the D(5) subtype has not been similarly examined. Here, mice lacking D(5) dopamine receptors were tested for dopamine agonist-induced phosphoinositide signaling both in vitro and in vivo. The results show that hippocampal, cortical, and striatal tissues of D(5) receptor knockout mice significantly or completely lost the ability to produce inositol phosphate or diacylglycerol messengers after stimulation with dopamine or several selective D(1)-like receptor agonists. Moreover, endogenous inositol-1,4,5-trisphosphate stimulation by the phospholipase C-selective D(1)-like agonist 3-methyl-6-chloro-7,8-dihydroxy-1-[3methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) was robust in wild-type animals but undetectable in the D(5) receptor mutants. Hence, D(5) receptors are required for dopamine and selective D(1)-like agonists to induce phospholipase C-mediated phosphoinositide signaling in the mammalian brain.


Acute interdural hematoma mimicking epidural hematoma: a case report.
Intracranial hematoma rarely presents between two dural layers of pachimeninges. Here, we present a case of an interdural hematoma with similar appearance to an epidural hematoma. A 51-year-old man presented with a left temporal contusion following a motor vehicle accident. After craniotomy and contusion removal, the post-operative CT scan showed a parietal intracranial hematoma located posterior and superior to the bone flap. The CT scan appearance of the new hematoma was similar to the CT scan appearance of an epidural hematoma. Upon operation, we determined that the hematoma was located between two layers of dura mater, i.e., an interdural hematoma. We removed the hematoma and sutured the two layers of dura to each other at multiple sites. Interdural hematoma is a rare entity. Its appearance in a CT scan can be mistaken for an extradural hematoma.


Detection of Haemophilus parasuis isolates from South China by loop-mediated isothermal amplification and isolate characterisation.
Haemophilus parasuis is the etiological agent of Glässer's disease, which is characterised by fibrinous polyserositis, meningitis and polyarthritis, causing severe economic losses to the swine industry. In this study, a loop-mediated isothermal amplification (LAMP) test was developed to improve the specificity, facility and speed of diagnosis of H. parasuis isolates. The LAMP assay rapidly amplified the target gene within 50 min incubation at 63 °C in a laboratory water bath. The LAMP amplicon could be visualised directly in the reaction tubes following the addition of SYBR Green I dye. The detection limit of this LAMP method was 10 CFU/mL, which was 10 times more sensitive than the earlier 16S rRNA polymerase chain reaction (PCR) test conducted by Oliveira, Galina and Pijoan (2001), and no cross-reactivity was observed from other non-H. parasuis strains. This LAMP test was evaluated further on 187 clinical specimens from pigs suspected of being infected with H. parasuis. Forty-three were found positive by bacterial isolation of H. parasuis, as well as by the 16S rRNA PCR and LAMP tests. The 43 H. parasuis isolates were classified into 9 serovars and had 37 genetic patterns when analysed by pulsed-field gel electrophoresis (PFGE). This displayed that various H. parasuis serovars and genotypes were widely distributed in South China. Therefore, the speed, specificity and sensitivity of the LAMP test, the lack of a need for expensive equipment, and the visual readout showed great potential for a correct clinical diagnosis of H. parasuis in favour of controlling Glässer's disease.


Competence for genetic transformation in Streptococcus pneumoniae: molecular cloning of com, a competence control locus.
To identify and map genes involved in competence for genetic transformation in Streptococcus pneumoniae, we have cloned DNA surrounding an ermB insertion mutation that causes a competence factor deficiency. We recovered the insert and approximately 500 base pairs of neighboring pneumococcal DNA in pMB9. Larger pieces of DNA from this region were unstable in pMB9 and pBR325. However, larger pieces were stable in pKK232-8, an Escherichia coli vector containing strong transcription terminators. Overlapping pieces of wild-type DNA from this competence control region were cloned and mapped in this vector. Insertion mutations were constructed in vitro throughout the cloned region. When crossed into the pneumococcus chromosome, they showed that the com locus was 4.2 to 5.2 kilobases long.


Comparison of micromorphological changes in enamel using SEM analysis after conventional and erbium, chromium:yttrium, scandium, gallium, and garnet hard-tissue laser fissurotomy: An in vitro study.
Well articulated by John Knowles - "Everything has to evolve or else it perishes." With the paradigm shift of emphasis toward the prevention of dental caries, it has been proven that laser irradiation protects against both caries initiation and caries progression. The aim of the study was to evaluate and compare the micromorphology of caries-free extracted premolars using a Scanning electron microscope (SEM) after fissurotomy by conventional fissurotomy bur and erbium, chromium: yttrium, scandium, gallium, and garnet (ER, CR: YSGG) hard-tissue laser. Sixty caries-free premolars extracted atraumatically for orthodontic treatment were included in the study. The samples were divided into two groups randomly (Group 1: fissurotomy by bur, n = 30, and Group 2: fissurotomy by hard-tissue laser, n = 30). Each sample was further divided into halves from the occlusal surface wherein one-half of the occlusal surface received fissurotomy procedure and the other half was control. Samples were analyzed by scanning electron microscopy (SEM) for micromorphological changes. Profile image of control samples revealed the disorganization of enamel surface at the junction of fissures forming a heterogeneous tissue and agglomeration of enamel with deep pit and fissure. On the contrary, the image of experimented samples (with laser fissurotomy) showed smooth enamel surface and homogeneous enamel subsurface with wider pit and fissure owing to self-cleansing ability. On the grounds of the present study results, it could be concluded that the intervention of ER, CR: YSGG hard-tissue laser possesses self-cleansable pit and fissures for caries prevention and has the potential to irradicate the smear layer entirely for superior attachment of remineralizing agents.


Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles.
Weanling rats were used to examine the role of leucine in in vitro protein turnover in skeletal muscles. In three experiments, rats were subjected to 24 or 72 hours of food deprivation or 5 days of consuming a protein-free diet or injection of streptozotocin. The soleus and extensor digitorum longus muscles were removed and utilized for measures of protein synthesis or degradation by using the isolated, incubated muscle technique of Li et al. These experiments demonstrate that supplementation of the incubation media with 0.5 mM leucine stimulates protein synthesis in these catabolic muscles and that during total starvation the stimulation decreases as the severity of the condition increases. Leucine supplementation failed to affect protein degradation in these skeletal muscles. This study demonstrates that the branched-chain amino acid leucine has the potential to stimulate protein synthesis in skeletal muscles, at least under specific catabolic conditions, but does not affect protein degradation in skeletal muscles under the conditions studied.


Clinical significance of tolerant strains of Staphylococcus aureus in patients with endocarditis.
We have studied 50 cases of endocarditis and 54 cases of bacteremia due to Staphylococcus aureus to ascertain the clinical significance of the newly described phenomenon of tolerance. In 32 of the patients with endocarditis and 35 of those with bacteremia strains were classified as tolerant (minimum bactericidal concentration/minimum inhibitory concentration greater than or equal to 16). Patients with endocarditis due to a tolerant strain responded less favorably than did patients with a sensitive strain. A larger number of patients with a tolerant strain had prolonged fever (58% versus 19%), a higher mean number of complications (1.6 versus 0.73), a greater number of intensive-care unit admissions (66% versus 33%), and a higher mortality (25% versus 11%). In contrast there was no difference in response to therapy in bacteremic patients without endocarditis having sensitive and tolerant strains. We conclude that infection with a tolerant organism adversely influences the outcome of staphylococcal endocarditis.


Inhaled insulin: a novel route for insulin delivery.
Insulin has been in use for the treatment of patients with diabetes mellitus for over 75 years. However, despite the known benefits of tight glycaemic control, multiple insulin injections have still not gained widespread clinical acceptance. Although there have been attempts to find effective non-invasive routes for insulin delivery, none of the novel non-invasive approaches have become part of established practice. In fact, until recently it was believed that as a result of limitations, non-invasive insulin was not a clinically realistic option. However, preliminary studies have indicated that inhaled insulin may emerge as an effective, well-tolerated, non-invasive alternative to subcutaneous regular insulin. The pharmacokinetics of inhaled insulin show a more physiological profile compared to conventional insulin; however, further studies to confirm long-term pulmonary safety and efficacy are needed.


Low-dose Amiodarone Is Safe: A Systematic Review and Meta-analysis.
Amiodarone is commonly used for a variety of arrhythmias and, in some parts of the world, is the only available antiarrhythmic drug (AAD). Yet, amiodarone is known to have a wide range of potential side effects, many of which are dose- and duration-dependent. We sought to study the incidence of side effects leading to the discontinuation of low-dose amiodarone, arbitrarily defined as 200 mg/day or less, and very-low-dose amiodarone, defined as 100 mg/day or less. In this study, literature databases were searched through June 2019. Studies that reported the incidence or prevalence of side effects of amiodarone were included. Effect estimates from individual studies were extracted and combined using the random-effects generic inverse variance method of DerSimonian and Laird. A total of 10 observational cohort studies involving 901 patients were included in the analysis. The pooled estimated incidence of overall side effects for low-dose amiodarone was 0.17 [95% confidence interval (CI): 0.12-0.22]. In addition, the pooled estimated incidence of side effects requiring medication discontinuation was 0.06 (95% CI: 0.03-0.11). As compared with 200 mg/day of amiodarone, the pooled estimated incidence of overall side effects was 0.11 (95% CI: 0.04-0.27), while the incidence of side effects requiring medication discontinuation was 0.02 (95% CI: 0.01-0.06) for the dose of 100 mg/day. In conclusion, very-low-dose amiodarone displays a low incidence of significant side effects requiring medication discontinuation.


Chlorogenic acid exhibits cholesterol lowering and fatty liver attenuating properties by up-regulating the gene expression of PPAR-α in hypercholesterolemic rats induced with a high-cholesterol diet.
Hypercholesterolemia is a major risk factor for the development of cardiovascular disease and nonalcoholic fatty liver disease. Natural compounds have been proved to be useful in lowering serum cholesterol to slow down the progression of cardiovascular disease and nonalcoholic fatty liver disease. In the present study, the hypocholesterolemic and hepatoprotective effects of the dietary consumption of chlorogenic acid were investigated by monitoring plasma lipid profile (total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein) in Sprague-Dawley rats fed with a normal diet, a high-cholesterol diet or a high-cholesterol diet supplemented with chlorogenic acid (1 or 10 mg/kg/day p.o.) for 28 days. Chlorogenic acid markedly altered the increased plasma total cholesterol and low-density lipoprotein but decreased high-density lipoprotein induced by a hypercholesterolemic diet with a dose-dependent improvement on both atherogenic index and cardiac risk factor. Lipid depositions in liver were attenuated significantly in hypercholesterolemic animals supplemented with chlorogenic acid. It is postulated that hypocholesterolemic effect is the primary beneficial effect given by chlorogenic acid, which leads to other secondary beneficial effects such as atheroscleroprotective, cardioprotective and hepatoprotective functions. The hypocholesterolemic functions of chlorogenic acid are probably due to the increase in fatty acids unitization in liver via the up-regulation of peroxisome proliferation-activated receptor α mRNA.


Combined Lifestyle and Herbal Medicine in Overweight Women with Polycystic Ovary Syndrome (PCOS): A Randomized Controlled Trial.
Polycystic ovary syndrome (PCOS) is a common, complex reproductive endocrinopathy characterized by menstrual irregularities, hyperandrogenism and polycystic ovaries. Lifestyle modification is a first-line intervention; however, there are barriers to success for this form of self-care, and women often seek adjunct therapies including herbal medicines. This pragmatic, randomized controlled trial, delivered in communities of Australia in overweight women with PCOS, compared the effectiveness and safety of a lifestyle intervention plus herbal medicine against lifestyle alone. All participants were helped to construct a personalized lifestyle plan. The herbal intervention consisted of two tablets. Tablet 1 contained Cinnamomum verum, Glycyrrhiza glabra, Hypericum perforatum and Paeonia lactiflora. Tablet 2 contained Tribulus terrestris. The primary outcome was oligomenorrhoea/amenorrhoea. Secondary outcomes were hormones; anthropometry; quality of life; depression, anxiety and stress; pregnancy; birth outcomes; and safety. One hundred and twenty-two women gave their consent. At 3 months, women in the combination group recorded a reduction in oligomenorrhoea of 32.9% (95% confidence interval 23.3-42.6, p < 0.01) compared with controls, estimated as a large effect (ηp2 = 0.11). Other significant improvements were found for body mass index (p < 0.01); insulin (p = 0.02) and luteinizing hormone (p = 0.04); blood pressure (p = 0.01); quality of life (p < 0.01); depression, anxiety and stress (p < 0.01); and pregnancy rates (p = 0.01). This trial provides evidence of improved effectiveness and safety for lifestyle intervention when combined with herbal medicines in women with PCOS. © 2017 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.


Breach Risk Magnitude: A Quantitative Measure of Database Security.
A quantitative methodology is described that provides objective evaluation of the potential for health record system breaches. It assumes that breach risk increases with the number of potential records that could be exposed, while it decreases when more authentication steps are required for access. The breach risk magnitude (BRM) is the maximum value for any system user of the common logarithm of the number of accessible database records divided by the number of authentication steps needed to achieve such access. For a one million record relational database, the BRM varies from 5.52 to 6 depending on authentication protocols. For an alternative data architecture designed specifically to increase security by separately storing and encrypting each patient record, the BRM ranges from 1.3 to 2.6. While the BRM only provides a limited quantitative assessment of breach risk, it may be useful to objectively evaluate the security implications of alternative database organization approaches.


Oriented Arrangement: The Origin of Versatility for Porous Graphene Materials.
Macroscopic porous graphene materials composed of graphene sheets have demonstrated their advantageous aspects in diverse application areas. It is essential to maximize their excellent performances by rationally controlling the sheet arrangement and pore structure. Bulk porous graphene materials with oriented pore structure and arrangement of graphene sheets are prepared by marrying electrolyte-assisted self-assembly and shear-force-induced alignment of graphene oxide sheets, and the super elasticity and anisotropic mechanical, electrical, and thermal properties induced by this unique structure are systematically investigated. Its application in pressure sensing exhibits ultrahigh sensitivity of 313.23 kPa-1 for detecting ultralow pressure variation below 0.5 kPa, and it shows high retention rate for continuously intercepting dye molecules with a high flux of ≈18.7 L m-2 h-1 bar-1 and a dynamic removal rate of 510 mg m-2 h-1 .


Isolated Spin-7/2 Species of Gadolinium (III) Chelate Complexes on the Surface of 5-nm Diamond Particles.
The magnetic characteristics of a system of triply charged gadolinium ions Gd3+ chelated with carboxyls on the surface of detonation nanodiamond (DND) particles have been studied. Gd3+ ions demonstrate almost perfect spin (S = 7/2) paramagnetism with negligible antiferromagnetic interaction between spins (Weiss temperature about -0.35 K) for a wide range of concentrations up to ~18 ions per 5 nm particle. The study of the concentration dependence of the electron paramagnetic resonance signal for DND intrinsic defects with spin ½ (g = 2.0027) shows that Gd3+ ions are located on average at a distance of no more than 1.4 nm from shallow subsurface defects with spin 1/2. At the same time, they are located (according to density functional theory calculations) at a distance of about or at least 0.28 nm from the particle surface. Magnetic studies also confirm the isolated nature of the gadolinium chelate complexes on the surface of DND particles. DND particles turn out to be an optimal carrier for high-spin 4f- ions (gadolinium) in a highly concentrated isolated state. This property makes DND-Gd particles a candidate for the role of a contrast agent for magnetic resonance imaging.


[Triatoma brasiliensis Neiva, 1911 (Hemiptera, Reduviidae): observations on dynamics of feeding behavior in an artificial ecotope].
In order to study the behavior of triatomine bugs under artificial ecotopic conditions, an experimental, double-walled poultry coop was built. Its inside walls were made of sun-dried clay blocks which could be broken apart for better access to the insects hiding in their crevices. The coop was subdivided into two main areas of different sizes using wire netting and a wall made of perforated bricks. The chickens, the only food source available for the triatomines, were kept in the larger, rectangular area, further subdivided diagonally. The triatomines were released in the smaller area and were allowed to migrate to the larger one though the holes in the bricks. Information about migration, survival, and hiding places of fourth-stage nymphs of Triatoma brasiliensis was thus gathered. At 30-day intervals, over a period of six months, the inner walls of the house were taken apart and inspected. The nymphs were marked with different colors according to the month and place of capture. It was found that 88.5% of the nymphs were captured near the roost and found engorged. After having taken their first blood meal, they would remain in the vicinity of their food source. The results obtained are considered epidemiologically relevant, and particularly so as pertaining to the control of the vectors of Chagas disease.


Association of PI-3 kinase with PAK1 leads to actin phosphorylation and cytoskeletal reorganization.
The family of p21-activated kinases (PAKs) have been implicated in the rearrangement of actin cytoskeleton by acting downstream of the small GTPases Rac and Cdc42. Here we report that even though Cdc42/Rac1 or Akt are not activated, phosphatidylinositol-3 (PI-3) kinase activation induces PAK1 kinase activity. Indeed, we demonstrate that PI-3 kinase associates with the N-terminal regulatory domain of PAK1 (amino acids 67-150) leading to PAK1 activation. The association of the PI-3 kinase with the Cdc42/Rac1 binding-deficient PAK1(H83,86L) confirms that the small GTPases are not involved in the PI-3 kinase-PAK1 interaction. Furthermore, PAK1 was activated in cells expressing the dominant-negative forms of Cdc42 or Rac1. Additionally, we show that PAK1 phosphorylates actin, resulting in the dissolution of stress fibers and redistribution of microfilaments. The phosphorylation of actin was inhibited by the kinase-dead PAK1(K299R) or the PAK1 autoinhibitory domain (PAK1(83-149)), indicating that PAK1 was responsible for actin phosphorylation. We conclude that the association of PI-3 kinase with PAK1 regulates PAK1 kinase activity through a Cdc42/Rac1-independent mechanism leading to actin phosphorylation and cytoskeletal reorganization.


Pharmaceutical Particulates and Membranes for the Delivery of Drugs and Bioactive Molecules.
The delivery of drugs and bioactive molecules using pharmaceutical particulates and membranes are of great significance for various applications such as the treatment of secondary infections, cancer treatment, skin regeneration, orthopedic applications and others [...].


Splenic Vein Thrombosis as a Rare Complication of Disseminated Tuberculosis - Imaging Diagnosis and Case Report.
Venous thromboembolism is a known but rare complication associated with Mycobacterium tuberculosis infection. The reported incidence of venous thromboembolism is 1.5-3.4% of infected patients, and it occurs due to a hypercoagulable state induced by the associated inflammation. A young woman with pulmonary tuberculosis was found to have disseminated tuberculosis and a clinically unsuspected partial thrombus in the splenic vein on imaging. Ultrasound demonstrated hepato-splenomegaly with multiple granulomas as well as ascites and a left-sided pleural effusion. An increased calibre of the splenic vein with a hyperechogenicity within it raised the suspicion of a thrombus, which was confirmed on a contrast-enhanced CT examination. CECT of the abdomen also showed a small peripheral splenic infarct, while CECT of the chest revealed bilateral miliary lesions in the lungs along with necrotic mediastinal lymphadenopathy. The final imaging diagnosis was disseminated tuberculosis complicated by splenic vein thrombosis. A timely institution of anti-coagulant and anti-tubercular treatment led to a complete resolution of the splenic vein thrombosis. Contrast-enhanced CT serves as a useful imaging tool for the detection of venous thrombosis and for the estimation of a complete burden of the disease. This condition should be kept in mind by both clinicians and radiologists and looked for in order to prevent life-threatening complications.


Unknown toxic exposures. Arts and crafts materials.
1. Arts and crafts material containing toxic chemicals have been found to be hazardous to human health. 2. Artists/craftspersons, who also may be employed in industry, often are unaware or not adequately informed about the toxic nature of many art products. 3. The occupational health nurse is in a critical position to identify and monitor the worker exposed to toxic chemicals both in the workplace and at home/art studio. 4. Education about hazardous substances can prevent illness or injury. With expertise in public health, occupational health nurses are in a key position to provide community education about the dangers of toxic art materials to the general public and the health care community.


Congenital dopamine-beta-hydroxylase deficiency in humans.
Dopamine-beta-hydroxylase (DbetaH) deficiency is a rare autosomal dominant disorder. Due to the absence of DbetaH, there is a blocked conversion of dopamine into norepinephrine. The biochemical hallmark of this syndrome consists of a complete absence of plasma norepinephrine and epinephrine levels in conjunction with an increased plasma dopamine level. Several mutations in the gene that encodes for DbetaH have been described. Up to now, worldwide, 12 patients have been reported. The most important clinical feature is a severe orthostatic hypotension. In addition, several other clinical features like blepharoptosis, hyperflexible joints, high palate, sluggish deep tendon reflexes, and a mild normocytic anemia have been described. The only effective treatment of DbetaH deficiency is L-threo-3,4-dihydroxyphenylserine (DOPS). DOPS is converted directly into norepinephrine. Treatment with DOPS results in a sustained relief of orthostatic symptoms.


'INSPIRED' COPD Outreach Program™: doing the right things right.
The well-documented gaps between needed and provided care for patients and families living with chronic obstructive pulmonary disease (COPD) mandate changes to clinical practice. The multifaceted evidence-based INSPIRED COPD Outreach Program™ was first implemented in Halifax, Nova Scotia, Canada in 2010 (INSPIRED = Implementing a Novel and Supportive Program of Individualized care for patients and families living with REspiratory Disease) and undergoes ongoing evaluation. By enhancing patient confidence to manage their illness more effectively in their homes and communities, there has been a sustained and substantial reduction in facility-based care in comparison with patient care experience pre-INSPIRED. Sustaining and spreading a program recently designated a leading practice by Accreditation Canada, and especially modifying the program as new evidence emerges, requires integrating and modeling at the 'bedside' both evidence-based medicine ('doing the right things') and quality improvement ('doing them right'). In Canada, where COPD care gaps are common, a new pan-Canadian INSPIRED-based quality improvement program is supporting multidisciplinary healthcare teams to bridge the chasm between evidence and practice by working together to 'do the right things right' in COPD care.


Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8+ T cell responses.
Cancer arises from the accumulation of genetic alterations, which can lead to the production of mutant proteins not expressed by normal cells. These mutant proteins can be processed and presented on the cell surface by major histocompatibility complex molecules as neoepitopes, allowing CD8+ T cells to mount responses against them. For solid tumors, only an average 2% of neoepitopes predicted by algorithms have detectable endogenous antitumor T cell responses. This suggests that low mutation burden tumors, which include many pediatric tumors, are poorly immunogenic. Here, we report that pediatric patients with acute lymphoblastic leukemia (ALL) have tumor-associated neoepitope-specific CD8+ T cells, responding to 86% of tested neoantigens and recognizing 68% of the tested neoepitopes. These responses include a public neoantigen from the ETV6-RUNX1 fusion that is targeted in seven of nine tested patients. We characterized phenotypic and transcriptional profiles of CD8+ tumor-infiltrating lymphocytes (TILs) at the single-cell level and found a heterogeneous population that included highly functional effectors. Moreover, we observed immunodominance hierarchies among the CD8+ TILs restricted to one or two putative neoepitopes. Our results indicate that robust antitumor immune responses are induced in pediatric ALL despite their low mutation burdens and emphasize the importance of immunodominance in shaping cellular immune responses. Furthermore, these data suggest that pediatric cancers may be amenable to immunotherapies aimed at enhancing immune recognition of tumor-specific neoantigens.


Workplace Social Support and Behavioral Health Prior to Long-Duration Spaceflight.
Preparation and training for long-duration spaceflight bring with them psychosocial stressors potentially affecting the well-being and performance of astronauts, before and during spaceflight. Social support from within the workplace may mitigate behavioral health concerns arising during the preflight period and enhance resiliency before and during extended missions. The purpose of this review was to evaluate evidence addressing the viability of workplace social support as a pre-mission countermeasure, specifically addressing: 1) the observed relationships between workplace social support and behavioral health; 2) perceived need, acceptability, and format preference for workplace social support among high-achievers; 3) potential barriers to delivery/receipt of workplace social support; 4) workplace social support interventions; and 5) delivery timeframe and anticipated duration of workplace social support countermeasure benefits. We conducted an evidence review examining workplace social support in professional contexts sharing one or more characteristics with astronauts and spaceflight. Terms included populations of interest, social support constructs, and behavioral health outcomes. Abstracts of matches were subsequently reviewed for relevance and quality. Research findings demonstrate clear associations between workplace social support and behavioral health, especially following exposure to stress. Further, studies indicate strong need for support and acceptability of support countermeasures, despite barriers. Our review revealed two general formats for providing support (i.e., direct provision of support and training to optimize skills in provision and receipt of support) with potential differentiation of expected duration of benefits, according to format. Workplace social support countermeasures hold promise for effective application during pre-mission phases of long-duration spaceflight. Specific recommendations are provided.Deming CA, Vasterling JJ. Workplace social support and behavioral health prior to long-duration spaceflight. Aerosp Med Hum Perform. 2017; 88(6):565-573.


Morphological changes in the pituitary gland of dogs chronically exposed to exogenous growth hormone.
Growth hormone (GH) synthesis and release from the pituitary is regulated by hypothalamic releasing hormone, insulin-like growth factor-1 (IGF-1), and somatostatin. However, the potential effects of pharmacological doses of exogenous GH on the pituitary are not well studied. To determine the potential chronic effects of exogenous GH on pituitary morphology in dogs, porcine GH (pGH) was administered subcutaneously to 3 groups of dogs (4 animals/sex/group) at doses of 0.025, 0.1, and 1.0 IU/kg/day for 14 wk. A group (4/sex) of dogs served as the vehicle control. The pituitaries from all dogs were weighed and fixed in appropriate fixatives for light and electron microscopic examination; in addition, cells of the pars distalis were quantitated by a point counting method following immunostaining to identify cells containing GH, prolactin (PRL), and adrenocorticotrophic (ACTH) hormones. Administration of pGH resulted in a statistically significant (p < or = 0.05) increased pituitary weight through the high dose. By light microscopy (LM), hypertrophy of pars distalis cells was evident in mid- and high-dose female dogs. The pituitaries of dogs given the lowest dose (0.025 IU/kg/day) of pGH were not remarkable based on weight and LM findings. In addition, transmission electron microscopic (TEM) examination of the pituitary gland of high-dose demonstrated, in both sexes, pituitary cells with variably dilated rough endoplasmic reticulum and decreased numbers of secretory granules; some of these cells reacted positively to GH immunostaining. Quantitative analysis of the pituitary gland of high-dose males and females showed an increase in the absolute volume of all cell populations studied: GH-, PRL-, and ACTH-positive cells. Based on the LM and TEM findings, the increased volume of the cell populations studied is likely related to cellular hypertrophy. The expected elevation in serum GH levels following repeated administration of pGH and an associated elevation in serum IGF-1 levels resulted in morphologic changes in the pituitary gland of dogs given high doses (> or = 0.1 IU/kg/day) of pGH; these observations differed from the reported findings in pituitaries of transgenic mice secreting large quantities of bovine GH.


Frequency of Hand Decontamination of Intraoperative Providers and Reduction of Postoperative Healthcare-Associated Infections: A Randomized Clinical Trial of a Novel Hand Hygiene System.
BACKGROUND Healthcare provider hands are an important source of intraoperative bacterial transmission events associated with postoperative infection development. OBJECTIVE To explore the efficacy of a novel hand hygiene improvement system leveraging provider proximity and individual and group performance feedback in reducing 30-day postoperative healthcare-associated infections via increased provider hourly hand decontamination events. DESIGN Randomized, prospective study. SETTING Dartmouth-Hitchcock Medical Center in New Hampshire and UMass Memorial Medical Center in Massachusetts. PATIENTS Patients undergoing surgery. METHODS Operating room environments were randomly assigned to usual intraoperative hand hygiene or to a personalized, body-worn hand hygiene system. Anesthesia and circulating nurse provider hourly hand decontamination events were continuously monitored and reported. All patients were followed prospectively for the development of 30-day postoperative healthcare-associated infections. RESULTS A total of 3,256 operating room environments and patients (1,620 control and 1,636 treatment) were enrolled. The mean (SD) provider hand decontamination event rate achieved was 4.3 (2.9) events per hour, an approximate 8-fold increase in hand decontamination events above that of conventional wall-mounted devices (0.57 events/hour); P<.001. Use of the hand hygiene system was not associated with a reduction in healthcare-associated infections (odds ratio, 1.07 [95% CI, 0.82-1.40], P=.626). CONCLUSIONS The hand hygiene system evaluated in this study increased the frequency of hand decontamination events without reducing 30-day postoperative healthcare-associated infections. Future work is indicated to optimize the efficacy of this hand hygiene improvement strategy. Infect Control Hosp Epidemiol 2016;37:888-895.


Platelet-induced vascular smooth muscle cell proliferation is modulated by the growth amplification factors serotonin and adenosine diphosphate.
Platelet-mediated mechanisms have been implicated in intimal lesion formation following vascular injury. Although the participation of peptide growth factors has been suspected in this process, little has been known about the possible mitogenic role of other platelet factors that are released at sites of vascular injury. We tested the hypothesis that platelet products, which are not peptide growth factors, are important modulators of the platelet-induced smooth muscle cell (SMC) proliferative response by acting as growth amplification factors. In these studies, cell proliferation was assessed by [3H]thymidine incorporation, flow cytometry, and direct cell counting. We examined the potential mitogenicity of several platelet products, including serotonin, ADP, norepinephrine, histamine, platelet-activating factor, the thromboxane A2 mimetic U46619, and bradykinin. Of the platelet products tested, serotonin and ADP induced a synergistic response with peptide growth factors. This synergy was greatest at low growth-factor concentrations. Addition of nonaggregated platelets to quiescent SMC cultures strongly stimulated cell proliferation. Since the addition of suramin to platelet-treated cultures markedly inhibited SMC proliferation, peptide growth factors are most likely the primary mitogens mediating this response. However, platelet-induced proliferation was also markedly reduced by the serotonin antagonists ketanserin and LY53857 (44%), and by the ADP antagonist apyrase (35%). Therefore, serotonin and ADP contribute significantly, in synergy with peptide growth factors, to the platelet-induced SMC proliferative response. We propose that in vivo serotonin and ADP act as amplification factors for SMC proliferation at sites of vascular injury.