Anxiety, Anxiety Symptoms, and Their Correlates in Persons with Dementia in Norwegian Nursing Homes: A Cause for Concern.
Little is known about anxiety and its associations among persons with dementia in nursing homes. This study aims to examine anxiety, anxiety symptoms, and their correlates in persons with dementia in Norwegian nursing homes. In all, 298 participants with dementia ≥65 years old from 17 nursing homes were assessed with a validated Norwegian version of the Rating Anxiety in Dementia scale (RAID-N). Associations between anxiety (RAID-N score) and demographic and clinical characteristics were analyzed with linear regression models. Anxiety, according to a cutoff of ≥12 on the RAID-N, was found in 34.2% (n = 102) of the participants. Irritability (59.7%) and restlessness (53.0%) were the most frequent anxiety symptoms. The participants' general physical health, a wide range of neuropsychiatric symptoms, and anxiolytic use were significant correlates of higher RAID-N scores. Knowledge about anxiety, anxiety symptoms, and their correlates may enhance early detection of anxiety and planning of necessary treatment and proactive measures among this population residing in nursing homes.


'Appropriate' medical treatment: what's in a word?
Following the amendments in the 2007 Act, there were several revisions made focusing largely on community treatment orders and deprivation of liberty of persons lacking capacity. One of the amendments included a requirement that 'appropriate treatment' be 'available' for compulsion to be imposed in a variety of contexts, most notably admission for treatment under section 3. The definition of appropriate medical treatment within the Act appears largely circular, and therefore of little assistance. The Code of Practice provides some guidance but does little to add to the statutory language. In terms of jurisprudence, there are three reported cases concerning the provision. These cases are analysed and their significance is discussed in an attempt to formulate a clearer definition for appropriate medical treatment.


Psychosocial factors and the response to influenza vaccination in older adults.
We examined the influence of psychological state (depression, negative affect, perceived stress) and social support on pre- and post-vaccination response to influenza vaccine. Venous blood was drawn from 37 nursing home residents before and following injection of the trivalent influenza vaccine (comprised of the New Caledonia (NC), Hong Kong (HK), and Panama (Pan) strains of flu). The Geriatric Depression Scale, Perceived Stress Scale, Positive and Negative Affect Schedule, and Multidimensional Scale of Perceived Social Support were completed following the initial blood draw. Social support and perceived stress were correlated with pre-vaccine antibody responses to two of the three vaccine components (HK and NC). Social support was negatively correlated with both pre- and post-vaccine titers to Pan. Depression, positive affect, and negative affect were not related to vaccine response. Perceived stress and social support influence the rate of decline of antibody titers to previous exposures to some strains of influenza occurring either naturally or via deliberate vaccination.


Echocardiography for the detection of valvulopathy associated with the use of ergot-derived dopamine agonists in patients with Parkinson's disease.
The ergot-derived dopamine agonists, cabergoline and pergolide, are associated with valvulopathy risk. In Japan, product labels were revised in April 2007 to recommend periodic echocardiography for patients taking these dopamine agonists, however, the compliance of physicians to follow through with this recommendation is unknown. This study assessed changes in echocardiography evaluation of patients with Parkinson's disease (PD) taking cabergoline or pergolide before and after the label revision and examined the factors related with echocardiography performance. Medical claim data from January 2005 to December 2008 were used. Patients were divided into a C-P group (prescribed either cabergoline or pergolide) or reference group (prescribed other anti-PD drugs), and further classified based on whether they were prescribed these drugs "pre-revision" or "post-revision." The Cochran-Armitage trend test was used to compare the proportion of echocardiograms obtained amongst these groups before and after the revision. The frequencies of echocardiograms performed among the treatment groups for each period were compared by Fisher's exact test. A total of 222 subjects (C-P, 73; reference, 149) were assessed. The proportion of C-P patients undergoing echocardiography increased from 4.8% to 27.9% after revision of product labels (p=0.001), which was higher than those in the reference group following label revisions (11.0%) (p=0.014). Prescription duration of C-P after the revision was longer in the patients with echocardiography than without echocardiography (p=0.026). Although echocardiography evaluations increased, more than 70% of PD patients prescribed cabergoline or pergolide did not undergo such assessment despite the product label recommendation. Adherence to drug safety recommendations should be facilitated with more feasible and effective measures.


Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants.
Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.


Effects of fluoride on the intracellular free Ca2+ and Ca2+-ATPase of kidney.
In the present study, the effect of fluoride on intracellular free calcium ([Ca2+]i) and Ca2+-ATPase of renal cells were examined. Some paradoxical experimental results about the mechanism of fluoride toxicity were observed. In vivo, 48 Wistar rats were divided into 4 groups, and half of rats were treated with sodium fluoride (NaF) by drinking water (per liter of tap water containing 100 mg F-). Compared with the respective control, the level of [Ca2+]i of the kidney in two fluoride-treated rats obviously increased (p < 0.05); and the activity of Ca2+-ATPase in 100 mg F-/L groups with a standard diet did not significantly increase, and the enzyme activity in 100-mg F-/L group with a low-calcium diet decreased significantly compared to the 100 mg F-/L group with a standard diet (p < 0.05). In vitro, renal tubular cells were cultured and respectively exposed to 1.0, 5.0, 7.5, and 12.5 mg/L fluoride in the culture medium. Results showed the significantly elevated activity of Ca2+-ATPase in the cells exposed to 1.0 and 5.0 mg/L fluoride (p < 0.05), and this enzyme activity indicated inhibitory trend in cells of the 7.5- and 12.5-mg/L fluoride-treated group. To sum up, the effect of fluoride on Ca2+-ATPase is a similar to a dose-effect relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, and the increase of [Ca2+]i probably plays a key role on the mechanism of renal injury in fluorosis.


Early Visual Cortex as a Multiscale Cognitive Blackboard.
Neurons in early visual cortical areas not only represent incoming visual information but are also engaged by higher level cognitive processes, including attention, working memory, imagery, and decision-making. Are these cognitive effects an epiphenomenon or are they functionally relevant for these mental operations? We review evidence supporting the hypothesis that the modulation of activity in early visual areas has a causal role in cognition. The modulatory influences allow the early visual cortex to act as a multiscale cognitive blackboard for read and write operations by higher visual areas, which can thereby efficiently exchange information. This blackboard architecture explains how the activity of neurons in the early visual cortex contributes to scene segmentation and working memory, and relates to the subject's inferences about the visual world. The architecture also has distinct advantages for the processing of visual routines that rely on a number of sequentially executed processing steps.


The Troyer syndrome (SPG20) protein spartin interacts with Eps15.
The hereditary spastic paraplegias comprise a group of inherited neurological disorders in which the primary manifestation is spastic weakness of the lower extremities. Troyer syndrome is an autosomal recessive form of spastic paraplegia caused by a frameshift mutation in the spartin (SPG20) gene. Currently, neither the localization nor the functions of the spartin protein are known. In this study, we generated anti-spartin antibodies and found that spartin is both cytosolic and membrane-associated. Using a yeast two-hybrid approach, we screened an adult human brain library for binding partners of spartin. We identified Eps15, a protein known to be involved in endocytosis and the control of cell proliferation. This interaction was confirmed by fusion protein "pull-down" experiments as well as a cellular redistribution assay. Our results suggest that spartin might be involved in endocytosis, vesicle trafficking, or mitogenic activity, and that impairment in one of these processes may underlie the long axonopathy in patients with Troyer syndrome.


A high frequency dielectric waveguide on the antennae of night-flying moths (Saturnidae).
When spines on the scape and pedicel of two species of saturnid moths were irradiated with visible coherent (6328 A) and incoherent radiation, the sensors responded to the light by sending a biphasic nerve impulse down the entire length of the central antennal nerve. The biphasic action potential apparently gates the antennae and prevents the moth from responding to environmental signals during daylight.


Attitudes of COPD patients towards tele-rehabilitation: a cross-sector case study.
The aim of this paper is to describe patients' attitudes towards tele-rehabilitation in the Danish TELEKAT (for Telehomecare, Chronic Patients and the Integrated Healthcare System) project, in order to better understand patients' behavior when performing tele-rehabilitation activities in home surroundings. A total of 111 COPD patients were included in the study, and they were randomized into an intervention group (n = 60) and a control group (n = 51). However, a non-randomized design was used to analyze the qualitative perspectives of the patients' attitudes towards tele-rehabilitation. From the intervention group, 22 COPD patients were selected for qualitative interviews and participant observation in their homes. The theoretical framework for this study is based on learning theory and the "communities of practice" approach inspired by Etienne Wenger. COPD patients exhibit four types of attitudes about their tele-rehabilitation: indifference, learning as part of situations in everyday life, feeling of security and motivation for performing physical training. The patients express the view that they circulate between these attitudes depending on their physical and emotional state as they perform their training. The COPD patients and healthcare professionals have created a community of tele-rehabilitation across sectors, exchanging experiences, stories and strategies for how to manage rehabilitation in home surroundings.


Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1.
Human leukocyte antigen (HLA)-independent, T cell-mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR-Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.


High Ionized Calcium Concentration Is Associated With Prolonged Length of Stay in the Intensive Care Unit for Postoperative Pediatric Cardiac Patients.
There has been controversy regarding the beneficial effects of calcium on myocardial contractility and the harmful effects on myocardial cells, especially in children. The aim of this study was to investigate an association between ionized calcium concentration (iCa) and outcomes for pediatric patients after cardiac surgery. A retrospective, single-center study from May 2013 to December 2014. Referral high-volume pediatric cardiac center in a tertiary teaching hospital. Patients <72 months old with congenital heart disease who underwent palliative or definitive surgery. None. The association between pH-corrected iCa within 24 hours after surgery and intensive care unit (ICU) length of stay (ILOS) was defined as the primary outcome. The highest iCa (iCamax), lowest iCa (iCamin), and time-weighted average iCa (iCaave) were stratified and compared with the outcomes. The authors reviewed 5,468 ionized calcium measurements from 357 consecutive pediatric patients during the study period. One patient died at postoperative day 34 in the ICU. Significant differences in ILOS were observed among patients after cardiopulmonary bypass (CPB) according to iCaave, iCamax, and iCamin but not among patients without CPB. Patients with CPB and an iCaave value of 1.31-to-1.40 mmol/L, 1.41-to-1.50 mmol/L, 1.51-to-1.60 mmol/L, and >1.60 mmol/L stayed in the ICU for 7 (interquartile range [IQR] 4-10) days, 8 (IQR 6-16) days, 10 (IQR 8-14) days, and 19 (IQR 12-38) days, respectively, which was significantly longer than the ILOS of 5 (4-8) days for patients with an iCaave of 1.21-to-1.30 mmol/L. Even after adjustment for other predictors of ILOS using multivariable analyses, there were significant relationships of ILOS with iCaave and iCamin values of >1.50 mmol/L among patients with CPB. Higher iCa within 24 hours after congenital cardiac surgery using CPB was independently associated with longer LOS in the ICU.


Effect of degeneration on the six degree of freedom mechanical properties of human lumbar spine segments.
While the effects of disc degeneration on compression and rotation motions have been studied, there is no data for shear loading. Clinical research has shown that those with low back pain (a potential consequence of degeneration) experience a 75% greater lateral shear force than those without it. Therefore, the aim was to compare the effect of degeneration on spine segment stiffness and phase angle in each of six degree of freedom (6DOF) loading directions. Fourteen intact functional spinal units (FSU) were dissected from human lumbar spines (mean (SD) age 76.2 (11) years, Thompson grades 3 (N = 5, mild), 4 (N = 6, moderate), 5 (N = 3, severe)). Each FSU was tested in ±6DOFs while subjected to a physiological preload, hydration, and temperature (37°C) conditions in a hexapod robot. A one-way ANOVA between degenerated groups was performed on stiffness and phase angle for each DOF. Significant differences in stiffness were found between mild and moderate degenerative groups in lateral shear (p = 0.001), and axial rotation (p = 0.001), where moderate degeneration had decreased stiffness. For phase angle, significant differences were seen in anterior shear (p = 0.017), and axial rotation (p = 0.026), where phase angle for mild degeneration was less than moderate. Trends of stiffness and phase angle changes between degenerative groups were similar within each DOF. Clinically, the identification of the DOFs that are most affected by degeneration could be used in rehabilitation to improve supplemental stabilization of core muscle groups. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1399-1409, 2016.


Physiotherapy for Parkinson's disease: a comparison of techniques.
Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy is to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and wellbeing, thereby enhancing quality of life. Trials have shown that physiotherapy has short-term benefits in PD. However, which physiotherapy intervention is most effective remains unclear. To assess the effectiveness of one physiotherapy intervention compared with a second approach in patients with PD. Relevant trials were identified by electronic searches of numerous literature databases (for example MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to the end of January 2012. Randomised controlled trials of one physiotherapy intervention versus another physiotherapy intervention in patients with PD. Data were abstracted independently from each paper by two authors. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. A total of 43 trials were identified with 1673 participants. All trials used small patient numbers (average trial size of 39 participants); the methods of randomisation and concealment of allocation were poor or not stated in most trials. Blinded assessors were used in just over half of the trials and only 10 stated that they used intention-to-treat analysis.A wide variety of validated and customised outcome measures were used to assess the effectiveness of physiotherapy interventions. The most frequently reported physiotherapy outcomes were gait speed and timed up and go, in 19 and 15 trials respectively. Only five of the 43 trials reported data on falls (12%). The motor subscales of the Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 were the most commonly reported clinician-rated disability and patient-rated quality of life outcome measures, used in 22 and 13 trials respectively. The content and delivery of the physiotherapy interventions varied widely in the trials included within this review, so no quantitative meta-analysis could be performed. Considering the small number of participants examined, the methodological flaws in many of the studies, the possibility of publication bias, and the variety of interventions, formal comparison of the different physiotherapy techniques could not be performed. There is insufficient evidence to support or refute the effectiveness of one physiotherapy intervention over another in PD.This review shows that a wide range of physiotherapy interventions to treat PD have been tested . There is a need for more specific trials with improved treatment strategies to underpin the most appropriate choice of physiotherapy intervention and the outcomes measured.


The effects of freezing on faecal microbiota as determined using MiSeq sequencing and culture-based investigations.
High-throughput sequencing has enabled detailed insights into complex microbial environments, including the human gut microbiota. The accuracy of the sequencing data however, is reliant upon appropriate storage of the samples prior to DNA extraction. The aim of this study was to conduct the first MiSeq sequencing investigation into the effects of faecal storage on the microbiota, compared to fresh samples. Culture-based analysis was also completed. Seven faecal samples were collected from healthy adults. Samples were separated into fresh (DNA extracted immediately), snap frozen on dry ice and frozen for 7 days at -80°C prior to DNA extraction or samples frozen at -80°C for 7 days before DNA extraction. Sequencing was completed on the Illumina MiSeq platform. Culturing of total aerobes, anaerobes and bifidobacteria was also completed. No significant differences at phylum or family levels between the treatment groups occurred. At genus level only Faecalibacterium and Leuconostoc were significantly different in the fresh samples compared to the snap frozen group (p = 0.0298; p = 0.0330 respectively). Diversity analysis indicated that samples clustered based on the individual donor, rather than by storage group. No significant differences occurred in the culture-based analysis between the fresh, snap or -80°C frozen samples. Using the MiSeq platform coupled with culture-based analysis, this study highlighted that limited significant changes in microbiota occur following rapid freezing of faecal samples prior to DNA extraction. Thus, rapid freezing of samples prior to DNA extraction and culturing, preserves the integrity of the microbiota.


Urdu translation of the ICD-10 chapter V (F), research diagnostic criteria (RDC): process and principles of translation.
Although there is some literature on translation and cultural adaptation of measurement scales, none is available on the translation of diagnostic guidelines, such as the International Classification of Diseases Tenth Edition (ICD-10). Our group translated ICD-10, Research Diagnostics Criteria (RDC) into Urdu, which is the official language of Pakistan but is also spoken in some states in India. Significant diasporas of Urdu speakers also exist in Western Countries. We describe the translation process and the principles that guided our work. The translation process consisted of preparation, forward-translation, external translation, synthesis, focus group discussions with laypersons to clarify terminology, and review by mental health professionals and laypersons. Translation also included a wider consultation process in which the final version was sent to Pakistani mental health professionals in Pakistan and abroad.


Bridge to cardiac transplant in children: Berlin Heart versus extracorporeal membrane oxygenation.
For small children requiring mechanical circulatory support as a bridge to transplantation (BTT), extracorporeal membrane oxygenation (ECMO) has been the only option until the recent introduction of the Berlin Heart EXCOR ventricular assist device (Berlin Heart AG, Berlin, Germany). We reviewed our recent experience with these two technologies with particular focus on early outcomes. Data for 55 consecutive children undergoing BTT between 2001 and 2008 were abstracted from an institutional database. The analysis excluded 13 patients because EXCOR was not used for acute postcardiotomy BTT. Patients were divided into ECMO (n = 21) and EXCOR groups (n = 21). Specific end points included survival to transplant, overall survival, and bridge to recovery. Incidences of adverse events and the duration of support were determined. Groups were similar in weight, age, and etiologies of heart failure. Likewise, the incidences of stroke and multisystem organ failure were similar. Survival to transplant, recovery, or continued support was 57% in ECMO and 86% in EXCOR (p = 0.040). EXCOR patients had overall significantly better survival (p = 0.049). Two ECMO patients and 1 EXOR patient were bridged to recovery. The mean duration of support was 15 +/- 12 days in the ECMO group and 42 +/- 43 days in the EXCOR group (p < 0.001). In children requiring BTT, EXCOR provided substantially longer support times than ECMO, without significant increase in the rates of stroke or multisystem organ failure. Survival to transplant and long-term survival was higher with EXCOR.


Immobilisation of β-galactosidase within a lipid sponge phase: structure, stability and kinetics characterisation.
In the formulation of an active enzyme enclosed in a matrix for controlled delivery, it is a challenge to achieve a high protein load and to ensure high activity of the protein. For the first time to our knowledge, we report the use of a highly swollen lipid sponge (L3) phase for encapsulation of the large active enzyme, β-galactosidase (β-gal, 238 kDa). This enzyme has large relevance for applications in, e.g. the production of lactose free milk products. The formulation consisted of diglycerol monooleate (DGMO), and a mixture of mono-, di- and triglycerides (Capmul GMO-50) stabilised by polysorbate 80 (P80). The advantage of this type of matrix is that it can be produced on a large scale with a fairly simple and mild process as the system is in practice self-dispersing, yet it has a well-defined internal nano-structure. Minor effects on the sponge phase structure due to the inclusion of the enzyme were observed using small angle X-ray scattering (SAXS). The effect of encapsulation on the enzymatic activity and kinetic characteristics of β-galactosidase activity was also investigated and can be related to the enzyme stability and confinement within the lipid matrix. The encapsulated β-galactosidase maintained its activity for a significantly longer time when compared to the free solution at the same temperature. Differences in the particle size and charge of sponge-like nanoparticles (L3-NPs) with and without the enzyme were analysed by dynamic light scattering (DLS) and zeta-potential measurements. Moreover, all the initial β-galactosidase was encapsulated within L3-NPs as revealed by size exclusion chromatography.


6 mJ, high-average-power, all-fiberized Q-switched fiber master oscillator power amplifier with low repetition rate.
We report an all-fiberized, high-pulse-energy, high-average-power, Q-switched fiber master oscillator power amplifier (MOPA) oscillated at 1064 nm. The seed source is an acousto-optic Q-switched fiber laser, which is driven by an arbitrary waveform generator. A preamplifier is developed to boost the average power to about 3 W. Finally, we achieved an average output power of more than 62 W and a pulse energy of 6.2 mJ at 10 kHz repetition rate. The pulse duration is about 157 ns corresponding to the peak power of 37.1 kW. The optical-to-optical efficiency of the main amplifier is 61.3%. The beam quality factors (M2) are 3.1 in both directions.


The Roles of Microtubules and Membrane Tension in Axonal Beading, Retraction, and Atrophy.
Axonal beading, or the formation of a series of swellings along the axon, and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here, we report controlled experiments that can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde, and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation, vis-à-vis beading or retraction. Elucidating the mechanisms of these shape transformations may facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.


Health professionals as mobile content creators: teaching medical students to develop mHealth applications.
Patient access to health information and patient-provider communication is integral to medicine, and can be facilitated by mobile applications ("apps"). Traditionally, student training in mobile Health (mHealth) has focussed on health professionals as consumers of information, with negative impacts on the quality and value of medical apps. This study focuses on teaching medical students to develop their own medical apps. At Sultan Qaboos University, Oman, an app development environment, iBuildApp, was taught to medical students and used to develop their first apps. Students were surveyed on their perceptions of the project. Of the 166 students, 107 (64.5%) completed the survey. There was an increase in the perceived need for such learning, apps were aimed primarily at patients, and previous programming experience was the strongest influencer of a positive experience. A majority (77.6%) wanted more sophisticated development environments in spite of their apparent struggles. The impact of previous experience is similar to other studies; the perceived value and focus on patient apps is indicative of an awareness of patients' use of the devices not reflected in all literature. It is possible to teach medical students the fundamentals of app design so that they may contribute to app development in the future.


Role of the amino acid 45 residue in reduced folate carrier function and ion-dependent transport as characterized by site-directed mutagenesis.
In previous reports, an E45K mutation in reduced folate carrier (RFC1) resulted in marked substrate-specific changes in folate binding and the induction of an obligatory inorganic anion requirement for carrier function. In this study, site-directed mutagenesis was employed to further characterize the role of glutamate-45 in carrier function by replacement with glutamine, arginine, aspartate, leucine, or tryptophan followed by tranfection of the mutated cDNAs into the MTX(r)A line, which lacks a functional endogenous carrier. Alterations in transport function with amino acid substitutions at this residue were not charge related. Hence, E45Q, E45R, and E45K all 1) increased carrier affinity for 5-formyltetrahydrofolate approximately 4-fold, 2) increased affinity for folic acid approximately 6- to 10-fold, 3) did not change affinity for 5-methyltetrahydrofolate, and 4) except for E45R decreased affinity for methotrexate (2- to 3-fold). In contrast, mutations E45D, E45L, and E45W generally reduced affinity for all these folates except for folic acid. Finally, chloride-dependent influx was only noted in the E45R mutant. These data further substantiate the important role that glutamate-45 plays in the selectivity of binding of folates to RFC1 and establish that it is the addition of a positive charge at this site and not the loss of a negative charge that results in the induced anion dependence. These and other studies indicate that mutations in the first transmembrane domain can have a markedly selective impact on the affinity of RFC1 for folate compounds and in particularly a highly salutary effect on binding of the oxidized folate, folic acid.


A somatotopic bidirectional hand prosthesis with transcutaneous electrical nerve stimulation based sensory feedback.
According to amputees, sensory feedback is amongst the most important features lacking from commercial prostheses. Although restoration of touch by means of implantable neural interfaces has been achieved, these approaches require surgical interventions, and their long-term usability still needs to be fully investigated. Here, we developed a non-invasive alternative which maintains some of the advantages of invasive approaches, such as a somatotopic sensory restitution scheme. We used transcutaneous electrical nerve stimulation (TENS) to induce referred sensations to the phantom hand of amputees. These sensations were characterized in four amputees over two weeks. Although the induced sensation was often paresthesia, the location corresponded to parts of the innervation regions of the median and ulnar nerves, and electroencephalographic (EEG) recordings confirmed the presence of appropriate responses in relevant cortical areas. Using these sensations as feedback during bidirectional prosthesis control, the patients were able to perform several functional tasks that would not be possible otherwise, such as applying one of three levels of force on an external sensor. Performance during these tasks was high, suggesting that this approach could be a viable alternative to the more invasive solutions, offering a trade-off between the quality of the sensation, and the invasiveness of the intervention.


C-methylated and C-prenylated isoflavonoids from root extract of Desmodium uncinatum.
A pterocarpan, 1,9-dihydroxy-3-methoxy-2-methylpterocarpan (named uncinacarpan) and two isoflavanones, 5,7-dihydroxy-2',3',4'-trimethoxy-6-(3-methylbut-2-enyl)isoflavanone (named uncinanone D) and 5,4'-dihydroxy-7,2'-dimethoxy-6-methylisoflavanone (named uncinanone E), were isolated from the CH(2)Cl(2) root extract of Desmodium uncinatum (Jacq.) DC and characterised by spectroscopic methods. In addition, a rare pterocarpan edudiol and two known abietane diterpenes, 7-oxo-15-hydroxydehydroabietic acid and 7-hydroxycallitrisic acid were identified. The fraction of the root extract that was analysed induced germination of Striga hermonthica seeds, but none of the isolated compounds showed this activity.


Helicity multiplexed broadband metasurface holograms.
Metasurfaces are engineered interfaces that contain a thin layer of plasmonic or dielectric nanostructures capable of manipulating light in a desirable manner. Advances in metasurfaces have led to various practical applications ranging from lensing to holography. Metasurface holograms that can be switched by the polarization state of incident light have been demonstrated for achieving polarization multiplexed functionalities. However, practical application of these devices has been limited by their capability for achieving high efficiency and high image quality. Here we experimentally demonstrate a helicity multiplexed metasurface hologram with high efficiency and good image fidelity over a broad range of frequencies. The metasurface hologram features the combination of two sets of hologram patterns operating with opposite incident helicities. Two symmetrically distributed off-axis images are interchangeable by controlling the helicity of the input light. The demonstrated helicity multiplexed metasurface hologram with its high performance opens avenues for future applications with functionality switchable optical devices.


Microscope-based static light-scattering instrument.
We describe a new design for a microscope-based static light-scattering instrument that provides simultaneous high-resolution images and static light-scattering data. By correlating real space images with scattering patterns, we can interpret measurements from heterogeneous samples, which we illustrate by using biological tissue.


Randomized, double-blinded, controlled non-inferiority trials evaluating the immunogenicity and safety of fractional doses of Yellow Fever vaccines in Kenya and Uganda.
Introduction: Yellow fever is endemic in specific regions of sub-Saharan Africa and the Americas, with recent epidemics occurring on both continents. The yellow fever vaccine is effective, affordable and safe, providing life-long immunity following a single dose vaccination. However, the vaccine production process is slow and cannot be readily scaled up during epidemics. This has led the World Health Organization (WHO) to recommend the use of fractional doses as a dose-sparing strategy during epidemics, but there are no randomized controlled trials of fractional yellow fever vaccine doses in Africa. Methods and analysis: We will recruit healthy adult volunteers, adults living with HIV, and children to a series of randomized controlled trials aiming to determine the immunogenicity and safety of fractional vaccine doses in comparison to the standard vaccine dose. The trials will be conducted across two sites; Kilifi, Kenya and Mbarara, Uganda. Recruited participants will be randomized to receive fractional or standard doses of yellow fever vaccine. Scheduled visits will include blood collection for serum and peripheral blood mononuclear cells (PBMCs) before vaccination and on various days - up to 2 years - post-vaccination. The primary outcome is the rate of seroconversion as measured by the plaque reduction neutralization test (PRNT 50) at 28 days post-vaccination. Secondary outcomes include antibody titre changes, longevity of the immune response, safety assessment using clinical data, the nature and magnitude of the cellular immune response and post-vaccination control of viremia by vaccine dose. Ethics and dissemination: The clinical trial protocols have received approval from the relevant institutional ethics and regulatory review committees in Kenya and Uganda, and the WHO Ethics Review Committee. The research findings will be disseminated through open-access publications and presented at relevant conferences and workshops. Registration: ClinicalTrials.gov NCT02991495 (registered on 13 December 2016) and NCT04059471 (registered on 15 August 2019).


Neurocognitive deficits in children with chronic health conditions.
Over 4 million children in the United States suffer from chronic health conditions, including cancer, sickle cell disease, and diabetes. Because of major advances in the early identification and treatment of these conditions, survival rates for these children continue to rise, and the majority now lives into adulthood. However, increases in survival have come with costs related to long-term effects of disease processes and treatments. Foremost among these consequences is impairment in brain development and neurocognitive function that may affect a substantial portion of children with chronic health conditions and follow many into adulthood. Impaired cognitive function may contribute to impairment in educational and occupational attainment, mental health, and quality of life for children with chronic conditions. Despite the significance and scope of this problem, advances in the identification and understanding of neurocognitive problems and the delivery of effective clinical care have been hindered in part because research has been "siloed"-conducted on each chronic condition in isolation. This review examines, for the first time, neurocognitive problems in a selected set of 6 chronic pediatric health conditions-leukemia, brain tumors, sickle cell disease, congenital heart disease, Type 1 diabetes, and traumatic brain injury-to define the magnitude of the problem and identify directions for future research and clinical care. Psychologists from many areas of specialization, including pediatric psychology, educational and school psychology, neuropsychology, behavioral medicine, and adult primary care, are uniquely positioned to contribute to every phase of this work, including research, identification, and intervention. (PsycINFO Database Record


Sexual Violence and Its Associated Psychosocial Effects in Ireland.
Current data on the prevalence and psychosocial correlates of sexual violence in the Republic of Ireland is lacking, with the most recent sexual abuse and violence survey dating back to 2001. The current study sought to identify what proportion of Irish adults have experienced sexual violence, if there are sex differences in exposure to different forms of sexual violence, and to what extent different forms of sexual violence are associated with adverse psychosocial outcomes. To achieve these objectives, we carried out a nationally representative sample of Irish adults (N = 1,020) completed self-report measures of history of sexual violence and mental health. Results suggest that approximately one-in-three (34.4%) Irish adults experienced some form of sexual violence, including 14.8% who were sexually assaulted (raped) and 31.1% who were sexually harassed. Women were significantly more likely than men to have experienced all forms of sexual violence (ps < .001), with the exception of sexual assault by a parent or guardian. All forms of sexual violence were associated with an increased likelihood of serious mental health problems, with sexual assault by a parent/guardian associated with several other psychosocial outcomes in life, including education achievement, history of being taken into state care, salary, and employment status. Sexual violence is a common experience in the general population and women are disproportionately affected (1-in-2 women versus 1-in-5 men). Additional resources to increase mental health care among survivors of sexual violence is urgently needed. How our findings compare to Ireland's previous sexual abuse and violence survey and the implications of our findings for policy are discussed.


Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D.
Cell surface proteins major histocompatibility complex (MHC) class I-related chain A (MICA) and UL16-binding proteins (ULBP) 1, 2, and 3 are up-regulated upon infection or tumor transformation and can activate human natural killer (NK) cells. Patches of cross-linked raft resident ganglioside GM1 colocalized with ULBP1, 2, 3, or MICA, but not CD45. Thus, ULBPs and MICA are expressed in lipid rafts at the cell surface. Western blotting revealed that glycosylphosphatidylinositol (GPI)-anchored ULBP3 but not transmembrane MICA, MHC class I protein, or transferrin receptor, accumulated in detergent-resistant membranes containing GM1. Thus, MICA may have a weaker association with lipid rafts than ULBP3, yet both proteins accumulate at an activating human NK cell immune synapse. Target cell lipid rafts marked by green fluorescent protein-tagged GPI also accumulate with ULBP3 at some synapses. Electron microscopy reveals constitutive clusters of ULBP at the cell surface. Regarding a specific molecular basis for the organization of these proteins, ULBP1, 2, and 3 and MICA are lipid modified. ULBP1, 2, and 3 are GPI anchored, and we demonstrate here that MICA is S-acylated. Finally, expression of a truncated form of MICA that lacks the putative site for S-acylation and the cytoplasmic tail can be expressed at the cell surface, but is unable to activate NK cells.


A Mail Audit Independent Peer Review System for Dosimetry Verification of a Small Animal Irradiator.
Dedicated precision orthovoltage small animal irradiators have become widely available in the past decade and are commonly used for radiation biology research. However, there is a lack of dosimetric standardization among these irradiators, which affects the reproducibility of radiation-based animal studies. The purpose of this study was to develop a mail-based, independent peer review system to verify dose delivery among institutions using X-RAD 225Cx irradiators (Precision X-Ray, North Branford, CT). A robust, user-friendly mouse phantom was constructed from high-impact polystyrene and designed with dimensions similar to those of a typical laboratory mouse. The phantom accommodates three thermoluminescent dosimeters (TLDs) to measure dose. The mouse peer review system was commissioned in a small animal irradiator using anterior-posterior and posterior-anterior beams of 225 kVp and then mailed to three institutions to test the feasibility of the audit service. The energy correction factor for TLDs in the mouse phantom was derived to validate the delivered dose using this particular animal irradiation system. This feasibility study indicated that three institutions were able to deliver a radiation dose to the mouse phantom within ±10% of the target dose. The developed mail audit independent peer review system for the verification of mouse dosimetry can be expanded to characterize other commercially available orthovoltage irradiators, thereby enhancing the reproducibility of studies employing these irradiators.


Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks' gestation.
Severe pre-eclampsia can cause significant mortality and morbidity for both mother and child, particularly when it occurs remote from term, between 24 and 34 weeks' gestation. The only known cure for this disease is delivery. Some obstetricians advocate early delivery to ensure that the development of serious maternal complications, such as eclampsia (fits) and kidney failure are prevented. Others prefer a more expectant approach delaying delivery in an attempt to reduce the mortality and morbidity for the child associated with being born too early. The objective of the review was to compare the effects of a policy of interventionist care and early delivery with a policy of expectant care and delayed delivery for women with early onset severe pre-eclampsia. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2013). Randomised trials comparing the two intervention strategies for women with early onset severe pre-eclampsia. Two review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. Data were checked for accuracy. Four trials, with a total of 425 women are included in this review. Trials were at low risk of bias for methods of randomisation and allocation concealment; high risk for blinding; unclear risk for incomplete outcome data and other bias; and low risk for selective reporting. There are insufficient data for reliable conclusions about the comparative effects on most outcomes for the mother. For the baby, there is insufficient evidence for reliable conclusions about the effects on stillbirth or death after delivery (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.69 to 1.71; four studies; 425 women). Babies whose mothers had been allocated to the interventionist group had more intraventricular haemorrhage (RR 1.82, 95% CI 1.06 to 3.14; one study; 262 women), more hyaline membrane disease (RR 2.30, 95% CI 1.39 to 3.81; two studies; 133 women), require more ventilation (RR 1.50, 95% CI 1.11 to 2.02; two studies; 300 women) and were more likely to have a lower gestation at birth in days (average mean difference (MD) -9.91, 95% CI -16.37 to -3.45; four studies; 425 women), more likely to be admitted to neonatal intensive care (RR 1.35, 95% CI 1.16 to 1.58) and have a longer stay in the neonatal intensive care unit (average MD 11.14 days, 95% CI 1.57 to 20.72 days; two studies; 125 women) than those allocated an expectant policy. Nevertheless, babies allocated to the interventionist policy were less likely to be small-for-gestational age (RR 0.30, 95% CI 0.14 to 0.65; two studies; 125 women). Women who had been allocated to the interventionist group were more likely to have a caesarean section (RR 1.09, 95% CI 1.01 to 1.18; four studies; 425 women) than those allocated an expectant policy. There were no statistically significant differences between the two strategies for any other outcomes. This review suggests that an expectant approach to the management of women with severe early onset pre-eclampsia may be associated with decreased morbidity for the baby. However, this evidence is based on data from only four trials. Further large trials are needed to confirm or refute these findings and establish if this approach is safe for the mother.


Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.


A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat.
The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations.


Lipid peroxidation: pathophysiological and pharmacological implications in the eye.
Oxygen-derived free radicals such as hydroxyl and hydroperoxyl species have been shown to oxidize phospholipids and other membrane lipid components leading to lipid peroxidation. In the eye, lipid peroxidation has been reported to play an important role in degenerative ocular diseases (age-related macular degeneration, cataract, glaucoma, diabetic retinopathy). Indeed, ocular tissues are prone to damage from reactive oxygen species due to stress from constant exposure of the eye to sunlight, atmospheric oxygen and environmental chemicals. Furthermore, free radical catalyzed peroxidation of long chain polyunsaturated acids (LCPUFAs) such as arachidonic acid and docosahexaenoic acid leads to generation of LCPUFA metabolites including isoprostanes and neuroprostanes that may further exert pharmacological/toxicological actions in ocular tissues. Evidence from literature supports the presence of endogenous defense mechanisms against reactive oxygen species in the eye, thereby presenting new avenues for the prevention and treatment of ocular degeneration. Hydrogen peroxide (H2O2) and synthetic peroxides can exert pharmacological and toxicological effects on tissues of the anterior uvea of several mammalian species. There is evidence suggesting that the retina, especially retinal ganglion cells can exhibit unique characteristics of antioxidant defense mechanisms. In the posterior segment of the eye, H2O2 and synthetic peroxides produce an inhibitory action on glutamate release (using [(3)H]-D-aspartate as a marker), in vitro and on the endogenous glutamate and glycine concentrations in vivo. In addition to peroxides, isoprostanes can elicit both excitatory and inhibitory effects on norepinephrine (NE) release from sympathetic nerves in isolated mammalian iris ciliary bodies. Whereas isoprostanes attenuate dopamine release from mammalian neural retina, in vitro, these novel arachidonic acid metabolites exhibit a biphasic regulatory effect on glutamate release from retina and can regulate amino acid neurotransmitter metabolism without inducing cell death in the retina. Furthermore, there appears to be an inhibitory role for neuroprostanes in the release of excitatory amino acid neurotransmitters in mammalian retina. The ability of peroxides and metabolites of LCPUFA to alter the integrity of neurotransmitter pools provides new potential target sites and pathways for the treatment of degenerative ocular diseases.


The kinetics of herpes virus on the ocular surface and suppression of its reactivation.
Herpes simplex virus type 1 (HSV-1) establishes a latent infection in sensory neurons that can sometimes be reactivated. HSV-1 keratitis often recurs and can be vision threatening. Reactivation of the latent virus can be stimulated by stress, immunosuppression, trauma, adrenergic iontophoresis, and UV radiation. Healthy and asymptomatic individuals are known to shed HSV-1, and this is a major factor in the spread of the virus. We investigated the frequency of shedding of HSV-1 DNA in tears of dry eye patients and individuals with conjunctivitis. Subjects were divided into 3 groups: normal (12 eyes), dry eye (11 eyes), and conjunctivitis (15 eyes). Quantitative real-time polymerase chain reaction was used for HSV DNA detection. The incidences of HSV positivity in the normal, dry eye, and conjunctivitis groups were 1 of 12 (8.3%), 3 of 11 (27.3%), and 4 of 15 (26.7%), respectively. We have previously shown that bromfenac sodium eye drops, intramuscular adenosine monophosphate, and geldanamycin effectively lower HSV-1 recurrence rates in a mouse model. Recently, we also found that nuclear factor κ-B, an IκB kinase-β inhibitor, could be a candidate for reducing HSV-1 reactivation. We sampled recipients' corneal buttons during keratoplasty and performed polymerase chain reaction. Cytomegalovirus (CMV) DNA was detected in corneas obtained from some patients, and the copy number of the detected CMV DNA was quantified. CMV DNA-positive samples were taken from 2 of the 3 patients with ocular pemphigoid; thus, in future work, the relationship between CMV in the cornea and the incidence/onset of ocular diseases of the anterior segment needs to be evaluated.


Dynamic Changes in Health-Promoting Properties and Eating Quality During Off-Vine Ripening of Tomatoes.
Tomato (Solanum lycopersicon L.) fruit is rich in various nutrients, vitamins and health-promoting molecules. Fresh tomatoes are an important part of the Mediterranean gastronomy, and their consumption is thought to contribute substantially to the reduced incidence of some chronic diseases in the Mediterranean populations in comparison with those of other world areas. Unfortunately, tomato fruit is highly perishable, resulting in important economic losses and posing a challenge to storage, logistic and supply management. This review summarizes the current knowledge on some important health-promoting and eating quality traits of tomato fruits after harvest and highlights the existence of substantial cultivar-to-cultivar variation in the postharvest evolution of the considered traits according to maturity stage at harvest and in response to postharvest manipulations. It also suggests the need for adapting postharvest procedures to the characteristics of each particular genotype to preserve the optimal quality of the fresh product.


Platinum nanoworms for imaging-guided combined cancer therapy in the second near-infrared window.
Cancer imaging and therapy in the second near-infrared (NIR II) window have gained increasing interest owing to the high light penetration depth and minimal optical scattering in the NIR II region (1000-1350 nm). Meanwhile, integrating multiple diagnostic and therapeutic functions into one simple nanoparticle system is of vital significance for cancer theranostics. Herein, we prepare worm-like platinum (Pt) nanoparticles (Pt nanoworms) in a facile way. The Pt nanoworms with surface modification show long blood circulation, high tumor accumulation, and negligible toxicity. With high optical absorption in the NIR II region and strong X-ray attenuation abilities, the Pt nanoworms serve as a good photoacoustic agent and CT contrast agent. Meanwhile, the tumor growth is completely inhibited by using mild photothermal therapy and radiotherapy due to the photothermally improved hypoxia and Pt increased X-ray absorption. Therefore, our work presents a biocompatible platinum nanoparticle system that is promising in image-guided tumor therapy.


Encapsulation in sub-micron species: a short review and alternate strategy for dye encapsulation.
The encapsulation of molecular species has received considerable attention in recent years. Polymers, dendrimers and microemulsions along with other systems have been used as precursors for the synthesis of encapsulating agents. Especially important in this field is the core-shell architecture. This structure offers the encapsulated species an extra level of protection due to the presence of a shell, covering the interior of a capsule. Dyes, porphyrines, drugs, cells and other active agents have been successfully encapsulated, and the host-guest interaction has been studied by various experimental techniques. A review is new provided of the progress made in this field in the last several years is presented. Different classes of synthetic approaches are presented and resulting encapsulation studies are summarised. An approach to the encapsulation of dansyl chloride dye in core-shell nanoparticles is also presented.


Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex.
The faithful duplication of genetic material depends on essential DNA replication initiation factors. Cellular initiators form higher-order assemblies on replication origins, using adenosine triphosphate (ATP) to locally remodel duplex DNA and facilitate proper loading of synthetic replisomal components. To better understand initiator function, we determined the 3.4 angstrom-resolution structure of an archaeal Cdc6/Orc1 heterodimer bound to origin DNA. The structure demonstrates that, in addition to conventional DNA binding elements, initiators use their AAA+ ATPase domains to recognize origin DNA. Together these interactions establish the polarity of initiator assembly on the origin and induce substantial distortions into origin DNA strands. Biochemical and comparative analyses indicate that AAA+/DNA contacts observed in the structure are dynamic and evolutionarily conserved, suggesting that the complex forms a core component of the basal initiation machinery.


Stillbirth: maternal and fetal evaluation.
Stillbirth occurs in approximately 1% of all pregnancies and, therefore, unfortunately, is an experience that most physicians caring for pregnant women will face in their professional careers. Because stillbirth is such an unpleasant and traumatic experience, a detailed evaluation is often deferred. The most common cause of stillbirth is believed to be chronic fetal hypoxia or asphyxia. However, this may not always be obvious initially. Therefore, the physician must be prepared to provide a complete evaluation. A protocol is provided to aid in that task. Obviously, not all the tests and studies described need to be performed in every case; a tailored evaluation, if possible, is always preferable.


Rare neuroendocrine tumours: results of the surveillance of rare cancers in Europe project.
Because of the low incidence, and limited opportunities for large patient volume experiences, there are very few relevant studies of neuroendocrine tumours (NETs). A large population-based database (including cancer patients diagnosed from 1978 to 2002 and registered in 76 population-based cancer registries [CRs]), provided by the project 'surveillance of rare cancers in Europe' (RARECARE) is used to describe the basic indicators of incidence, prevalence and survival of NETs, giving a unique overview on the burden of NETs in Europe. NETs at all cancer sites, excluding lung, were analysed in this study. In total over 20,000 incident cases of NETs were analysed and a data quality check upon specific NETs was performed. The overall incidence rate for NETs was 25/1,000,000 and was highest in patients aged 65 years and older with well differentiated endocrine carcinomas (non-functioning pancreatic and gastrointestinal) (40 per 1,000,000). We estimated that slightly more than 100,000 people were diagnosed with NETs and still alive in EU27 at the beginning of 2008. Overall, NETs had a 5 year relative survival of 50%; survival was low (12%) for poorly differentiated endocrine carcinoma, and relatively high (64%) for well differentiated carcinoma (not functioning of the pancreas and digestive organs). Within NETs, endocrine carcinoma of thyroid gland had the best 5-year relative survival (82%). Because of the complexity and number of the different disciplines involved with NETs (as they arise in many organs), a multidisciplinary approach delivered in highly qualified reference centres and an international network between those centres is recommended.


Profiling of the molecular weight and structural isomer abundance of macroalgae-derived phlorotannins.
Phlorotannins are a group of complex polymers of phloroglucinol (1,3,5-trihydroxybenzene) unique to macroalgae. These phenolic compounds are integral structural components of the cell wall in brown algae, but also play many secondary ecological roles such as protection from UV radiation and defense against grazing. This study employed Ultra Performance Liquid Chromatography (UPLC) with tandem mass spectrometry to investigate isomeric complexity and observed differences in phlorotannins derived from macroalgae harvested off the Irish coast (Fucus serratus, Fucus vesiculosus, Himanthalia elongata and Cystoseira nodicaulis). Antioxidant activity and total phenolic content assays were used as an index for producing phlorotannin fractions, enriched using molecular weight cut-off dialysis with subsequent flash chromatography to profile phlorotannin isomers in these macroalgae. These fractions were profiled using UPLC-MS with multiple reaction monitoring (MRM) and the level of isomerization for specific molecular weight phlorotannins between 3 and 16 monomers were determined. The majority of the low molecular weight (LMW) phlorotannins were found to have a molecular weight range equivalent to 4-12 monomers of phloroglucinol. The level of isomerization within the individual macroalgal species differed, resulting in substantially different numbers of phlorotannin isomers for particular molecular weights. F. vesiculosus had the highest number of isomers of 61 at one specific molecular mass, corresponding to 12 phloroglucinol units (PGUs). These results highlight the complex nature of these extracts and emphasize the challenges involved in structural elucidation of these compounds.


Twice weekly polymerase chain reaction (PCR) surveillance swabs are not as effective as daily antigen testing for containment of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) outbreaks: A modeling study based on real world data from a child and adolescent psychiatry clinic.
In the coronavirus disease 2019 (COVID-19) pandemic, child and adolescent psychiatry wards face the risk of severe acute respiratory coronavirus 2 (SARS-CoV-2) introduction and spread within the facility. In this setting, mask and vaccine mandates are hard to enforce, especially for younger children. Surveillance testing may detect infection early and enable mitigation measures to prevent viral spread. We conducted a modeling study to determine the optimal method and frequency of surveillance testing and to analyze the effect of weekly team meetings on transmission dynamics. Simulation with an agent-based model reflecting ward structure, work processes, and contact networks from a real-world child and adolescent psychiatry clinic with 4 wards, 40 patients, and 72 healthcare workers. We simulated the spread of 2 SARS-CoV-2 variants over 60 days under surveillance testing with polymerase chain reaction (PCR) tests and rapid antigen tests in different scenarios. We measured the size, peak, and the duration of an outbreak. We compared medians and percentage of spillover events to other wards from 1,000 simulations for each setting. The outbreak size, peak, and duration were dependent on test frequency, test type, SARS-CoV-2 variant, and ward connectivity. Under surveillance conditions, joint staff meetings and therapists shared between wards did not significantly change median outbreak size under surveillance conditions. With daily antigen testing, outbreaks were mostly confined to 1 ward and median outbreak sizes were lower than with twice-weekly PCR testing (1 vs 22; P < .001). Modeling can help to understand transmission patterns and guide local infection control measures.


Aleukemic leukemia cutis preceding acute monocytic leukemia: a case report.
Aleukemic leukemia cutis is an extremely rare clinical presentation in patients who eventually develop acute leukemia, usually of monocytic lineage. This condition is associated with a very poor prognosis and is often difficult to diagnose. We report a case of a 33 years old female with leukemia cutis preceding the onset of acute monocytic leukemia by four months. The patient received induction and consolidation chemotherapy followed by allogeneic bone marrow transplant and has been free of disease for six years. To our knowledge, this is the first documented case in Puerto Rico with the diagnosis of leukemia cutis preceding acute monocytic leukemia.


Accessory role of human peritoneal mesothelial cells in antigen presentation and T-cell growth.
To assess the role of human peritoneal mesothelial cells (HPMCs) in the generation of an immune response during peritonitis, we tested their ability to activate T-cells by antigen presentation (AP) and by the secretion of interleukin-15 (IL-15). IL-15 is a potent leukocyte activator that stimulates the proliferation of CD4+, CD8+, and B and natural killer (NK) cells. HPMCs and mononuclear cells were derived from six volunteer patients who underwent elective abdominal surgery. Flow cytometry was used to analyze human lymphocyte antigen-DR (HLA-DR), intercellular adhesion molecule-1 (ICAM-1), and B7 molecules on HPMCs. Affinity-purified CD4 cells were used for AP assays. We used a specific enzyme-linked immunosorbent assay to detect interferon-gamma (IFN-gamma), IL-2, and IL-15 protein and reverse transcription-polymerase chain reaction for mRNA analysis. HPMCs expressed HLA-DR molecules following IFN-gamma treatment. ICAM-1 molecules were expressed at high levels, and B7-1 and B7-2 molecules could not be detected. The accessory function of HPMCs was assayed by T-cell stimulation using anti-CD3 antibodies (OKT3). HPMCs were essential for a significant OKT3-induced T-cell proliferation. Anti-ICAM-1 antibodies blocked OKT3-induced proliferation. HPMCs served as effective antigen-presenting cells when Tetanus toxoid (TT) or Staphylococcus aureus-alpha-toxin were used as antigens. IFN-gamma, IL-2, and IL-15 accumulated during AP reactions. We found that IL-15 is produced by HPMCs, and IFN-gamma up-regulated its mRNA levels and protein secretion in a dose-dependent manner. We also detected IL-15 in the peritoneal effluent of patients undergoing continuous peritoneal dialysis treatment. In patients suffering from peritonitis, IL-15 levels were elevated (35.0 +/- 6.0 pg/mL, N = 10) as compared with noninfected patients (16.2 +/- 4.0 pg/mL, N = 7). HPMCs participate in the peritoneal immune response against invading pathogens by AP. For this process, ICAM-1 is the major accessory molecule. In addition, HPMCs may contribute to T-cell activation by secretion of IL-15.


Evaluating impact of a multi-dimensional education programme on perceived performance of primary care professionals in diabetes care.
The purpose of this study is to evaluate an educational programme, 'Diabetes Connect: Connecting Professions', which was developed to enhance communication across primary care networks, to support best practice in clinical interventions and progress multidisciplinary team work to benefit patients in diabetes care. A total of 26 workshops were successfully delivered for 309 primary care professionals across the state of Queensland in Australia from November 2011. It consists of two separate, but complementary training elements: a series of online clinical education training modules and state-wide interprofessional learning workshops developed to enhance professional competencies. The evaluation design included completion of online surveys by the participants at two time points: first upon registering for the online modules or workshops; second, one week after attending a workshop. The survey included questions to evaluate the change in role performance measures. Overall, significant increases in participants' current knowledge, perceived ability to adopt this knowledge at work and willingness to change professional behaviour in the short term were observed. The study suggests that for maximum benefit both, workshop and online training, should be combined and made available widely. Future programmes should use a randomised trial design to test the delivery model.


Role of genetics in osteoporosis.
Osteoporosis is a disease characterized by fragile bones and high susceptibility to low-trauma fractures. It is a serious health problem, especially in elderly women. Bone mineral density (BMD) has been employed most commonly as the index for defining and studying osteoporosis. BMD has high genetic determination, with heritability ranging from 50 to 90%. Various gene-mapping approaches have been applied to identify specific genes underlying osteoporosis, largely using BMD as the study phenotype. We review here the genetic determination of osteoporosis as defined by BMD and discuss a fundamental issue we encounter in genetic research in osteoporosis: the choice of phenotype(s) to study. We briefly summarize and discuss advantages and disadvantages of various approaches used in genetic studies of osteoporosis. Finally, we review and discuss the current status for mapping and identification of genes for osteoporosis. We focus on linkage studies in humans and quantitative trait loci mapping in mice to supplement the already extensive reviews of association studies made by many investigators for candidate genes.


Arrangement of coding and intervening sequences of chicken lysozyme gene.
Hybrid phages that contain chicken lysozyme gene sequences have been isolated from a chicken DNA library. Two overlapping clones covering a region of 22 kilobase pairs around this gene have been studied by restriction mapping. Southern hybridization, and electron microscopic analysis of hybrids between lysozyme mRNA and the cloned cellular DNA. Three intervening sequences interrupt the lysozyme structural gene. The cellular gene is at least 3.9 kilobases long, about 6 times the length of the structural gene.


Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA.
The ubiquitously expressed latent interferon regulatory factor (IRF) 3 transcription factor is activated in response to virus infection by phosphorylation events that target a cluster of Ser/Thr residues, (382)GGASSLENTVDLHISNSHPLSLTSDQY(408) at the C-terminal end of the protein. To delineate the minimal phosphoacceptor sites required for IRF-3 activation, several point mutations were generated and tested for transactivation potential and cAMP-response element-binding protein-binding protein/p300 coactivator association. Expression of the IRF-3 S396D mutant alone was sufficient to induce type I IFN beta, IFNalpha1, RANTES, and the interferon-stimulated gene 561 promoters. Using SDS-PAGE and immunoblotting with a novel phosphospecific antibody, we show for the first time that, in vivo, IRF-3 is phosphorylated on Ser(396) following Sendai virus infection, expression of viral nucleocapsid, and double-stranded RNA treatment. These results demonstrate that Ser(396) within the C-terminal Ser/Thr cluster is targeted in vivo for phosphorylation following virus infection and plays an essential role in IRF-3 activation. The inability of the phosphospecific antibody to detect Ser(396) phosphorylation in lipopolysaccharide-treated cells suggests that other major pathways may be involved in IRF-3 activation following Toll-like receptor 4 stimulation.


Bioinformatic tools for inferring functional information from plant microarray data: tools for the first steps.
Microarrays are a very powerful tool for quantifying the amount of RNA in samples; however, their ability to query essentially every gene in a genome, which can number in the tens of thousands, presents analytical and interpretative problems. As a result, a variety of software and web-based tools have been developed to help with these issues. This article highlights and reviews some of the tools for the first steps in the analysis of a microarray study. We have tried for a balance between free and commercial systems. We have organized the tools by topics including image processing tools (Section 2), power analysis tools (Section 3), image analysis tools (Section 4), database tools (Section 5), databases of functional information (Section 6), annotation tools (Section 7), statistical and data mining tools (Section 8), and dissemination tools (Section 9).


Yb3+ sensitized Er3+ doped La2O3 phosphor in temperature sensors and display devices.
The frequency upconversion emissions in the Er(3+)/Er(3+)-Yb(3+) doped/codoped hexagonal shaped La2O3 phosphor characterized by X-ray diffraction (XRD) upon excitation with 980 nm and 800 nm CW lasers have been investigated. The upconversion emissions corresponding to the (2)H(9/2) → (4)I(15/2), (2)H(11/2) → (4)I(15/2), (4)S(3/2) → (4)I(15/2) and (4)F(9/2) → (4)I(15/2) transitions peaking at 409 nm, 523 nm, 548 nm and 660 nm have been observed under 980 nm excitation whereas 523 nm, 548 nm and 660 nm upconversion emission bands have been visualized under 808 nm excitation. The upconversion emission intensity of Er(3+) ions is enhanced by several times due to the codoping with Yb(3+) ions, under 980 nm excitation while there is a reduction in intensity in the codoped sample under 808 nm excitation. The decay curve analysis for the green UC emission band corresponding to the (4)S(3/2) → (4)I(15/2) transition in the Er(3+)/Er(3+)-Yb(3+) doped/codoped La2O3 phosphor upon 980 nm excitation has been done. The colour coordinate of the phosphor sample has been calculated at different pump powers and its value is observed to be almost similar to that of the standard green colour and also independent of the excitation power density. The effect of temperature on the upconversion emission intensity of the green emissions has been determined and noted that the present phosphor material can be used in making temperature sensing device upto 600 K.


Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement.
Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chigh monocytes infiltrate the nerve first and rapidly give way to Ly6Cnegative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages 'eat' apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF-deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion-induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion-induced neurorepair.


ACCase mutations in Avena sterilis populations and their impact on plant fitness.
Avena sterilis (sterile oat) populations originating from wheat-growing regions of Greece, developed resistance to fenoxaprop, clodinafop and other herbicides. The partial ACCase gene sequence revealed six point mutations (Ile-1781-Leu, Trp-1999-Cys, Trp-2027-Cys, Ile-2041-Asn, Asp-2078-Gly, and Cys-2088-Arg) in 24 out of the 26 resistant (R) populations, confirming the molecular mechanism of resistance to ACCase-inhibiting herbicides. However, DNA sequence of two R populations did not reveal any known ACCase mutations, suggesting possible presence of unknown mutation or metabolism-based mechanism of resistance. The Cys-2088-Arg mutation is the first record for ACCase mutant conferring target-site resistance in A. sterilis worldwide. The evaluation of 12 R and 6 susceptible (S) populations under non-competitive field conditions did not indicate consistent mean growth rate differences, whereas the pot evaluation of the same (12 R and 6 S) populations grown in competition with wheat or in pure stands showed significant growth (fresh weight and panicle number) differences between six S populations and between six R populations containing the same ACCase mutation (Ile-2041-Asn). Finally, one S and five R (Trp-1999-Cys, Trp-2027-Cys, Ile-2041-Asn, Asp-2078-Gly, and Cys-2088-Arg) populations grown under field competitive conditions indicated fresh weight and panicle number differences in competition with other populations as compared with pure stands. These findings suggest clearly that the inconsistent fitness differences between R and S A. sterilis populations are not related with the ACCase resistance trait but they may result from other non-resistance fitness traits selected in their different geographical locations.


Manometric tests of anorectal function in healthy adults.
Although tests of anorectal function are useful in the assessment of defecation disorders, there is inadequate and inconsistent information regarding normative data. Also, there are discrepancies in manometric techniques and data interpretation. Our aim was to perform a comprehensive evaluation of anorectal function in healthy adults. We used a 6-mm diameter probe containing six radially arrayed microtransducers, and a 4-cm-long latex balloon for performing anorectal manometry in 45 healthy subjects who were controlled for gender and age. Sequentially, subjects were asked to squeeze, bear down, or blow up a party balloon. Subsequently, rectal sensation, rectal compliance, and rectoanal reflexes were assessed simultaneously by performing intermittent phasic balloon distentions. Additionally, balloon defecation, pudendal nerve latency, and saline continence tests were performed. In men, the anal sphincter was longer (p < 0.05) and squeeze sphincter pressure and squeeze duration were higher (p < 0.01), but resting sphincter pressure was similar to that in women. When bearing down, although not significant, the defecation index was higher in men. Distinct thresholds for rectal sensation were identified but there was no gender difference. Likewise, rectal compliance and balloon expulsion time were similar. However, during saline infusion, the onset of first leak and total volume retained were higher (p < 0.001) and pudendal nerve latency was shorter (p < 0.05) in men. Overall, parity or age did not influence anorectal function. This study represents the most comprehensive age- and gender-controlled assessment of anorectal function using solid state technology. Gender influences some parameters of anorectal function. Our results could serve as a valuable resource of normative data.


Chromosomal insertion of phenazine-1-carboxylic acid biosynthetic pathway enhances efficacy of damping-off disease control by Pseudomonas fluorescens.
A disarmed Tn5 vector (pUT::Ptac-phzABCDEFG) was used to introduce a single copy of the genes responsible for phenazine-1-carboxylic acid (PCA) biosynthesis into the chromosome of a plant-growth-promoting rhizobacterium Pseudomonas fluorescens. The PCA gene cluster was modified for expression under a constitutive Ptac promoter and lacked the phzIR regulators. PCA-producing variants significantly improved the ability of the wild-type P. fluorescens to reduce damping-off disease of pea seedlings caused by Pythium ultimum, even under conditions of heavy soil infestation. Under conditions of oxygen limitation that are typical of the rhizosphere, PCA production per cell in vitro was greater than that recorded in fast-growing, nutrient-rich cultures. Similarly, when the in vitro nutrient supply was limited, P fluorescens::phz variants that produced the most PCA effectively competed against P. ultimum by suppressing mycelial development. Soil-based bioassays confirmed that the level of PCA biosynthesis correlated directly with the efficacy of biological control and the persistence of inocula in soil microcosms. They also showed that soil pretreatment with bacteria provides a suitable method for plant protection by reducing infection, effectively decontaminating the soil. These data demonstrate that the insertion of a single chromosomal copy of the genes for a novel antifungal compound, PCA, enhances the ecological fitness of a natural isolate already adapted to the rhizosphere and capable of suppressing fungal disease.


Screening for Harassment, Abuse, and Discrimination among Surgery Residents: An EAST Multicenter Trial.
Estimating the prevalence of harassment, verbal abuse, and discrimination among residents is difficult as events are often under-reported. The purpose of this study was to determine the prevalence of discrimination and abuse among surgical residents using the HITS (Hurt, Insulted, Threatened with harm or Screamed at) screening tool. A multicenter, cross-sectional, survey-based study was conducted at five academic teaching hospitals. Of 310 residents, 76 (24.5%) completed the survey. The HITS screening tool was positive in 3.9 per cent. The most common forms of abuse included sexual harassment (28.9%), discrimination based on gender (15.7%), and discrimination based on ethnicity (7.9%). There was a positive correlation between individuals who reported gender discrimination and racial discrimination (r = 0.778, n = 13, P = 0.002). Individuals who experienced insults were more likely to experience physical threats (r = 0.437, n = 79, P < 0.001) or verbal abuse (r = 0.690, n = 79, P < 0.001). Discrimination and harassment among surgical residents in academic teaching hospitals across the United States is not uncommon. Further research is needed to determine the impact of these findings on resident attrition.


Functional adaptations of the transcriptome to mastitis-causing pathogens: the mammary gland and beyond.
Application of microarrays to the study of intramammary infections in recent years has provided a wealth of fundamental information on the transcriptomics adaptation of tissue/cells to the disease. Due to its heavy toll on productivity and health of the animal, in vivo and in vitro transcriptomics works involving different mastitis-causing pathogens have been conducted on the mammary gland, primarily on livestock species such as cow and sheep, with few studies in non-ruminants. However, the response to an infectious challenge originating in the mammary gland elicits systemic responses in the animal and encompasses tissues such as liver and immune cells in the circulation, with also potential effects on other tissues such as adipose. The susceptibility of the animal to develop mastitis likely is affected by factors beyond the mammary gland, e.g. negative energy balance as it occurs around parturition. Objectives of this review are to discuss the use of systems biology concepts for the holistic study of animal responses to intramammary infection; providing an update of recent work using transcriptomics to study mammary and peripheral tissue (i.e. liver) as well as neutrophils and macrophage responses to mastitis-causing pathogens; discuss the effect of negative energy balance on mastitis predisposition; and analyze the bovine and murine mammary innate-immune responses during lactation and involution using a novel functional analysis approach to uncover potential predisposing factors to mastitis throughout an animal's productive life.


Blood pressure and intra-erythrocyte sodium during normal and high salt intake in middle-aged men: relationship to family history of hypertension, and neurogenic and hormonal variables.
During 4 weeks 37 normotensive 50-year-old men identified by screening in a random population sample were given 12 g of NaCl daily, in addition to their usual dietary sodium intake. Blood pressure, heart rate, weight, urinary excretion of sodium, potassium and catecholamines, plasma aldosterone and noradrenaline and intra-erythrocyte sodium content were determined on normal and increased salt intake. The subjects were divided into those with a positive family history of hypertension (n = 11) and those without such a history (n = 26). Systolic blood pressure and weight increased significantly irrespective of a positive family history of hypertension. On normal salt intake intra-erythrocyte sodium content was significantly higher in those with a positive family history of hypertension. During high salt intake intra-erythrocyte sodium content decreased significantly in that group and the difference between the hereditary subgroups was no longer significant. In the whole group urinary excretion of noradrenaline, adrenaline and dopamine increased whereas plasma aldosterone decreased during the increased salt intake. Thus, in contrast to some earlier studies performed in young subjects, our results indicate that moderately increased sodium intake acts as a pressor agent in normotensive middle-aged men whether there was a positive family history of hypertension or not. We confirm that men with positive family history of hypertension have an increased intra-erythrocyte sodium content, and that an increase in salt intake seems to increase overall sympathetic activity.


Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit.
Heparin biocompatible coating frequently is used to reduce inflammation and blood coagulation during cardiopulmonary bypass (CPB) in cardiac surgery. Whether heparin coating is protective or damaging to the vascular endothelium is unclear. The authors investigated whether heparin-coated (HC) circuits are associated with better preservation of microcirculatory perfusion and glycocalyx dimensions compared with nonheparin phosphorylcholine-coated (PC) circuits. Prospective, randomized blinded study. Tertiary university hospital. A total of 26 adults undergoing elective coronary artery bypass graft surgery with CPB. PC (n = 13) versus HC circuits (n = 13). Sublingual microcirculatory perfusion was measured before, during, and after CPB using sidestream dark field imaging and analyzed for perfused vessel density and perfused boundary region, an inverse parameter for glycocalyx dimensions. Onset of CPB was associated with an increase in perfused boundary region in the PC group that continued until the third postoperative day (2.0 ± 0.2 to 2.5 ± 0.2 µm; p = 0.018). This was paralleled by increased plasma syndecan-1 levels in the PC group. Contrastingly, both parameters remained unaltered in the HC group compared with baseline levels. CPB decreased perfused vessel density in both groups (CPB v pre-CPB: PC: 17 ± 2 to 13 ± 2 mm/mm2, p = 0.006; HC: 16 ± 2 to 11 ± 2 mm/mm2, p = 0.003) and remained equally altered in the first 3 postoperative days. The use of an HC circuit is associated with better preservation of the endothelial glycocalyx compared with PC circuits, whereas microcirculatory perfusion was disturbed equally in both groups. Hence, CPB-induced microcirculatory perfusion disturbances seem to be coating independent.


Radiofrequency catheter ablation of supraventricular tachycardias in pediatric patients.
Supraventricular tachycardia (SVT) is the most common cardiac arrhythmia in children. Atrioventricular (AV) reciprocating tachycardia utilizing an accessory pathway and AV nodal reentrant tachycardia (AVNRT) constitute a majority of SVTs. Radiofrequency energy ablation has recently become the treatment of choice in adults. Initial experience in pediatric patients in this Institute is reported in this study. Six consecutive patients (aged 5-22 years, mean age 13 years; 3 boys, 3 girls) with narrow-QRS SVT were studied from July to October in 1993. They had experienced symptomatic SVT for a mean period of five years (ranged from 1 to 15 years). Anti-arrhythmic agents, including beta-antagonists and calcium channel blockers, were unable to satisfactorily suppress these SVTs. Four of the six patients were shown to have a left-sided concealed accessory connection as the retrograde limb of the reentrant circuit. After identification of the earliest retrograde activation site, a steerable 7F catheter with a 4-mm-long electrode at the distal tip was placed within the left ventricle and positioned against the atrio-ventricular annulus. Another two patients were proved to have AVNRT. The ablation catheter was placed at the posterior/inferior aspect of the tricuspid annulus and guided by putative slow potential. Radiofrequency current was delivered at a power from 15 to 25W for four to six times with a mean duration of 40 seconds in patients with AV reciprocating tachycardia, and a single time in those with AVNRT. All six SVTs were successfully ablated. No complication was noted in any patient. Follow-up for three to seven months has indicated no recurrence of SVT.(ABSTRACT TRUNCATED AT 250 WORDS)


Emerging therapeutic potential of the iridoid molecule, asperuloside: A snapshot of its underlying molecular mechanisms.
Over the years, the attention of researchers in the field of modern drug discovery and development has become further intense on the identification of active compounds from plant sources and traditional remedies, as they exhibit higher therapeutic efficacies and improved toxicological profiles. Among the large diversity of plant extracts that have been discovered and explored for their potential therapeutic benefits, asperuloside, an iridoid glycoside, has been proven to provide promising effects as a therapeutic agent for several diseases. Although, this potent substance exists in several genera, it is primarily found in plants belonging to the genus Eucommia. Recent decades have seen a surge in the research on Asperuloside, making it one of the most studied natural products in the field of medicine and pharmacology. In this review, we have attempted to study the various reported mechanisms of asperuloside that form the basis of its wide spectrum of pharmacological activities.


Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review.
Induction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB. We performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled. Eight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin. Although the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.


Abdominal and pelvic adipose tissue distribution and risk of prostate cancer recurrence after radiation therapy.
Fat distribution varies between individuals of similar body mass index (BMI). We hypothesized that visceral obesity is more strongly associated with poor prostate cancer outcomes than overall obesity defined by BMI. We quantified abdominal visceral and subcutaneous fat area (VFA and SFA), and pelvic periprostatic adipose tissue area (PPAT), using computed tomography scans from radiation-treated prostate cancer patients at the Durham North Carolina Veterans Administration Hospital. Multivariable-adjusted Cox regression examined associations between each adiposity measure and risk of recurrence, overall and stratified by race and receipt of androgen deprivation therapy (ADT). Of 401 patients (59% black) treated from 2005 to 2011, 84 (21%) experienced recurrence during 9.3 years median follow-up. Overall, obesity defined by BMI was not associated with recurrence risk overall or stratified by race or ADT, nor was any measure of fat distribution related to the risk of recurrence overall or by race. However, higher VFA was associated with increased risk of recurrence in men who received radiation only (hazard ratio [HR], 1.79; 95% confidence interval [CI], 0.87-3.66), but inversely associated with recurrence risk in men treated with radiation and ADT (HR, 0.49; 95% CI, 0.24-1.03; P-interaction = .002), though neither association reached statistical significance. Similar patterns of ADT-stratified associations were observed for PPAT and SFA. Associations between abdominal and pelvic adiposity measures and recurrence risk differed significantly by ADT receipt, with positive directions of association observed only in men not receiving ADT. If confirmed, our findings suggest that obesity may have varying effects on prostate cancer progression risk dependent on the hormonal state of the individual.


Cytogenetics and fluorescence in situ hybridization assessment of sex-chromosome mosaicism in Klinefelter's syndrome.
A retrospective study was carried out in 152 infertile men to determine the prevalence of sex chromosome abnormalities among non-obstructive azoospermic and severe oligospermic men (n = 51) and to evaluate the feasibility of fluorescence in situ hybridization (FISH) techniques to assess mosaicism in Klinefelter's patients in comparison with conventional cytogenetics. Cytogenetic analysis were performed for 51 infertile men and among 14 chromosomal abnormalities found, nine were compatible with Klinefelter's syndrome. FISH staining with a CEP X/CEP Y probes were performed for Klinefelter's patients and for five of them; testes were biopsied for histopathologic examination. Six Klinefelter's patients showed a non-mosaic 47,XXY and three showed a 47,XXY/46,XY mosaic by G or R banding analysis of 20 cells with a ratio of 17%, 20% and 33%, respectively. FISH analysis confirmed mosaicism in only one patient (the first) in whom a third cells population was found. There was no relationship between the ratios of mosaicism by banding and FISH analysis. Conventional histopathologic findings in five non-mosaic Klinefelter's patients confirm the diagnosis of Sertoli Only Cells syndrome. FISH is recommended in Klinefelter's syndrome to define exactly the cytogenetic statute as mosaic or non-mosaic and then discussing prognosis and decision regarding fertility counseling.