Emotional Expression of Persons with Dementia: An Integrative Review with Implications for Evidence-Based Practice.
The ability to express emotion typically is preserved longer than language and cognitive function in persons living with dementia. Emotional expression may be an important indicator of underlying individual needs and feelings and may therefore facilitate person-centered care. This review aimed to examine how emotional expression has been described, measured, and utilized in empirical studies. The design of this study was an integrative literature review. A systematic search was conducted through electronic databases using defined search terms. Articles published up to March 2018 were included. The method proposed by Whittemore and Knafl was used for data synthesis and review integration. Quality appraisal of the selected articles was evaluated by the Mixed Methods Assessment Tool. Most of the articles used feeling-related terms without specific definitions. Less frequently, terms such as affect, emotion, and mood were defined. Although these terms were used interchangeably in the articles, affect, which was defined as expressed emotion in general, was a comprehensive term to encompass other terms. Measurement of emotional expression was performed using observational methods, with direct observation or video recording using a hand-held camera. In both cases, observed emotion was coded with diverse methods or tools. In studies, the emotional expression was utilized as (a) an outcome to demonstrate the effect of interventions, (b) a factor to show relationship with other variables, or (c) an observed value itself. This review provides insights about measurement options for emotional expressions among persons with dementia in long-term care. Long-term care staff should pay attention to emotional expression of persons with dementia to understand underlying unmet needs. Development of adequate measurement of emotional expression could facilitate development of emotion-oriented intervention program to improve psychological well-being and the behavioral and functional health of persons living with dementia.


Integrative package for low back pain with leg pain in Korea: a prospective cohort study.
Back pain significantly affects both patients and society through personal suffering, supporting burden, work loss, and incurred expenses. With no unequivocal support for surgery versus conservative treatment, an integrative approach has become popular in Korea. To investigate the outcomes of an integrative package for low back pain with leg pain. A prospective cohort study involving patients with low back and leg pain and confirmed disc herniation was carried out at an outpatient clinic in Korea. The treatment package comprised of herbal medicines, acupuncture, bee venom acupuncture, and a Korean version of spinal manipulation (Chuna). Study participants were evaluated at baseline and every 4 weeks for 24 weeks. Low back and leg pain intensity levels were measured on a visual analog scale (0-10), back function was evaluated with the Oswestry Disability Index (0-100), and the overall quality of life was assessed using the SF-36 Health Survey (0-100 in 8 different subcategories). Out of 150 patients, 128 completed the 24 weeks of therapy. Patients reported improvements in all outcome measures. At the completion of the study, low back pain scores improved by a mean of 3.3 (95% CI=2.8 to 3.8), and leg pain scores improved by a mean of 6.3 (95% CI=5.9 to 6.6). Significant improvements in ODI and SF-36 scores were observed at 4 weeks and sustained throughout. This integrative package was effective in the treatment of LBP with leg pain and warrants further rigorous investigations.


Disseminating best practice through publication in journals.
This article, the second in a five-part series, explores the ways in which best practice might be presented successfully through articles published within journals. The article discusses the importance of preparatory research and 'thinking time', the need for an article plan and how to target journals and approach staff. Information and advice is provided on writing, redrafting and dealing with the peer review process. There is an emphasis on consultation and obtaining feedback on the potential article throughout the planning and writing process.


Monitoring of ethylene by a pulsed quantum cascade laser.
We report on the development and performance of a gas sensor based on a quantum cascade laser operating at a wavelength of approximately 10 microns to measure ethylene (C2H4) concentrations by use of a rotational component of the fundamental nu 7 band. The laser is thermoelectrically cooled and operates in a pulsed mode. The influence of pulse-to-pulse fluctuations is minimized by use of a reference beam and a single detector with time discriminating electronics. Gas absorption is recorded in a 100-m optical path-length astigmatic Herriott cell. With a 10-kHz pulse repetition rate and an 80-s total acquisition time, a noise equivalent sensitivity of 30 parts per billion has been demonstrated. The sensor has been applied to monitor C2H4 in vehicle exhaust as well as in air collected in a high-traffic urban tunnel.


Differences in myocardial velocities during supine and upright exercise stress echocardiography in healthy adults.
Tissue Velocity Imaging (TVI) is a method for quantitative analysis of longitudinal myocardial velocities, which can be used during exercise and pharmacological stress echocardiography. It is of interest to evaluate cardiac response to different types of stress tests and the differences between upright and supine bicycle exercise tests have not been fully investigated. Therefore, the aim of this study was to compare cardiac response during supine and upright exercise stress tests. Twenty young healthy individuals underwent supine and upright stress test. The initial workload was set to 30 W and was increased every minute by a further 30 W until physical exhaustion. Tissue Doppler data from the left ventricle were acquired at the end of every workload level using a GE Vivid7 Dimension system (>200 frames s(-1)). In the off-line processing, isovolumic contraction velocity (IVCV), peak systolic velocity (PSV), isovolumic relaxation velocity (IVRV), peak early diastolic velocity (E') and peak late diastolic velocity (A') were identified at every workload level. No significant difference between the tests was found in PSV. On the contrary, E' was shown to be significantly higher (P<0.001) during supine exercise than during upright exercise and IVRV was significantly lower (P<0.001) during supine exercise compared to upright exercise. Upright and supine exercise stress echocardiography give a comparable increase in measured systolic velocities and significant differences in early diastolic velocities.


Epigenetic Mechanisms of Integrative Medicine.
Since time immemorial humans have utilized natural products and therapies for their healing properties. Even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (CAM) approaches represents a popular branch of health care. Furthermore, there is a trend towards a unified medical philosophy referred to as Integrative Medicine (IM) that represents the convergence of CAM and conventional medicine. The IM model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. Justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. We review this data and propose a unifying theme: IM's ability to affect healing is due at least in part to epigenetic mechanisms. This hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of IM and modulation of gene expression and epigenetic state. Emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits.


Engineering Polar Oxynitrides: Hexagonal Perovskite BaWON2.
Non-centrosymmetric polar compounds have important technological properties. Reported perovskite oxynitrides show centrosymmetric structures, and for some of them high permittivities have been observed and ascribed to local dipoles induced by partial order of nitride and oxide. Reported here is the first hexagonal perovskite oxynitride BaWON2 , which shows a polar 6H polytype. Synchrotron X-ray and neutron powder diffraction, and annular bright-field in scanning transmission electron microscopy indicate that it crystalizes in the non-centrosymmetric space group P63 mc, with a total order of nitride and oxide at two distinct coordination environments in cubic and hexagonal packed BaX3 layers. A synergetic second-order Jahn-Teller effect, supported by first principle calculations, anion order, and electrostatic repulsions between W6+ cations, induce large distortions at two inequivalent face-sharing octahedra that lead to long-range ordered dipoles and spontaneous polarization along the c axis. The new oxynitride is a semiconductor with a band gap of 1.1 eV and a large permittivity.


The pharmacologic treatment of Dravet syndrome.
Dravet syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. Valproate is used as a first-line agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used for any long-lasting seizures, but these agents are most often insufficient. Lamotrigine, carbamazepine, and high doses of intravenous phenobarbital should be avoided because they may worsen seizures. Topiramate, levetiracetam, bromide, and the ketogenic diet may provide substantial efficacy as adjunctive therapy/procedure. Stiripentol is the only compound that proved its efficacy in DS through two independent randomized placebo-controlled trials, when combined with valproate and clobazam. Their dose has to be decreased to minimize the side effects (mostly loss of appetite) resulting from pharmacokinetic interactions of stiripentol powerfully inhibiting cytochromes P450. Stiripentol acts as a γ-aminobutyric acid (GABA)ergic agent, mainly via the α3 subunit of GABA(A) receptors. Stiripentol (Diacomit) was approved as an orphan drug in 2007 in Europe for adjunctive therapy in DS. Up to now, >500 children have been safely treated, and recent experiment in Japan confirmed stiripentol benefit in DS children with comedications other than valproate and clobazam. Because early status epilepticus is likely to negatively impact cognitive outcome, we recommend the introduction of stiripentol as soon as the diagnosis of DS is clinically confirmed. Topiramate and the ketogenic diet are alternatives in pharmacoresistant cases.


Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms.
Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP-dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP-dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-κB (NF-κB; Bay11-7082) did not affect nobiletin‑induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH•), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin‑induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies.


A cooperatively-controlled image guided robot system for skull base surgery.
We created an image-guided robot system to assist with skull base drilling by integrating a robot, a commercial navigation system, and an open source visualization platform. The objective of this procedure is to create a cavity in the skull base to allow access for neurosurgical interventions. The motivation for introducing an image-guided robot is to improve safety by preventing the surgeon from accidentally damaging critical structures during the drilling procedure. Our approach is to attach the cutting tool to the robot end-effector and operate the robot in a cooperative control mode, where robot motion is determined from the forces and torques applied by the surgeon. We employ "virtual fixtures" to constrain the motion of the cutting tool so that it remains in the safe zone that was defined on a preoperative CT scan. This paper presents the system design and the results of phantom and cadaveric experiments. Both experiments have demonstrated the feasibility of the system, with average overcut error at about 1 mm and maximum errors at 2.5 mm.


Usefulness of Gold Thread Implantation for Crow's Feet.
Conservative techniques designed to block or delay the aging process have been utilized in various ways for many years. However, their effects can be relatively minimal and short-term in most cases compared to surgery. The objective of this study was to evaluate the efficacy and safety of gold thread implantation for the treatment of periorbital wrinkles. A total of 78 consecutive patients who showed mild to severe periorbital wrinkles were deemed appropriate candidates, including 69 women and 9 men ranging from 31 to 59 years (mean, 47 years). Six gold threads about 4 cm in length were inserted subdermally in each patient at intervals of about 0.5 cm. Follow-up assessments were performed 1, 4, and 12 weeks after the procedure. The efficacy was rated by the physician using the Wrinkle Severity Rating Scale and patients who made global assessments of changes in periorbital wrinkles using the Visual Analog Scale. Adverse events were monitored throughout the course of the study. The patients showed significant improvements after the procedure. There were minor complications such as foreign body sensation in the eye (2.63%) and eye pain (1.32%) that improved spontaneously without any specific treatments. Subdermal implantation of gold thread improves the appearance of periorbital wrinkles and does not appear to have serious side effects. Insertion of gold thread may be an effective and safe method for facial rejuvenation.


Morphine versus oxycodone analgesia after percutaneous kidney stone surgery: a randomised double blinded study.
According to previous studies oxycodone might have some advantages over morphine in the treatment of visceral pain. This study investigated the opioid consumption (primary outcome), pain relief and side effects (secondary outcomes) of morphine versus oxycodone after percutaneous nephrolithotomy using a method where the somatic pain component was minimized. Forty-four adult patients were studied. The patients were randomised to receive either morphine or oxycodone intravenously as postoperative pain treatment. During the first 4 h after surgery the opioid consumption, pain scores and side effects (nausea, dizziness, sedation, respiratory effects and itching) were registered. The postoperative opioid consumption varied considerably between the patients but the mean opioid consumption in the morphine and oxycodone group was comparable (18.93 mg versus 16.15 mg, P = 0.7). Nausea was significantly less frequent with morphine (P = 0.03). In this study morphine and oxycodone produced similar analgesia the first 4 h after surgery but the frequency of nausea was significantly less patient-reported with morphine. The hypothesis that oxycodone would be superior in the treatment of visceral pain after percutaneous kidney stone operation was not confirmed.


Horizon 2020 priorities in clinical mental health research: results of a consensus-based ROAMER expert survey.
Within the ROAMER project, which aims to provide a Roadmap for Mental Health Research in Europe, a two-stage Delphi survey among 86 European experts was conducted in order to identify research priorities in clinical mental health research. Expert consensus existed with regard to the importance of three challenges in the field of clinical mental health research: (1) the development of new, safe and effective interventions for mental disorders; (2) understanding the mechanisms of disease in order to be able to develop such new interventions; and (3) defining outcomes (an improved set of outcomes, including alternative outcomes) to use for clinical mental health research evaluation. Proposed actions involved increasing the utilization of tailored approaches (personalized medicine), developing blended eHealth/mHealth decision aids/guidance tools that help the clinician to choose between various treatment modalities, developing specific treatments in order to better target comorbidity and (further) development of biological, psychological and psychopharmacological interventions. The experts indicated that addressing these priorities will result in increased efficacy and impact across Europe; with a high probability of success, given that Europe has important strengths, such as skilled academics and a long research history. Finally, the experts stressed the importance of creating funding and coordinated networking as essential action needed in order to target the variety of challenges in clinical mental health research.


Ubiquitous human computing.
Ubiquitous computing means network connectivity everywhere, linking devices and systems as small as a drawing pin and as large as a worldwide product distribution chain. What could happen when people are so readily networked? This paper explores issues arising from two possible emerging models of ubiquitous human computing: fungible networked brainpower and collective personal vital sign monitoring.


Supervising international students in clinical placements: perceptions of experiences and factors influencing competency development.
Health professional education programs attract students from around the world and clinical supervisors frequently report that international students find learning in clinical placement contexts particularly challenging. In existing literature clinical supervisors, who support international students on placement have identified concerns about their communication and interactions within clinical environments. However, clinical supervisors' perspectives about their experiences with international students on placement and the strategies they utilise to facilitate international student learning have not been described. As a result we have little insight into the nature of these concerns and what clinical supervisors do to support international students' competency development. Five focus group interviews were conducted with twenty Speech-Language Pathology clinical supervisors, recruited from 2 Australian universities. Interview data were analysed thematically. Themes identified were interpreted using cognitive load and sociocultural learning theories to enhance understanding of the findings. Four themes were identified: 'Complex teaching and learning relationships', 'Conceptions of students as learners'; Student communication skills for professional practice', and 'Positive mutual learning relationships'. Findings indicated that clinical supervisors felt positive about supporting international students in clinical placements and experienced mutual learning benefits. However, they also identified factors inherent to international students and the placement environment that added to workload, and made facilitating student learning complex. Clinical supervisors described strategies they used to support international students' cultural adjustment and learning, but communication skills were reported to be difficult to facilitate within the constraints of placements. Future research should address the urgent need to develop and test strategies for improving international students' learning in clinical settings.


Use of osmotic minipumps for sustained drug delivery in rat pups: effects on physical and neurobehavioural development.
Osmotic minipumps are often used as an alternative to repetitive injections for prolonged drug delivery in adult rats. The appropriateness of using this technology for sustained drug delivery in newborn rats, however, has not been validated. Our objective was to determine if implantation of osmotic minipumps, and the associated surgical stress, during a critical developmental period, affects early development and subsequent behaviour. SD rat pups were assigned to control, minipump, or sham surgery treatment conditions (n=12/group). On P8, pups were briefly anaesthetised with isoflurane in oxygen, and Alzet 1007D osmotic minipumps, loaded with normal saline, were aseptically implanted (removed on P17). Sham-treated rats received identical treatment (with the exception of pump placement), while control pups were left undisturbed. Development was examined daily using a standard test battery (P9-P21), and learning and memory in pups was assessed in a T-maze (P15, P17 and P19). Weight (P27 and P72), open-field (P25, P26 and P27) and novel water maze performance (P60-P72) were examined in the resulting adult. With the exception of a transient decrease in weight gain, pump-treated animals did not differ from either sham or control rats, on any pre- or postweaning assessment. Based on these results we conclude that the use of osmotic minipumps in rat pups is a viable alternative to repeated injections for sustained drug delivery.


Understanding Substance Use and Addiction Through the Lyrics of Black Sabbath: A Content Analysis.
Heavy metal music is distinguished for its deep sound and lyrical fixation with dark themes including war, destruction, doom, and misery. Such subjects permeate the music of Black Sabbath, the band generally considered the pioneers of heavy metal. One theme-substance use-is recurrent in Black Sabbath's songs and personal lives of its members. This study explored the band's relationship with substance use though a content analysis of all songs containing lyrics written and recorded in studio by Black Sabbath. The analysis included 156 songs across 19 albums recorded from 1970 to 2013. Three key findings emerged. First, a minority of songs (13%) contained substance references. Second, the songs with substance references were overwhelmingly (60%) negative, a pattern that increased over time. Third, despite many line-up changes over the band's 43-year period, every song referencing substance use except one featured vocalist Ozzy Osbourne and lyricist Geezer Butler. Contrary to the notion that heavy metal music glorifies or encourages substance use (Record Labeling, United States Senate, 1985), Black Sabbath's lyrics as a whole weave a cautionary tale of how persistent substance use can hijack free will, become the dominant focus of the affected individual, and produce myriad forms of human misery. The insidiousness of chronic substance use depicted by the lyrics mirrors findings from natural-history studies of individuals with substance use disorders and aligns with neurobiological heuristics of addiction.


Comparative investigation of the effects of different materials used with a titanium barrier on new bone formation.
In this study, we aimed to study the effects on new bone formation of autogenous blood, deproteinized bovine bone graft (DBBG), and biphasic calcium phosphate (BCP) bioceramic graft materials placed under titanium barriers. Twenty-four adult male New Zealand white rabbits were used in this study. Two titanium barriers were fixed on each rabbit's calvarium. The study included four groups, one of which was a control group. The experiment groups, autogenous blood, DBBG (Bio-Oss(®) ; Geistlich Biomaterials, Wolhusen, Switzerland) and BCP (4Bone(TM) ; Biomatlante, Vigneux de Bretagne, France) were placed under titanium barriers; in the control group, no materials were used. Half of the animals were sacrificed after 1 month, and the rest were sacrificed after 3 months. After this, micro-computerized tomography images were taken, and a histomorphometric evaluation was carried out. The amounts of new bone formation were found to be higher at the third month than at the first month. The differences between the groups were examined with both a micro-computerized tomography and histomorphometric analysis, and no statistical significance was noted in the first month. In contrast, the increase in the amount of new bone formation at the third month was found to be statistically significant only between the DBBG and control groups (P < 0.05). Autogenous blood with titanium barriers in guided bone regeneration seems to be as successful as DBBG and BCP bioceramic graft material.


Activation of nerve growth factor-induced B alpha by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth.
Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-B alpha (Nur77, TR3) is overexpressed in bladder tumors and bladder cancer cells compared with nontumorous bladder tissue. 1,1-Bis(3'-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH(3)) and 1,1-bis(3'-indolyl)-1-(p-phenyl)methane have previously been identified as activators of Nur77, and both compounds inhibited growth and induced apoptosis of UC-5 and KU7 bladder cancer cells. The proapoptotic effects of methylene-substituted diindolylmethanes (C-DIMs) were unaffected by cotreatment with leptomycin B and were dependent on nuclear Nur77, and RNA interference with a small inhibitory RNA for Nur77 (iNur77) demonstrated that C-DIM-induced activation of apoptosis was Nur77-dependent. Microarray analysis of DIM-C-pPhOCH(3)-induced genes in UC-5 bladder cancer cells showed that this compound induced multiple Nur77-dependent proapoptotic or growth inhibitory genes including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), cystathionase, p21, p8, and sestrin-2. DIM-C-pPhOCH(3) (25 mg/kg/d) also induced apoptosis and inhibited tumor growth in athymic nude mice bearing KU7 cells as xenografts, demonstrating that Nur77-active C-DIMs exhibit potential for bladder cancer chemotherapy by targeting Nur77, which is overexpressed in this tumor type.


Protein crystallization facilitated by molecularly imprinted polymers.
We present a previously undescribed initiative and its application, namely the design of molecularly imprinted polymers (MIPs) for producing protein crystals that are essential for determining high-resolution 3D structures of proteins. MIPs, also referred to as "smart materials," are made to contain cavities capable of rebinding protein; thus the fingerprint of the protein created on the polymer allows it to serve as an ideal template for crystal formation. We have shown that six different MIPs induced crystallization of nine proteins, yielding crystals in conditions that do not give crystals otherwise. The incorporation of MIPs in screening experiments gave rise to crystalline hits in 8-10% of the trials for three target proteins. These hits would have been missed using other known nucleants. MIPs also facilitated the formation of large single crystals at metastable conditions for seven proteins. Moreover, the presence of MIPs has led to faster formation of crystals in all cases where crystals would appear eventually and to major improvement in diffraction in some cases. The MIPs were effective for their cognate proteins and also for other proteins, with size compatibility being a likely criterion for efficacy. Atomic force microscopy (AFM) measurements demonstrated specific affinity between the MIP cavities and a protein-functionalized AFM tip, corroborating our hypothesis that due to the recognition of proteins by the cavities, MIPs can act as nucleation-inducing substrates (nucleants) by harnessing the proteins themselves as templates.


Plumage color patterns of an extinct dinosaur.
For as long as dinosaurs have been known to exist, there has been speculation about their appearance. Fossil feathers can preserve the morphology of color-imparting melanosomes, which allow color patterns in feathered dinosaurs to be reconstructed. Here, we have mapped feather color patterns in a Late Jurassic basal paravian theropod dinosaur. Quantitative comparisons with melanosome shape and density in extant feathers indicate that the body was gray and dark and the face had rufous speckles. The crown was rufous, and the long limb feathers were white with distal black spangles. The evolution of melanin-based within-feather pigmentation patterns may coincide with that of elongate pennaceous feathers in the common ancestor of Maniraptora, before active powered flight. Feathers may thus have played a role in sexual selection or other communication.


Identification of multiple regulatory elements of human L-histidine decarboxylase gene.
Previously, we reported the structure of human L-histidine decarboxylase gene. To identify the regions that regulate the tissue-specific expression of HDC, we constructed a fusion DNA with the 5'-flanking region from -1003 to +99 of the HDC gene and chloramphenicol acetyltransferase (CAT) gene, which was then transfected into human basophilic leukemia KU-812-F cells or human epithelial carcinoma HeLa cells. The 1102 bp DNA fragment stimulated the CAT activity in KU-812-F cells, but not in HeLa cells. CAT analysis with a series of 5'-deletion constructs of the HDC-CAT gene revealed the existence of two positive and one negative regulatory elements at -855 to -841 and -532 to -497 and -829 to -821, respectively. Sequence analysis showed a nuclear factor c-Myb binding motif, TAACTG, at position -520. Gel mobility shift analysis showed that the nuclear extract of KU-812-F cells, but not that of HeLa cells, contains a factor which can bind to this motif. These results suggest that the 5'-flanking region of the HDC gene contains multiple regulatory elements for HDC gene expression and that at least one element, including a c-Myb binding motif, is responsible for the tissue-specific expression of HDC.


Acute infection with Epstein-Barr virus is associated with atherogenic lipid changes.
To evaluate the effects of acute infection with Epstein-Barr virus (infectious mononucleosis, IM) on lipids and lipoproteins. Fasting serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), apolipoproteins (apo) A-I, B, E, C-II, C-III and lipoprotein (a) [Lp(a)] were determined in patients with IM on diagnosis and 4 months after the resolution of febrile illness and in age- and sex-matched controls. Activities of cholesteryl-ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) as well as levels of several cytokines were determined. LDL subclass analysis was performed with the Lipoprint LDL System. Twenty-nine patients (16 males, aged 24.3±14.6 years) and 30 controls were included. TC, HDL-C, LDL-C, apoA-I, apoB, apoC-III and Lp(a) levels were lower at baseline whereas apoB/apoA-I ratio, TG levels and CETP activity were elevated compared with 4 months later. At baseline, higher levels in cytokines and the cholesterol concentration of small-dense LDL particles (sdLDL-C) were noticed, whereas LDL particle size was lower compared with follow-up. Activities of Lp-PLA2 and PON1 were similar at baseline and 4 months later. Four months after the resolution of IM levels of TGs, apoE, apoC-III, Lp(a), sdLDL-C and cytokines as well as LDL particle size, apoB/apoA-I ratio, CETP and Lp-PLA2 activities were similar to controls. PON1 activities both at baseline and 4 months later were lower in patients compared with controls. IM is associated with atherogenic changes of lipids and lipoproteins that are partially restored 4 months after its resolution.


Research on leukaemia cells surplus to diagnostic needs in children.
The ability to improve diagnosis and refine prognosis in children with acute leukaemia is improving steadily. A growing number of tests can and are being performed on leukaemic cells. These include surface-marker analysis, DNA content, cytogenetics and studies of gene rearrangements. Increasingly large bone-marrow samples, now usually obtained under general anaesthesia, are required to make secure diagnoses. Ethical issues arise from three major areas. 1) Current research on leukaemia cells requested by the Medical Research Council is considered by local research ethics committees, but parents are not regularly given detailed information about or asked specifically to consent to such research; 2) substantial quantities of excess cells are stored indefinitely. This archive of stored material is a valuable resource for research but there has been little consideration of the ethical issues which arise from this practice, and 3) there is a potential for pressure to obtain increasingly large samples. 'Creeping growth' in sample size is likely to continue unless ethics committees consider future research proposals in more detail. These issues deserve attention in order that worthwhile research and its publication are not impeded for want of ethical consideration. The implications extend beyond the field of childhood leukaemia.


Beta oscillation dynamics in extrastriate cortex after removal of primary visual cortex.
The local field potential (LFP) in visual cortex is typically characterized by the following spectral pattern: before the onset of a visual stimulus, low-frequency oscillations (beta, 12-20 Hz) dominate, whereas during the presentation of a stimulus these oscillations diminish and are replaced by fluctuations at higher frequencies (gamma, >30 Hz). The origin of beta oscillations in vivo remains unclear, as is the basis of their suppression during visual stimulation. Here we investigate the contribution of ascending input from primary visual cortex (V1) to beta oscillation dynamics in extrastriate visual area V4 of behaving monkeys. We recorded LFP activity in V4 before and after resecting a portion of V1. After the surgery, the visually induced gamma LFP activity in the lesion projection zone of V4 was markedly reduced, consistent with previously reported spiking responses (Schmid et al., 2013). In the beta LFP range, the lesion had minimal effect on the normal pattern of spontaneous oscillations. However, the lesion led to a surprising and permanent reversal of the normal beta suppression during visual stimulation, with visual stimuli eliciting beta magnitude increases up to 50%, particularly in response to moving stimuli. This reversed beta activity pattern was specific to stimulus locations affected by the V1 lesion. Our results shed light on the mechanisms of beta activity in extrastriate visual cortex: The preserved spontaneous oscillations point to a generation mechanism independent of the geniculostriate pathway, whereas the positive beta responses support the contribution of visual information to V4 via direct thalamo-extrastriate projections.


Analytical reconstruction of the bioluminescent source with priors.
Bioluminescence imaging has been a popular tool in small animal imaging. During the last decade, the efforts have focused on the development of tomographic systems. However, due to the difficulties in the nature of inverse source problem, multi-modal systems have been the center of attention for the last couple of years. These systems provide complementary information such that the difficulties of the inverse source problem could be overcome using the a priori information obtained. Motivated by these advances in multi-modal systems, this work presents a novel analytical reconstruction of the bioluminescent source. It is shown that if source strength is known a priori then source position could be calculated or vice versa, if source location is known a priori, source strength could be calculated as well as the photon fluence rate. The determination of the source location can be achieved by another imaging system such as X-ray computed tomography. Therefore, in bioluminescence tomography together with an imaging system can be utilized as a multi-modal system. In this work, conventional finite element based simulations are also performed and the numerical results are compared with the analytical ones. It turns out to be that the analytical results are in a good accordance with the numerical results.


Oscillation in cycle length induces transient discordant and steady-state concordant alternans in the heart.
Alternans is a beat-to-beat alternation of the cardiac action potential duration (APD) or intracellular calcium (Ca(i)) transient. In cardiac tissue, alternans can be spatially concordant or discordant, of which the latter has been shown to increase dispersion of repolarization and promote a substrate for initiation of ventricular fibrillation. Alternans has been studied almost exclusively under constant cycle length pacing conditions. However, heart rate varies greatly on a beat-by-beat basis in normal and pathological conditions. The purpose of this study was to determine if applying a repetitive but non-constant pacing pattern, specifically cycle length oscillation (CLO), promotes or suppresses a proarrhythmic substrate. We performed computational simulations and optical mapping experiments to investigate the potential consequences of CLO. In a single cell computational model, CLO induced APD and Ca(i) alternans, which became "phase-matched" with the applied oscillation. As a consequence of the phase-matching, in one-dimensional cable simulations, neonatal rat ventricular myocyte monolayers, and isolated adult guinea pig hearts CLO could transiently induce spatial and electromechanical discordant alternans followed by a steady-state of concordance. Our results demonstrated that under certain conditions, CLO can initiate ventricular fibrillation in the isolated hearts. On the other hand, CLO can also exert an antiarrhythmic effect by converting an existing state of discordant alternans to concordant alternans.


Intra-operative high frequency ultrasound improves surgery of intramedullary cavernous malformations.
Intra-operative ultrasound (ioUS) is a very useful tool in surgery of spinal lesions. Here we focus on modern ioUS to analyze its use for localisation, visualisation and resection control in intramedullary cavernous malformations (IMCM). A series of 35 consecutive intradural lesions were operated in our hospital in a time period of 24 months using modern ioUS with a high frequency 7-15 MHz transducer and a true real time 3D transducer (both Phillips iU 22 ultrasound system). Six of those cases were treated with the admitting diagnosis of a deep IMCM (two cervical, four thoracic lesions). IoUS images were performed before and after the IMCM resection. Pre-operative and early postoperative MRI images were performed in all patients. In all six IMCM cases a complete removal of the lesion was achieved microsurgically resulting in an improved neurological status of all patients. High frequency ioUS emerged to be a very useful tool during surgery for localization and visualization. Excellent resection control by ultrasound was possible in three cases. Minor resolution of true real time 3D ioUS decreases the actual advantage of simultaneous reconstruction in two planes. High frequency ioUS is the best choice for intra-operative imaging in deep IMCM to localize and to visualize the lesion and to plan the perfect surgical approach. Additionally, high frequency ioUS is suitable for intra-operative resection control of the lesion in selected IMCM cases.


An autoradiographic analysis of [3H]alpha-bungarotoxin distribution in the rat brain after intraventricular injection.
Purified alpha-bungarotoxin was isolated by chromatography and made radioactive with tritium ([3H]acetamidino-alpha-bungarotoxin). Infusions of [3H]alpha-bungarotoxin alone or preceded by tubocurarine or atropine were given into the third ventricle. 2. 12, or 24 h after injection the brains were prepared for autoradiography. Injections of alpha-bungarotoxin (radioinert) in buffer, or of [3H]parathyroid hormone in buffer, served as controls. The various patterns of labeling suggest the presence of nicotinic-cholinergic neurons within the arcuate and basolateral regions of the hypothalamus including the supraoptic and suprachiasmatic nuclei and, in addition, the central nucleus of the amygdala.


Membrane invaginations reveal cortical sites that pull on mitotic spindles in one-cell C. elegans embryos.
Asymmetric positioning of the mitotic spindle in C. elegans embryos is mediated by force-generating complexes that are anchored at the plasma membrane and that pull on microtubules growing out from the spindle poles. Although asymmetric distribution of the force generators is thought to underlie asymmetric positioning of the spindle, the number and location of the force generators has not been well defined. In particular, it has not been possible to visualize individual force generating events at the cortex. We discovered that perturbation of the acto-myosin cortex leads to the formation of long membrane invaginations that are pulled from the plasma membrane toward the spindle poles. Several lines of evidence show that the invaginations, which also occur in unperturbed embryos though at lower frequency, are pulled by the same force generators responsible for spindle positioning. Thus, the invaginations serve as a tool to localize the sites of force generation at the cortex and allow us to estimate a lower limit on the number of cortical force generators within the cell.


Copulatory vocalizations of chacma baboons (Papio ursinus), gibbons (Hylobates hoolock), and humans.
The copulatory vocalizations of female baboons (Papio ursinus) are more complex than those of female gibbons (Hylobates hoolock) or human females. Adult males of all these species begin calling later than the female, but subordinate baboon males do not call. Copulatory vocalizations may serve to mutually stimulate the mating partners or to incite male competition.


Design and manufacture of a coronary stent INC-1 and initial tests in experimental animal model.
In this paper, we describe our coronary stent (INC-1) design and development, the way that we found the specific characteristics needed for our device including biophysics aspects, design, finite element testing, manufacturing, and mechanic trials, we submitted and animal models experiences. The stent platform was cobalt-chromium L605 (Co-Cr), with struts thickness of 80 μm, balloon expandable. We placed the coronary stent INC-1 on a rabbit and dog models so we can evaluate efficacy and security of the device in relationship to its biomechanical properties including navigation capacity, traceability, symmetric expansion, and safety, as well as endothelial attachment, thrombogenicity, and lack of involvement of secondary branches in these models. We succeeded in efficacy and safety of the device after fluoroscopy-guided implant proving excellent capacity of release system, traceability, fluoroscopic visualization, symmetric expansion, and complete endothelial attach. Furthermore, we obtained a good post-implant balloon withdrawal, functional integrity, and no vascular complications. We observed adequate clinical evolution 3 weeks after the stent implantation.


Obese Older Type 2 Diabetes Mellitus Patients with Muscle Insulin Resistance Benefit from an Enriched Protein Drink during Combined Lifestyle Intervention: The PROBE Study.
(1) Background: Recent research showed that subtypes of patients with type 2 diabetes may differ in response to lifestyle interventions based on their organ-specific insulin resistance (IR). (2) Methods: 123 Subjects with type 2 diabetes were randomized into 13-week lifestyle intervention, receiving either an enriched protein drink (protein+) or an isocaloric control drink (control). Before and after the intervention, anthropometrical and physiological data was collected. An oral glucose tolerance test was used to calculate indices representing organ insulin resistance (muscle, liver, and adipose tissue) and β-cell functioning. In 82 study-compliant subjects (per-protocol), we retrospectively examined the intervention effect in patients with muscle IR (MIR, n = 42) and without MIR (no-MIR, n = 40). (3) Results: Only in patients from the MIR subgroup that received protein+ drink, fasting plasma glucose and insulin, whole body, liver and adipose IR, and appendicular skeletal muscle mass improved versus control. Lifestyle intervention improved body weight and fat mass in both subgroups. Furthermore, for the MIR subgroup decreased systolic blood pressure and increased VO2peak and for the no-MIR subgroup, a decreased 2-h glucose concentration was found. (4) Conclusions: Enriched protein drink during combined lifestyle intervention seems to be especially effective on increasing muscle mass and improving insulin resistance in obese older, type 2 diabetes patients with muscle IR.


Assessment of the origins and spread of putative resistance-conferring mutations in Plasmodium vivax dihydropteroate synthase.
Infection with Plasmodium vivax is usually treated with chloroquine, but parasites are often exposed inadvertently to sulfadoxine-pyrimethamine. To infer patterns of selection and spread of resistant parasites in natural populations, we determined haplotypes of P. vivax dihydropteroate synthase ( dhps ) alleles that could confer resistance to sulfadoxine. We amplified the P. vivax pyrophosphokinase ( pppk )- dhps region and its flanking intergenic regions from 92 contemporary global isolates. Introns and exons of pppk-dhps were highly polymorphic, as were the flanking intergenic regions. Eighteen haplotypes were associated with wild-type alleles, but several different putatively sulfadoxine-resistant alleles have arisen in areas of intensive sulfadoxine-pyrimethamine use. Even when they encoded changes to the same amino acid, these mutant alleles were associated with multiple different haplotypes. Two main conclusions can be drawn from these data. First, dhps alleles resistant to sulfadoxine have arisen multiple times under drug pressure. Second, there has been convergent evolution of a variety of alleles that could confer resistance to sulfa drugs.


An essential role of Th1 responses and interferon gamma in infection-mediated suppression of neoplastic growth.
We had previously demonstrated that in mice acute toxoplasmosis leads to systemic inhibition of angiogenesis and, consequently, strong suppression of neoplastic growth. Here we investigated the role of Th1 cytokines, in particular interferon gamma (IFN-gamma), in this phenomenon. Besides toxoplasma, neoplastic growth was readily blocked during acute infection with other Th1 response-inducing pathogens such as Listeria monocytogenes and lymphocytic choriomeningitis virus (LCMV). In contrast, chronic infection with LCMV (when Th1 responses were strongly suppressed) and acute infection with Schistosoma mansoni (when Th2 responses predominated) afforded no anti-tumor protection. To corroborate the involvement of Th1 cytokines in infection-mediated suppression of neoplastic growth, we utilized mice deficient in interleukin-10 (IL10), a suppressor of Th1 responses. When challenged with B16 cells concomitantly with toxoplasma infection, both IL10-null and wild type mice exhibited resistance to neoplastic growth. However, tumors borne by IL10-null animals were even smaller than those borne by their wild type counterparts. This enhanced resistance correlated with dramatically elevated levels of circulating IFN-gamma, a principal Th1 cytokine. Furthermore, while interleukin-12 and tumor necrosis factor a were dispensable for tumor suppression, in animals deficient in IFN-gamma production or signaling, tumor growth and neovascularization were markedly enhanced. Interestingly, the enhancement was also apparent in uninfected animals suggesting that IFN-gamma and its anti-angiogenic effects underlie both infection-dependent and -independent tumor surveillance.


Acute myocardial infarction: state of the art.
The proper management of patients with acute myocardial infarction changes frequently as new data develop in this complex area. The present recommendations concerning the use of oxygen and morphine and the treatment of hypotension and congestive heart failure require little change save the addition of new agents. However, considerable new data have been derived in the area of limitation of myocardial infarct size. Several studies suggest that the early administration of beta-blockers or intravenous nitroglycerin may benefit patients with acute infarction. We must seriously consider whether the data supporting the use of these agents justify a recommendation that they be used routinely for patients with acute infarction. The role of thrombolytic agents, although widely used already, must also be addressed as data supporting its use build. Additionally, there are suggestive data that the aggressive treatment of hypertension is beneficial, and this approach may well merit advocacy. The prophylactic use of lidocaine and the ubiquitous use of nitrates necessitate reevaluation, although presently both agents are widely used. The aggressive use of electrical therapy for supraventricular arrhythmias and the lack of indication for the treatment of asymptomatic bradycardia with atropine in patients with acute infarction must be added to the previous National Conference standards.


Black-white differences in avoidable mortality in the USA, 1980-2005.
Avoidable Mortality (AM) describes causes of death that should not occur in the presence of high-quality and timely medical treatment and from causes that can be influenced at least in part by public policy/behaviour. This study analyses black-white disparities in AM. Mortality under age 65 was analysed from: (1) conditions amenable to medical care; (2) those sensitive to public policy and/or behaviour change; (3) ischaemic heart disease; (4) HIV/AIDS; and (5) the remaining causes of death. Age-standardised death rates (ASDRs) were constructed for each race and sex group using vital statistics and census data from 1980-2005. Absolute rate differences and the proportionate contribution of each cause of death group to all-cause black-white mortality disparities are calculated based on the ASDRs. Negative binomial regression was used to model relative risks of death. In 2005, medical care amenable mortality was the largest source of absolute black-white mortality disparity, contributing 30% of the black-white difference in all-cause mortality among men and 42% among women; mortality subject to policy/behaviour interventions contributed 20% of the black-white difference for men and 4% for women. Although absolute black-white differences for most conditions diminished over time, relative disparities as measured by rate ratios showed little change, except for HIV/AIDS for which relative risks increased substantially for black men and women. There is considerable potential for narrowing of the black-white difference in AM, especially from causes amenable to medical care and (for men) policy/behaviour interventions.


Characterization of an endonuclease associated with the drug resistance plasmid pKM101.
An endonuclease was detected in strains of Salmonella typhimurium containing the drug resistance plasmid pKM101. The enzyme was not detectable in strains lacking this plasmid, but it was present in strains containing mutants of pKM101 that were no longer able to enhance host cell mutagenesis. The endonuclease had a molecular weight of roughly 75,000 and, at pH 7.0, was equally active on single-stranded and duplex deoxyribonucleic acid (DNA). The reaction with single-stranded DNA was optimal at pH 5.5, whereas with duplex DNA the optimum was pH 6.8. The enzyme required a divalent cation for activity, and it had no detectable exonuclease activity with single-stranded or duplex DNA. The endonuclease extensively degraded DNA with no apparent base specificity, forming 5'-phosphomonoester termini. Although characterization of the endonuclease has not revealed its function, the enzyme does not appear to be a restriction endonuclease.


Assessment of facilities management process capability: a NHS facilities case study.
Describes a process to assess facilities management (FM) process capabilities: the structured process improvement for construction environments--facilities management (SPICE FM) approach. The SPICE FM framework is a method that FM organizations can use to monitor continuously and subsequently improve their performance. The SPICE FM framework is being tested in a series of case studies to ensure that its outputs are appropriate to the FM sector and of value in the real world. Documents the outcomes of a study undertaken at a facilities directorate of a healthcare NHS trust, in searching its applicability within the NHS. Further describes the study methodology and the key activities undertaken and reviews the key communication and management processes that are in place to support the implementation of the strategic FM objectives within the specific NHS facilities directorate.


Behavior of left ventricular mechanoreceptors with myelinated and nonmyelinated afferent vagal fibers in cats.
The purpose of this study was to determine the behavior of left ventricular mechanoreceptors with myelinated vagal afferents and to compare them with endings with nonmyelinated vagal afferents. Single unit activity was recorded from 13 endings with nonmyelinated vagal afferents (conduction velocity 2.1 +/- 0.3 m/sec) and from 16 endings with myelinated vagal afferents (conduction velocity 7.3 +/- 1.3 m/sec). Resting discharge frequencies of nonmyelinated afferents and of myelinated vagal afferents were 1.7 +/- 0.3 and 2.7 +/- 0.5 imp/sec (P less than 0.1), respectively (at left ventricular end diastolic pressure of 6 mm Hg for both groups). Ten of 16 myelinated vagal afferents had pulse synchronous discharge under basal condition, whereas only 3 of 13 nonmyelinated vagal afferents had such activity. During aortic occlusion, the discharge of myelinated vagal afferents increased 1.7 +/- 0.3 imp/sec per mm Hg, whereas nonmyelinated vagal afferents increased significantly (P less than 0.05) less (0.5 +/- 0.1 imp/sec per mm Hg). Discharge for both groups was linearly related to left ventricular end-diastolic pressure but not to left ventricular systolic pressure. Increases in left ventricular systolic pressure alone did not increase firing for either group. During aortic occlusion, the maximum discharge rates of myelinated vagal afferents (43 +/- 7 imp/sec) were significantly higher than those of nonmyelinated vagal afferents (14 +/- 3 imp/sec) at left ventricular end-diastolic pressure of 30 +/- 2 and 24 +/- 2 mm Hg, respectively. Both groups increased their discharge during volume expansion with myelinated vagal afferents showing greater sensitivity than nonmyelinated vagal afferents. All endings studied were in the inferoposterior wall of the left ventricle. All nonmyelinated vagal afferents were in or near the epicardium. In contrast, myelinated vagal afferents were equally distributed between the endocardium and the epicardium. Myelinated vagal afferents had discrete receptive fields (1-2 mm2) whereas those of nonmyelinated vagal afferents were much larger (1 cm2). In conclusion, the discharge of left ventricular endings with nonmyelinated vagal afferents and myelinated vagal afferents both appear to be determined mainly by changes in left ventricular end-diastolic pressure. They may be located at different depths in the left ventricular wall. Myelinated vagal afferents have greater sensitivity and maximum firing frequencies than nonmyelinated vagal afferents.


Developmentally regulated activity of CRM1/XPO1 during early Xenopus embryogenesis.
In this work, we have investigated the role of CRM1/XPO1, a protein involved in specific export of proteins and RNA from the nucleus, in early Xenopus embryogenesis. The cloning of the Xenopus laevis CRM1, XCRM1, revealed remarkable conservation of the protein during evolution (96.7% amino acid identity between Xenopus and human). The protein and mRNA are maternally expressed and are present during early embryogenesis. However, our data show that the activity of the protein is developmentally regulated. Embryonic development is insensitive to leptomycin B, a specific inhibitor of CRM1, until the neurula stage. Moreover, the nuclear localization of CRM1 changes concomitantly with the appearance of the leptomycin B sensitivity. These data suggest that CRM1, present initially in an inactive form, becomes functional before the initiation of the neurula stage during gastrula-neurula transition, a period known to correspond to a critical transition in the pattern of gene expression. Finally, we confirmed the gastrula-neurula transition-dependent activation of CRM1 by pull-down experiments as well as by the study of the intracellular localization of a green fluorescent protein tagged with a nuclear export signal motif during early development. This work showed that the regulated activity of CRM1 controls specific transitions during normal development and thus might be a key regulator of early embryogenesis.


Peripheral Arteriovenous Malformations-A Case Series.
Arteriovenous malformations (AVMs) are aggressive vascular malformations that often result in significant morbidity. Patients may present to a dermatologist due to associated skin changes. Early diagnosis is important as treatment is available to halt their progression toward irreversible destruction of adjacent tissues. To study the clinical profile of peripheral AVMs presenting to the dermatologist and to provide a diagnostic algorithm. A retrospective study of patients of all age groups with peripheral AVMs who presented to the Department of Dermatology at a tertiary care hospital in India was performed. Syndromic forms were also included. We conducted a search of patients with peripheral AVMs, which were seen over a period of 51 months, i.e., from July 2014 to September 2018, from electronic medical records and reviewed their clinical details. Descriptive statistics such as frequency, mean, and median were computed. We report a series of 13 patients with peripheral AVMs, which constituted 6.7% (13/193) of all vascular malformations during this period. Of these, 8.3% (1/12) belonged to Schobinger's stage 1, 41.7% (5/12) to stage 2, 50% (6/12) to stage 3, and one with subcutaneous involvement devoid of cutaneous changes. The most common location was the extremities, which was seen in 53.8% (7/13). Syndromic association was present in 46.2% (6/13). Management included embolization, surgery, and medical treatment. The proportion of peripheral AVMs out of all vascular malformations was similar to reported studies. The extremities were more frequently involved as compared to the head and neck. The diagnostic algorithm provided will help us to optimize investigations and direct early management.


Seasonal exposure of fish to neurotoxic pesticides in an intensive agricultural catchment, Uma-oya, Sri Lanka: linking contamination and acetylcholinesterase inhibition.
The annual cultivation pattern in the Uma-oya catchment in Sri Lanka is characterized by Yala and Maha rainfall periods and associated cropping. Two cultivation seasons were compared for pesticide residues: base flow, field drainage, and the runoff and supplementary sediment data for three sites in the catchment. Organophosphate and N-methyl carbamate pesticide analysis confirmed a higher concentration in the Yala season with low-flow conditions. Acetylcholinesterase (AChE) activity was measured by standard spectrometry in the brain, muscle, and eye tissues of three freshwater cyprinid fishes, Garra ceylonensis, Devario malabaricus, and Rasbora daniconius from three study sites during months overlapping two seasons in 2010 (December) and 2011 (July). Baseline AChE data were measured from fish samples from a forested reserve in the Knuckles. A 73% inhibition in muscle AChE activity in G. ceylonensis was associated with intense pesticide exposure months in the Yala season. The AChE inhibition more than 70% in G. ceylonensis eyes in both Yala (76%) and Maha (72.5%) seasons indicates particular sensitivity of eye tissue to inhibitors. The less dramatic AChE inhibition in the eye tissues in D. malabaricus and R. daniconius in both seasons indicates exemplary protective capacity of muscle AChE in fish. The highest inhibition of AChE (up to 60% in brain and up to 56% in muscle AChE activity in R. daniconius and up to 47.8% in brain and up to 64.6% in muscle AChE activity in D. malabaricus) occurred during the Yala season. Tissue AChE activity and physiological activity in fish were correlated. The results collectively indicate that AChE is a consistent biomarker for diffused contaminant exposure in agricultural catchments.


The challenges of investigating antimicrobial resistance in Vietnam - what benefits does a One Health approach offer the animal and human health sectors?
The One Health concept promotes the enhancement of human, animal and ecosystem health through multi-sectorial governance support and policies to combat health security threats. In Vietnam, antimicrobial resistance (AMR) in animal and human health settings poses a significant threat, but one that could be minimised by adopting a One Health approach to AMR surveillance. To advance understanding of the willingness and abilities of the human and animal health sectors to undertake investigations of AMR with a One Health approach, we explored the perceptions and experiences of those tasked with investigating AMR in Vietnam, and the benefits a multi-sectorial approach offers. This study used qualitative methodology to provide key informants' perspectives from the animal and human health sectors. Two scenarios of food-borne AMR bacteria found within the pork value chain were used as case studies to investigate challenges and opportunities for improving collaboration across different stakeholders and to understand benefits offered by a One Health approach surveillance system. Fifteen semi-structured interviews with 11 participants from the animal and six from the human health sectors at the central level in Hanoi and the provincial level in Thai Nguyen were conducted. Eight themes emerged from the transcripts of the interviews. From the participants perspectives on the benefits of a One Health approach: (1) Communication and multi-sectorial collaboration; (2) Building comprehensive knowledge; (3) Improving likelihood of success. Five themes emerged from participants views of the challenges to investigate AMR: (4) Diagnostic capacity; (5) Availability and access to antibiotics (6) Tracing ability within the Vietnamese food chain; (7) Personal benefits and (8) Managing the system. The findings of this study suggest that there is potential to strengthen multi-sectorial collaboration between the animal and human health sectors by building upon existing informal networks. Based on these results, we recommend an inclusive approach to multi-sectorial communication supported by government network activities to facilitate partnerships and create cross-disciplinary awareness and participation. The themes relating to diagnostic capacity show that both sectors are facing challenges to undertake investigations in AMR. Our results indicate that the need to strengthen the animal health sector is more pronounced.


The Evolving Profile of the Signature Amino Acid Residues in HIV-1 Subtype C Tat.
Using several HIV-1 tat exon 1 amino acid sequences available from public databases and additional sequences derived from a southern Indian clinical cohort, we compared the profile of the signature amino acid residues (SAR) between two different time periods, 1986-2004 and 2005-2014. The analysis identified eight positions as signature residues in subtype C Tat and demonstrated a changing pattern at four of these positions between the two periods. At three locations (histidine 29, serine 57, and proline 60), there appears to be a nonuniform negative selection against the SAR. The negative selection appears to be severe, especially against histidine 29 (p < .0001) and moderate against proline 60 (p < .0001). The negative selection against serine 57 is statistically insignificant and appears to have begun recently. At position 63, the frequency of signature residue glutamic acid increased over the past decade, although the difference was not significant. Importantly, at the three locations where the negative selection is in progress, the substitute amino acids are the generic residues present in most of the other HIV-1 subtypes. Our data demonstrate that viral evolution can subject specific amino acid residues to subtle and progressive selection pressures without affecting the prevalence of other amino acid residues.


Topological Electromagnetic Effects and Higher Second Chern Numbers in Four-Dimensional Gapped Phases.
Higher-dimensional topological phases play a key role in understanding the lower-dimensional topological phases and the related topological responses through a dimensional reduction procedure. In this work, we present a Dirac-type model of four-dimensional Z_{2} topological insulator (TI) protected by CP symmetry, whose 3D boundary supports an odd number of Dirac cones. A specific perturbation splits each bulk massive Dirac cone into two valleys separated in energy-momentum space with opposite second Chern numbers, in which the 3D boundary modes become a nodal sphere or a Weyl semimetallic phase. By introducing the electromagnetic (EM) and pseudo-EM fields, exotic topological responses of our 4D system are revealed, which are found to be described by the (4+1)D mixed Chern-Simons theories in the low-energy regime. Notably, several topological phase transitions occur from a CP-broken Z_{2} TI to a Z TI when the bulk gap closes by giving rise to exotic double-nodal-line or nodal-hyper-torus gapless phases. Finally, we propose to probe experimentally these topological effects in cold atoms.


Severe and critical cases of H1N1 influenza in pregnancy: a Chinese perspective.
In 2009, an outbreak of A/H1N1 influenza spread worldwide. Following the start of winter in Liaoning province in China, the number of pregnant women infected with influenza increased significantly. Some of them developed respiratory failure and multiple organ failure. The aim of this study was to determine the high-risk factors associated with the development of critical illness in the hospitalized pregnant women with A/H1N1 infection. This retrospective cohort study was carried out in the tertiary care obstetric department of a large general hospital. The clinical data of H1N1 pregnant women hospitalized from November 2009 to January 2010 was reviewed. We classified these cases into severe and critical grades according to H1N1 influenza treatment guidelines. We selected maternal age, gestational age, and the time interval between symptom-onset and hospital admission as related factors of critical illness. Logistic regression analyses to determine the relevance and importance of factors significantly associated with critical illness. Eighteen cases of H1N1 influenza pregnant women were admitted. Ten pregnant women were severe cases and eight pregnant women were critical cases. The maternal age (OR=0.979, 95% CI: 0.749~1.279)and the time interval between symptom-onset and hospital admission (OR=1.41, 95% CI: 0.917~2.169) were not found to be risk factors for critical cases. The significant risk factor associated with critical illness is gestational age (OR=53.726, 95% CI: 131.165~2477.918). The risk varied by weeks of gestation, with an odds ratio of 1.034 (95% CI: 0.968-1.106) during the first trimester, 9.667 (95% CI: 0.750-124.59) during the second trimester, and 87 (95% CI: 6.750-1121.39) during the third trimester. Gestational age is associated with the risk of developing critical infection. The risk increases with increasing weeks of gestation.


Associations of Impaired Renal Function With Declines in Muscle Strength and Muscle Function in Older Men: Findings From the CHAMP Study.
Advanced kidney disease is associated with reduced muscle strength and physical performance. However, associations between early stages of renal impairment and physical outcomes are unclear. The Concord Health and Ageing in Men Project is a prospective study of 1,705 community-dwelling men aged 70 years and older. Participants with estimated glomerular filtration rate (eGFR) more than 30 mL/min/1.73 m2 were included and further divided into four eGFR categories. Physical parameters including grip strength, gait speed, appendicular lean mass (ALM, a sum of skeletal mass of arms and legs), ALM adjusted for body mass index (ALMBMI), and muscle function (measured using grip strength divided by arm lean mass) were assessed at both baseline and 5-year follow-up. Associations between kidney function and changes in physical parameters were analyzed using linear and logistic regression models. Our study included 789 men with a median age of 75 years and median eGFR of 72 mL/min/1.73 m2 at baseline. Over 5 years, grip strength, gait speed, ALMBMI, and muscle function all declined in the whole cohort, compared with baseline. The multivariable analyses showed that poorer renal function was associated with more rapid declines in grip strength, gait speed, and muscle function in participants with mild-to-moderate renal impairment (GFR category stage G3, eGFR < 60 mL/min/1.73 m2) (p = .01, p < .01, p = .02, respectively) but less so in those with eGFR more than 60 mL/min/1.73 m2, whereas eGFR category did not have a significant impact on declines in ALMBMI. These results remained unchanged with or without adjustment for age. In community-dwelling older men, mild-to-moderate renal impairment at baseline was associated with declines in grip strength, gait speed, and muscle function over time despite preservation of muscle mass.


A pilot feasibility study of a questionnaire to determine European Union-wide CAM use.
No questionnaire specifically measuring the core components of complementary and alternative medicine (CAM) use has been validated for use across European Union (EU) countries. We aimed to determine the face validity, acceptability and the participants' comprehension of a pre-existing questionnaire designed to measure 'CAM use', to provide a comparative, standardised questionnaire for use by health care providers, policy makers and purchasers throughout Europe. Established procedures were employed to translate the questionnaire into 4 EU languages. The translated questionnaires were piloted on 50 healthy adults from each country who may never have used CAM. 10 participants per country also took part in audio-recorded think aloud interviews about the questionnaire. The interviews were transcribed and analysed in the language in which they were conducted; findings were summarised in English. Questionnaire data were pooled across countries, and patterns of completion and missing data were analysed. The questionnaire was translated into Italian, Spanish, Dutch and Romanian. The mean age of the participants was 43.6 years. 34% were male, 87.4% were either light or heavy CAM users, and 12.6% were non-users. Qualitative analysis identified common problems across countries including a 'hard-to-read' layout, misunderstood terminology and uncertainty in choosing response options. Quantitative analysis confirmed that a substantial minority of respondents failed to follow questionnaire instructions and that some questions had substantial rates of missing data. The I-CAM-Q has low face validity and low acceptability, and is likely to produce biased estimates of CAM use if applied in England, Romania, Italy, The Netherlands or Spain. Further work is required to develop the layout, terms, some response options and instructions for completion before it can be used across the EU.


Supportive programs increase medical students' research interest and productivity.
Advances in biomedical research during the last decade have highlighted the necessity of attracting greater numbers of physicians to careers that include a research component. Physician participation in research is essential to increase the number of clinical and translational studies performed, as well as to educate the public about the importance of clinical trials and to assist in recruiting participants. We hypothesized that attractive research opportunities that included faculty mentoring, recognition of participation, and rewards for accomplishments would encourage medical student participation. The Medical Student Research Office was created at Mount Sinai School of Medicine in 1996 to develop structured research programs and advise students looking to undertake a research project. Data from students participating in the summer research program and Medical Student Research Day, from the research section of the Medical Student Performance Evaluation, were collected from 1996 to 2004. For the last 4 years, the majority of medical students did research following the first year of school. Students did basic and clinical research, although most preferred clinically oriented or translational projects. Participation in Research Day and the number of publications suggest that interest is growing, including that by traditionally underrepresented groups. Although it is too early to assess the long-term effects, the research programs offered led to greater numbers of students who did research, including those in traditionally underrepresented groups. Moreover, students were highly satisfied with their experiences, with 80% feeling that it increased their interest in applying principles they learned to the practice of medicine.


Social health and dementia: a European consensus on the operationalization of the concept and directions for research and practice.
Because the pattern of illnesses changes in an aging population and many people manage to live well with chronic diseases, a group of health care professionals recently proposed reformulating the static WHO definition of health towards a dynamic one based on the ability to physically, mentally and socially adapt and self-manage. This paper is the result of a collaborative action of the INTERDEM Social Health Taskforce to operationalize this new health concept for people with dementia, more specifically the social domain, and to formulate directions for research and practice to promote social health in dementia. Based on the expertise of the Social Health Taskforce members (N = 54) three groups were formed that worked on operationalizing the three social health dimensions described by Huber et al.: (1) capacity to fulfil potential and obligations; (2) ability to manage life with some degree of independence; (3) participation in social activities. For each dimension also influencing factors, effective interventions and knowledge gaps were inventoried. After a consensus meeting, the operationalizations of the dimensions were reviewed by the European Working Group of People with Dementia (EWGPWD). The social health dimensions could be well operationalized for people with dementia and are assessed as very relevant according to the Social Health Taskforce and EWGPWD. Personal (e.g. sense of coherence, competencies), disease-related (e.g. severity of cognitive impairments, comorbidity), social (support from network, stigma) and environmental factors (e.g. enabling design, accessibility) that can influence the person with dementia's social health and many interventions promoting social health were identified. A consensus-based operationalization of social health in dementia is proposed, and factors that can influence, and interventions that improve, social health in dementia identified. Recommendations are made for research and practice.


Field diagnosis and genotyping of chikungunya virus using a dried reverse transcription loop-mediated isothermal amplification (LAMP) assay and MinION sequencing.
Detection and sequencing of chikungunya virus (CHIKV) genome was performed using a combination of a modified reverse transcription loop-mediated isothermal amplification (RT-LAMP) method and a MinION sequencer. We developed the protocol for drying all the reagents for the RT-LAMP in a single reaction tube. Using this system, the CHIKV genome was effectively amplified under isothermal conditions, and used as a template for MinION sequencing with a laptop computer. Our in-house RT-LAMP method and MinION sequencing system were also validated with RNAs and serum samples from recent outbreaks of CHIKV patients in Brazil. The obtained sequence data confirmed the CHIKV outbreaks and identified the genotype. In summary, our established inexpensive on-site genome detection and sequencing system is applicable for both diagnosis of CHIKV infected patients and genotyping of the CHIKV virus in future outbreak in remote areas.


Detecting tuberculosis in radiographs using combined lung masks.
Tuberculosis (TB) is a major health threat in many regions of the world, while diagnosing tuberculosis still remains a challenge. Mortality rates of patients with undiagnosed TB are high. Modern diagnostic techniques are often too slow or too expensive for highly-populated developing countries that bear the brunt of the disease. In an effort to reduce the burden of the disease, this paper presents an automated approach for detecting TB on conventional posteroanterior chest radiographs. The idea is to provide developing countries, which have limited access to radiological services and radiological expertise, with an inexpensive detection system that allows screening of large parts of the population in rural areas. In this paper, we present results produced by our TB screening system. We combine a lung shape model, a segmentation mask, and a simple intensity model to achieve a better segmentation mask for the lung. With the improved masks, we achieve an area under the ROC curve of more than 83%, measured on data compiled within a tuberculosis control program.


Access to electronic health knowledge in five countries in Africa: a descriptive study.
Access to medical literature in developing countries is helped by open access publishing and initiatives to allow free access to subscription only journals. The effectiveness of these initiatives in Africa has not been assessed. This study describes awareness, reported use and factors influencing use of on-line medical literature via free access initiatives. Descriptive study in four teaching hospitals in Cameroon, Nigeria, Tanzania and Uganda plus one externally funded research institution in The Gambia. Survey with postgraduate doctors and research scientists to determine Internet access patterns, reported awareness of on-line medical information and free access initiatives; semi structured interviews with a sub-sample of survey participants to explore factors influencing use. In the four African teaching hospitals, 70% of the 305 postgraduate doctors reported textbooks as their main source of information; 66% had used the Internet for health information in the last week. In two hospitals, Internet cafés were the main Internet access point. For researchers at the externally-funded research institution, electronic resources were their main source, and almost all had used the Internet in the last week. Across all 333 respondents, 90% had heard of PubMed, 78% of BMJ on line, 49% the Cochrane Library, 47% HINARI, and 19% BioMedCentral. HINARI use correlates with accessing the Internet on computers located in institutions. Qualitative data suggested there are difficulties logging into HINARI and that sometimes it is librarians that limit access to passwords. Text books remain an important resource for postgraduate doctors in training. Internet use is common, but awareness of free-access initiatives is limited. HINARI and other initiatives could be more effective with strong institutional endorsement and management to promote and ensure access.


Kabirimine, a New Cyclic Imine from an Okinawan Dinoflagellate.
On our quest for new bioactive molecules from marine sources, two cyclic imines (1, 2) were isolated from a dinoflagellate extract, inhibiting the growth of the respiratory syncytial virus (RSV). Compound 1 was identified as a known molecule portimine, while 2 was elucidated to be a new cyclic imine, named kabirimine. The absolute stereochemistry of 1 was determined by crystallographic work and chiral derivatization, whereas the structure of 2 was elucidated by means of spectroscopic analysis and computational study on all the possible isomers. Compound 1 showed potent cytotoxicity (CC50 < 0.097 µM) against HEp2 cells, while 2 exhibited moderate antiviral activity against RSV with IC50 = 4.20 µM (95% CI 3.31-5.33).


C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option.
Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life-threatening. These attacks are treated with C1-inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far.


The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis.
Rapid Ca2+ efflux from intracellular stores during cardiac muscle excitation-contraction coupling is mediated by the ryanodine-sensitive calcium-release channel, a large homotetrameric complex present in the sarcoplasmic reticulum. We report here the identification, primary structure and topological analysis of the ryanodine receptor-calcium release channel from human cardiac muscle (hRyR-2). Consistent with sedimentation and immunoblotting studies on the hRyR-2 protein, sequence analysis of ten overlapping cDNA clones reveals an open reading frame of 14901 nucleotides encoding a protein of 4967 amino acid residues with a predicted molecular mass of 564 569 Da for hRyR-2. In-frame insertions corresponding to eight and ten amino acid residues were found in two of the ten cDNAs isolated, suggesting that novel, alternatively spliced transcripts of the hRyR-2 gene might exist. Six hydrophobic stretches, which are present within the hRyR-2 C-terminal 500 amino acids and are conserved in all RyR sequences, may be involved in forming the transmembrane domain that constitutes the Ca(2+)-conducting pathway, in agreement with competitive ELISA studies with a RyR-2-specific antibody. Sequence alignment of hRyR-2 with other RyR isoforms indicates a high level of overall identity within the RyR family, with the exception of two important regions that exhibit substantial variability. Phylogenetic analysis suggests that the RyR-2 isoform diverged from a single ancestral gene before the RyR-1 and RyR-3 isoforms to form a distinct branch of the RyR family tree.


Economic evaluation of vitamin D and calcium food fortification for fracture prevention in Germany.
The study evaluates the economic benefit of population-wide vitamin D and Ca food fortification in Germany. Based on a spreadsheet model, we compared the cost of a population-wide vitamin D and Ca food-fortification programme with the potential cost savings from prevented fractures in the German female population aged 65 years and older. The annual burden of disease and the intervention cost were assessed for two scenarios: (i) no food fortification; and (ii) voluntary food fortification with 20 µg (800 IU) of cholecalciferol (vitamin D3) and 200 mg of Ca. The analysis considered six types of fractures: hip, clinical vertebral, humerus, wrist, other femur and pelvis. Subgroups of the German population defined by age and sex. The implementation of a vitamin D and Ca food-fortification programme in Germany would lead to annual net cost savings of €315 million and prevention of 36 705 fractures in the target population. Vitamin D and Ca food fortification is an economically beneficial preventive health strategy that has the potential to reduce the future health burden of osteoporotic fractures in Germany. The implementation of a vitamin D and Ca food-fortification programme should be a high priority for German health policy makers because it offers substantial cost-saving potential for the German health and social care systems.


Characterization of the Biodistribution of a Silica Vesicle Nanovaccine Carrying a Rhipicephalus (Boophilus) microplus Protective Antigen With in vivo Live Animal Imaging.
Development of veterinary subunit vaccines comes with a spectrum of challenges, such as the choice of adjuvant, antigen delivery vehicle, and optimization of dosing strategy. Over the years, our laboratory has largely focused on investigating silica vesicles (SVs) for developing effective veterinary vaccines for multiple targets. Rhipicephalus microplus (cattle tick) are known to have a high impact on cattle health and the livestock industry in the tropical and subtropical regions. Development of vaccine using Bm86 antigen against R. microplus has emerged as an attractive alternative to control ticks. In this study, we have investigated the biodistribution of SV in a live animal model, as well as further explored the SV ability for vaccine development. Rhodamine-labeled SV-140-C18 (Rho-SV-140-C18) vesicles were used to adsorb the Cy5-labeled R. microplus Bm86 antigen (Cy5-Bm86) to enable detection and characterization of the biodistribution of SV as well as antigen in vivo in a small animal model for up to 28 days using optical fluorescence imaging. We tracked the in vivo biodistribution of SVs and Bm86 antigen at different timepoints (days 3, 8, 13, and 28) in BALB/c mice. The biodistribution analysis by live imaging as well as by measuring the fluorescent intensity of harvested organs over the duration of the experiment (28 days) showed greater accumulation of SVs at the site of injection. The Bm86 antigen biodistribution was traced in lymph nodes, kidney, and liver, contributing to our understanding how this delivery platform successfully elicits antibody responses in the groups administered antigen in combination with SV. Selected tissues (skin, lymph nodes, spleen, kidney, liver, and lungs) were examined for any cellular abnormalities by histological analysis. No adverse effect or any other abnormalities were observed in the tissues.


Lactobacillus rhamnosus GG SpaC pilin subunit binds to the carbohydrate moieties of intestinal glycoconjugates.
Lactobacillus rhamnosus GG (LGG) is a well-established probiotic strain. The beneficial properties of this strain are partially dependent on its prolonged residence in the gastrointestinal tract, and are likely influenced by its adhesion to the intestinal mucosa. The pilin SpaC subunit, located within the Spa pili structure, is the most well studied LGG adhesion factor. However, the binding epitopes of SpaC remain largely unknown. The aim of this study was to evaluate the binding properties of SpaC to the carbohydrate moieties of intestinal glycoconjugates using a recombinant SpaC protein. In a competitive enzyme-linked immunosorbent assay, SpaC binding was markedly reduced by addition of purified mucin and the mucin oligosaccharide fraction. Histochemical staining revealed that the binding of SpaC was drastically reduced by periodic acid treatment. Moreover, in the surface plasmon resonance-based Biacore assay, SpaC bound strongly to the carbohydrate moieties containing β-galactoside at the non-reducing terminus of glycolipids. We here provide the first demonstration that SpaC binds to the oligosaccharide chains of mucins, and that the carbohydrate moieties containing β-galactoside at the non-reducing termini of glycoconjugates play a crucial role in this binding. Our results demonstrate the importance of carbohydrates of SpaC for mucus interactions.


Mineralised organic remains from cesspits at the Roman town of Silchester: processes and preservation.
Mineralised organic remains (including apple pips and cereal grains) collected during the ongoing excavations of Insula IX at the Roman town of Silchester, Hampshire have been analysed by a combination of SEM-EDX, powder XRD and IR spectroscopy. The experiments included mapping experiments using spatially resolved versions of each technique. IR and powder XRD mapping have been carried out utilising the synchrotron source at The Daresbury Laboratory on stations 11.1 and 9.6. It is concluded that these samples are preserved by rapid mineralisation in the carbonate-substituted calcium phosphate mineral, dahllite. The rapid mineralisation leads to excellent preservation of the samples and a small crystal size. The value of IR spectroscopy in studying materials like this where the crystal size is small is demonstrated. A comparison is made between the excellent preservation seen in this context and the much poorer preservation of mineralised remains seen in Context 5276 or Cesspit 5251. Comments on the possible mechanism of mineralisation of these samples are made.


Echinacea complex--chemical view and anti-asthmatic profile.
Echinacea purpurea (L.) Moench is one of the mostly used herbs in the traditional medicine for the treatment of respiratory diseases. Modern interest in Echinacea is directed to its immunomodulatory activity. Recent studies have shown that secretion of asthma-related cytokines in the bronchial epithelial cells can be reversed by Echinacea preparations. To examine the pharmacodynamics profile of Echinacea active principles, a complex has been isolated from its flowers by alkaline extraction and has been tested using an animal model of allergic asthma. The structural features of Echinacea purpurea complex was determined using chemical and spectroscopic methods. Allergic inflammation of the airways was induced by repetitive exposure of guinea pigs to ovalbumin. Echinacea complex was then administered 14 days in 50mg/kg b.w. daily dose perorally. Bronchodilatory effect was verified as decrease in the specific airway resistance (sRaw) in vivo and by reduced contraction amplitude (mN) of tracheal and pulmonary smooth muscle to cumulative concentrations of acetylcholine and histamine in vitro. The impact on mucociliary clearance evaluated measurement of ciliary beat frequency (CBF) in vitro using LabVIEW™ Software. Anti-inflammatory effect of Echinacea complex was verified by changes in exhaled NO levels and by Bio-Plex® assay of Th2 cytokine concentrations (IL-4, IL-5, IL-13 and TNF-alpha) in serum and bronchoalveolar lavage fluid (BALF). Chemical and spectroscopic studies confirmed the presence of carbohydrates, phenolic compounds and proteins, as well as the dominance of rhamnogalacturonan and arabinogalactan moieties in Echinacea complex. The significant decrease in sRaw values and suppressed histamine and acetylcholine-induced contractile amplitude of isolated airways smooth muscle that were similar to effects of control drug salbutamol confirmed Echinacea complex bronchodilatory activity. The anti-inflammatory effect was comparable with that of control agent budesonide and was verified as significantly reduced exhaled NO levels and concentration of Th2 cytokines in serum and BALF. The values of CBF were changed only insignificantly on long-term administration of Echinacea complex suggested its minimal negative impact on mucociliary clearance. Pharmacodynamic studies have confirmed significant bronchodilatory and anti-inflammatory effects of Echinacea complex that was similar to effects of classic synthetic drugs. Thus, results provide a scientific basis for the application of this herb in traditional medicine as a supplementary treatment of allergic disorders of the airways, such as asthma.


Effects of treatment with lispro and neutral protamine Hagedorn insulins on serum fructosamine and postprandial blood glucose concentrations in dogs with clinically well-controlled diabetes mellitus and postprandial hyperglycemia.
To assess effects of basal-bolus insulin treatment (BBIT) with lispro and neutral protamine Hagedorn (NPH) insulins, compared with NPH insulin alone, on serum fructosamine concentration (SFC) and postprandial blood glucose concentration (BGC) in dogs with clinically well-controlled diabetes mellitus and postprandial hyperglycemia fed a high insoluble fiber-content diet. 6 client-owned dogs with diabetes mellitus. Blood samples were collected for BGC and SFC measurement in hospitalized dogs just before feeding and routine SC NPH insulin administration (time 0); samples were collected for BGC measurement every 30 minutes for 2 hours, then every 2 hours for up to 10 additional hours. Postprandial hyperglycemia was identified when BGC 30 minutes after insulin administration exceeded BGC at time 0 or the 1-hour time point. For BBIT, owners were instructed to continue NPH insulin administration at the usual dosage at home (q 12 h, with feeding) and to administer lispro insulin (0.1 U/Kg, SC) separately at the time of NPH injections. Two weeks later, SFC and BGC measurements were repeated; results at the start and end of the study were compared statistically. Median SFC was significantly higher at the start (400 μmol/L) than at the end (390 μmol/L) of the study. Median 1-hour (313 mg/dL) and 1.5-hour (239 mg/dL) BGC measurements at the start of the study were significantly higher than those at the end of the study (117 and 94 mg/dL, respectively). In this sample of dogs with well-controlled diabetes mellitus, addition of lispro insulin to an existing treatment regimen of NPH insulin and dietary management significantly decreased postprandial BGCs. Further study of BBIT for dogs with diabetes mellitus is warranted.


Relationship between endothelial dysfunction and cardiovascular risk factors and the extent and severity of coronary artery disease.
Endothelial dysfunction (ED) is associated with coronary artery disease (CAD) and cardiovascular risk factors. The relationship between cardiovascular risk factors, ED and the presence, extent and severity of CAD, was evaluated in patients with and without angiographically defined CAD in our study. Eighty patients with CAD and 20 subjects with normal coronary arteries were included. Endothelial function was evaluated by endothelium-dependent, flow-mediated dilatation (FMD) and nitroglycerine-mediated dilatation (NMD) measurements, using brachial artery Doppler ultrasonography (USG). Cardiovascular risk factors were identified. The extent and severity of CAD was determined via vessel and modified Gensini scores. FMD% and NMD% were significantly decreased in the CAD(+) group compared with the CAD(-) group (p=0.0001). In the CAD(+) group, the cut-off values of FMD% and NMD% in distinguishing between single-vessel and multi-vessel diseases were 8.5% (sensitivity: 95%, specificity: 62%) and 13.6% (sensitivity: 91%, specificity: 62%), respectively. Additionally, a modified Gensini score was significantly correlated with both FMD and NMD (r=-0.825, r=-0.778, respectively; p=0.0001) in the CAD(+) group. ED was more prevalent in the CAD(+) group, and the degree of ED correlated well with the extent and severity of CAD.


Conduct Problems and Adherence to COVID-19 Guidelines: A Developmental Psychopathology-Informed Approach.
COVID-19 underscores the importance of understanding variation in adherence to rules concerning health behaviors. Children with conduct problems have difficulty with rule adherence, and linking early conduct problems with later adherence to COVID-19 guidelines can provide new insight into public health. The current study employed a sample (N = 744) designed to examine the longitudinal consequences of childhood conduct problems (Mean age at study entry = 8.39). The first objective was to link early conduct problems with later adherence to both general and specific COVID-19 guidelines during emerging adulthood (M age = 19.07). The second objective was to prospectively examine how interactional (i.e., callous unemotional traits, impulsivity) and cumulative (i.e., educational attainment, work status, substance use) continuity factors mediated this association. The third objective was to examine differences in sex assigned at birth in these models. Direct associations were observed between childhood conduct problems and lower general, but not specific COVID-19 guideline adherence. Conduct problems were indirectly associated with both general and specific adherence via higher levels of callous unemotional traits, and with specific adherence via higher problematic substance use. No differences in the models were observed across sex assigned at birth. Findings provide insight into both how developmental psychopathology constructs are useful for understanding COVID-19 guideline adherence, and the ways in which conduct problems may shape health outcomes.