Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia?
Our objective was to determine whether measurement of placenta growth factor (PLGF), inhibin A, or soluble fms-like tyrosine kinase-1 (sFlt-1) at 2 times during pregnancy would usefully predict subsequent preeclampsia (PE) in women at high risk. We analyzed serum obtained at enrollment (12(0/7) to 19(6/7) weeks) and follow-up (24-28 weeks) from 704 patients with previous PE and/or chronic hypertension (CHTN) enrolled in a randomized trial for the prevention of PE. Logistic regression analysis assessed the association of log-transformed markers with subsequent PE; receiver operating characteristic analysis assessed predictive value. One hundred four developed preeclampsia: 27 at 37 weeks or longer and 77 at less than 37 weeks (9 at less than 27 weeks). None of the markers was associated with PE at 37 weeks or longer. Significant associations were observed between PE at less than 37 weeks and reduced PLGF levels at baseline (P = .022) and follow-up (P < .0001) and elevated inhibin A (P < .0001) and sFlt-1 (P = .0002) levels at follow-up; at 75% specificity, sensitivities ranged from 38% to 52%. Using changes in markers from baseline to follow-up, sensitivities were 52-55%. Associations were observed between baseline markers and PE less than 27 weeks (P < or = .0004 for all); sensitivities were 67-89%, but positive predictive values (PPVs) were only 3.4-4.5%. Inhibin A and circulating angiogenic factors levels obtained at 12(0/7) to 19(6/7) weeks have significant associations with onset of PE at less than 27 weeks, as do levels obtained at 24-28 weeks with onset of PE at less than 37 weeks. However, because the corresponding sensitivities and/or PPVs were low, these markers might not be clinically useful to predict PE in women with previous PE and/or CHTN.


Recent trends in maternal, newborn, and child health in Brazil: progress toward Millennium Development Goals 4 and 5.
We analyzed Brazil's efforts in reducing child mortality, improving maternal and child health, and reducing socioeconomic and regional inequalities from 1990 through 2007. We compiled and reanalyzed data from several sources, including vital statistics and population-based surveys. We also explored the roles of broad socioeconomic and demographic changes and the introduction of health sector and other reform measures in explaining the improvements observed. Our findings provide compelling evidence that proactive measures to reduce health disparities accompanied by socioeconomic progress can result in measurable improvements in the health of children and mothers in a relatively short interval. Our analysis of Brazil's successes and remaining challenges to reach and surpass Millennium Development Goals 4 and 5 can provide important lessons for other low- and middle-income countries.


[Possibilities of magnetotherapy in stabilization of visual function in patients with glaucoma].
Courses of magnetotherapy (MT) using ATOS device with 33 mT magnetic field induction were administered to 31 patients (43 eyes) with primary open-angle glaucoma with compensated intraocular pressure. The operation mode was intermittent, with 1.0 to 1.5 Hz field rotation frequency by 6 radii. The procedure is administered to a patient in a sitting posture with magnetic inductor held before the eye. The duration of a session is 10 min, a course consists of 10 sessions. Untreated eyes (n = 15) of the same patients were examined for control. The patients were examined before and 4 to 5 months after MT course. Vision acuity improved by 0.16 diopters, on an average, in 29 eyes (96.7%) out of 30 with vision acuity below 1.0 before treatment. Visocontrastometry was carried out using Visokontrastometer-DT device with spatial frequency range from 0.4 to 19 cycle/degree (12 frequencies) and 125 x 125 monitor. The orientation of lattices was horizontal and vertical. The contrasts ranged from 0.03 to 0.9 (12 levels). MT brought about an improvement of spatial contrast sensitivity by at least 7 values of 12 levels in 22 (84.6%) out of 26 eyes and was unchanged in 4 eyes. Visual field was examined using Humphry automated analyzer. A 120-point threshold test was used. After a course of MT, visual field deficit decreased by at least 10% in 31 (72%) out of 43 eyes, increased in 3, and was unchanged in 9 eyes; on an average, visual field deficit decreased by 22.4% vs. the initial value. After 4 to 5 months the changes in the vision acuity and visual field deficit were negligible. In controls these parameters did not appreciably change over the entire follow-up period.


Heart failure after myocardial infarction in the era of primary percutaneous coronary intervention: Mechanisms, incidence and identification of patients at risk.
Myocardial infarction (MI) remains the most common cause of heart failure (HF) worldwide. For almost 50 years HF has been recognised as a determinant of adverse prognosis after MI, but efforts to promote myocardial repair have failed to translate into clinical therapies. Primary percutaneous coronary intervention (PPCI) has driven improved early survival after MI, but its impact on the incidence of downstream HF is debated. The effects of PPCI are confounded by the changing epidemiology of MI and HF, with an ageing patient demographic, an increasing proportion of non-ST-elevation myocardial infarction, and the recognition of HF with preserved ejection fraction. Herein we review the mechanisms of HF after MI and discuss contemporary data on its incidence and outcomes. We review current and emerging strategies for early detection of patients at risk of HF after MI, with a view to identification of patient cohorts for novel therapeutic agents.


Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease.
This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer's disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.


Fast optical source for quantum key distribution based on semiconductor optical amplifiers.
A novel integrated optical source capable of emitting faint pulses with different polarization states and with different intensity levels at 100 MHz has been developed. The source relies on a single laser diode followed by four semiconductor optical amplifiers and thin film polarizers, connected through a fiber network. The use of a single laser ensures high level of indistinguishability in time and spectrum of the pulses for the four different polarizations and three different levels of intensity. The applicability of the source is demonstrated in the lab through a free space quantum key distribution experiment which makes use of the decoy state BB84 protocol. We achieved a lower bound secure key rate of the order of 3.64 Mbps and a quantum bit error ratio as low as 1.14×10⁻² while the lower bound secure key rate became 187 bps for an equivalent attenuation of 35 dB. To our knowledge, this is the fastest polarization encoded QKD system which has been reported so far. The performance, reduced size, low power consumption and the fact that the components used can be space qualified make the source particularly suitable for secure satellite communication.


The 2011 magnitude 9.0 Tohoku-Oki earthquake: mosaicking the megathrust from seconds to centuries.
Geophysical observations from the 2011 moment magnitude (M(w)) 9.0 Tohoku-Oki, Japan earthquake allow exploration of a rare large event along a subduction megathrust. Models for this event indicate that the distribution of coseismic fault slip exceeded 50 meters in places. Sources of high-frequency seismic waves delineate the edges of the deepest portions of coseismic slip and do not simply correlate with the locations of peak slip. Relative to the M(w) 8.8 2010 Maule, Chile earthquake, the Tohoku-Oki earthquake was deficient in high-frequency seismic radiation--a difference that we attribute to its relatively shallow depth. Estimates of total fault slip and surface secular strain accumulation on millennial time scales suggest the need to consider the potential for a future large earthquake just south of this event.


Melatonin and melatonin agonists to prevent and treat delirium in critical illness: a systematic review protocol.
Delirium is a syndrome characterized by acute fluctuations and alterations in attention and arousal. Critically ill patients are at particularly high risk, and those that develop delirium are more likely to experience poor clinical outcomes such as prolonged duration of ICU and hospital length of stay, and increased mortality. Melatonin and melatonin agonists (MMA) have the potential to decrease the incidence and severity of delirium through their hypnotic and sedative-sparing effects, thus improving health-related outcomes. The objective of this review is to synthesize the available evidence pertaining to the efficacy and safety of MMA for the prevention and treatment of ICU delirium. We will search Ovid MEDLINE, Web of Science, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL to identify studies evaluating MMA in critically ill populations. We will also search http://apps.who.int/trialsearch for ongoing and unpublished studies and PROSPERO for registered reviews. We will not impose restrictions on language, date, or journal of publication. Authors will independently screen for eligible studies using pre-defined criteria; data extraction from eligible studies will be performed in duplicate. The Cochrane Risk of Bias Scale and the Newcastle-Ottawa Scale will be used to assess the risk of bias and quality of randomized and non-randomized studies, respectively. Our primary outcome of interest is delirium incidence, and secondary outcomes include duration of delirium, number of delirium- and coma-free days, use of physical and chemical (e.g., antipsychotics or benzodiazepines) restraints, duration of mechanical ventilation, ICU and hospital length of stay, mortality, long-term neurocognitive outcomes, hospital discharge disposition, and adverse events. We will use Review Manager (RevMan) to pool effect estimates from included studies. We will present results as relative risks with 95% confidence intervals for dichotomous outcomes and as mean differences, or standardized mean differences, for continuous outcomes. Current guidelines make no pharmacological recommendations for either the prevention or treatment of ICU delirium. This systematic review will synthesize the available evidence on the efficacy and safety of MMA for this purpose, thus potentially informing clinical decision-making and improving patient outcomes. PROSPERO CRD42015024713.


A novel mouse model of in situ stenting.
Animal models of stenting are mostly limited to larger animals or involve substantial abdominal surgery in rodents. We aimed to develop a simple, direct model of murine stenting. We designed a miniature, self-expanding, nitinol wire coil stent that was pre-loaded into a metal stent sheath. This was advanced into the abdominal aorta of the mouse, via femoral access, and the stent deployed. In-stent restenosis was investigated at 1, 3, 7, and 28 days post-stenting. The model was validated by investigation of neointima formation in mice deficient in signalling via the interleukin-1 receptor (IL-1R1), compared with other injury models. Ninety-two per cent of mice undergoing the procedure were successfully stented. All stented vessels were patent. Inflammatory cells were seen in the adventitia and around the stent strut up to 3 days post-stenting. At 3 days, an early neointima was present, building to a mature neointima at 28 days. In mice lacking IL-1R1, the neointima was 64% smaller than that in wild-type controls at the 28-day timepoint, in agreement with other models. This is the first description of a successful model of murine in situ stenting, using a stent specifically tailored for use in small thin-walled arteries. The procedure can be undertaken by a single operator without the need for an advanced level of microsurgical skill and is reliable and reproducible. The utility of this model is demonstrated by a reduction in in-stent restenosis in IL-1R1-deficient mice.


Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence.
Cocaine stimuli often trigger relapse of drug-taking, even following periods of prolonged abstinence. Here, electrophysiological recordings were made in rats (n = 29) to determine how neurons in the prelimbic (PrL) or infralimbic (IL) regions of the medial prefrontal cortex (mPFC) encode cocaine-associated stimuli and cocaine-seeking, and whether this processing is differentially altered after 1 month of cocaine abstinence. After self-administration training, neurons (n = 308) in the mPFC were recorded during a single test session conducted either the next day or 1 month later. Test sessions consisted of three phases during which (i) the tone-houselight stimulus previously paired with cocaine infusion during self-administration was randomly presented by the experimenter, (ii) rats responded on the lever previously associated with cocaine during extinction and (iii) the tone-houselight was presented randomly between cocaine-reinforced responding during resumption of cocaine self-administration. PrL neurons showed enhanced encoding of the cocaine stimulus and drug-seeking behavior (under extinction and self-administration) following 30 days of abstinence. In contrast, although IL neurons encoded cocaine cues and cocaine-seeking, there were no pronounced changes in IL responsiveness following 30 days of abstinence. Importantly, cue-related changes do not represent a generalised stimulus-evoked discharge as PrL and IL neurons in control animals (n = 4) exhibited negligible recruitment by the tone-houselight stimulus. The results support the view that, following abstinence, neural encoding in the PrL but not IL may play a key role in enhanced cocaine-seeking, particularly following re-exposure to cocaine-associated cues.


Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta.
Cryo-EM has revealed the structures of many challenging yet exciting macromolecular assemblies at near-atomic resolution (3-4.5Å), providing biological phenomena with molecular descriptions. However, at these resolutions, accurately positioning individual atoms remains challenging and error-prone. Manually refining thousands of amino acids - typical in a macromolecular assembly - is tedious and time-consuming. We present an automated method that can improve the atomic details in models that are manually built in near-atomic-resolution cryo-EM maps. Applying the method to three systems recently solved by cryo-EM, we are able to improve model geometry while maintaining the fit-to-density. Backbone placement errors are automatically detected and corrected, and the refinement shows a large radius of convergence. The results demonstrate that the method is amenable to structures with symmetry, of very large size, and containing RNA as well as covalently bound ligands. The method should streamline the cryo-EM structure determination process, providing accurate and unbiased atomic structure interpretation of such maps.


Varieties of abstract concepts: development, use and representation in the brain.
The capacity for abstract thought is one of the hallmarks of human cognition. However, the mechanisms underlying the ability to form and use abstract concepts like 'fantasy' and 'grace' have not been elucidated yet. This theme issue brings together developmental, social and cognitive psychologists, linguists, anthropologists, cognitive scientists, neuroscientists, philosophers and computer scientists to present theoretical insights and novel evidence on how abstract concepts are acquired, used and represented in the brain. Many of the contributions conceive concepts as grounded in sensorimotor systems and constrained by bodily mechanisms and structures. The theme issue develops along two main axes, related to the most promising research directions on abstract concepts. The axes focus on (i) the different kinds of abstract concepts (numbers, emotions, evaluative concepts like moral and aesthetic ones, social concepts); (ii) the role played by perception and action, language and sociality, and inner processes (emotions, interoception, metacognition) in grounding abstract concepts. Most papers adopt a cognitive science/neuroscience approach, but the theme issue also includes studies on development, on social cognition, and on how linguistic diversity shapes abstract concepts. Overall, the theme issue provides an integrated theoretical account that highlights the importance of language, sociality and inner processes for abstract concepts, and that offers new methodological tools to investigate them.This article is part of the theme issue 'Varieties of abstract concepts: development, use and representation in the brain'.


Caffeine, creatine, GRIN2A and Parkinson's disease progression.
Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.


Demographic variables for wild Asian elephants using longitudinal observations.
Detailed demographic data on wild Asian elephants have been difficult to collect due to habitat characteristics of much of the species' remaining range. Such data, however, are critical for understanding and modeling population processes in this endangered species. We present data from six years of an ongoing study of Asian elephants (Elephas maximus) in Uda Walawe National Park, Sri Lanka. This relatively undisturbed population numbering over one thousand elephants is individually monitored, providing cohort-based information on mortality and reproduction. Reproduction was seasonal, such that most births occurred during the long inter-monsoon dry season and peaked in May. During the study, the average age at first reproduction was 13.4 years and the 50(th) percentile inter-birth interval was approximately 6 years. Birth sex ratios did not deviate significantly from parity. Fecundity was relatively stable throughout the observed reproductive life of an individual (ages 11-60), averaging between 0.13-0.17 female offspring per individual per year. Mortalities and injuries based on carcasses and disappearances showed that males were significantly more likely than females to be killed or injured through anthropogenic activity. Overall, however, most observed injuries did not appear to be fatal. This population exhibits higher fecundity and density relative to published estimates on other Asian elephant populations, possibly enhanced by present range constriction. Understanding the factors responsible for these demographic dynamics can shed insight on the future needs of this elephant population, with probable parallels to other populations in similar settings.


Electrochemical energy storage devices for wearable technology: a rationale for materials selection and cell design.
Compatible energy storage devices that are able to withstand various mechanical deformations, while delivering their intended functions, are required in wearable technologies. This imposes constraints on the structural designs, materials selection, and miniaturization of the cells. To date, extensive efforts have been dedicated towards developing electrochemical energy storage devices for wearables, with a focus on incorporation of shape-conformable materials into mechanically robust designs that can be worn on the human body. In this review, we highlight the quantified performances of reported wearable electrochemical energy storage devices, as well as their micro-sized counterparts under specific mechanical deformations, which can be used as the benchmark for future studies in this field. A general introduction to the wearable technology, the development of the selection and synthesis of active materials, cell design approaches and device fabrications are discussed. It is followed by challenges and outlook toward the practical use of electrochemical energy storage devices for wearable applications.


Controlling the magnetic and optical responses of a MoS2 monolayer by lanthanide substitutional doping: a first-principles study.
The electronic, magnetic and optical properties of lanthanide substitutional doping (∼2% concentration) on the MoS2 monolayer have been investigated within the density functional theory formalism together with the Hubbard correction (DFT+U). The dopants investigated include Ce, Eu, Gd, Lu and Tm. The calculated dopant substitutional energies under both Mo-rich and S-rich conditions suggest that it is possible to experimentally realize the lanthanide doped MoS2 monolayer systems. The Eu, Gd and Tm dopants induce strong magnetization in the host lattice. The electronic structure calculations reveal that the dopants have a p-type character and they exhibit a half-metallic behavior in the Gd and Eu doped systems. A dilute magnetic semiconducting behavior can also be realized in Gd, Eu and Tm doped systems by slightly tuning the Fermi level. All the dopants refine the optical responses of the host system with the onset of the optical absorption edge shifting to lower energies within the visible range (red shift phenomenon). We observe an optical anisotropy for two different directions of the electric field (E) polarizations, i.e. parallel, E∥, and perpendicular, E⊥, to the xy-plane. Lanthanide substitutional doping significantly influences the electron energy loss spectra (EELS), absorption spectra, and dielectric properties of the host MoS2 monolayer. Furthermore, we notice that lanthanide substitutional doping could enhance the photocatalytic properties of the MoS2 monolayer.


In vivo subdiffuse scanning laser oximetry of the human retina.
Scanning laser ophthalmoscopes (SLOs) have the potential to perform high speed, high contrast, functional imaging of the human retina for diagnosis and follow-up of retinal diseases. Commercial SLOs typically use a monochromatic laser source or a superluminescent diode for imaging. Multispectral SLOs using an array of laser sources for spectral imaging have been demonstrated in research settings, with applications mainly aiming at retinal oxygenation measurements. Previous SLO-based oximetry techniques are predominantly based on wavelengths that depend on laser source availability. We describe an SLO system based on a supercontinuum (SC) source and a double-clad fiber using the single-mode core for illumination and the larger inner cladding for quasi-confocal detection to increase throughput and signal-to-noise ratio. A balanced detection scheme was implemented to suppress the relative intensity noise of the SC source. The SLO produced dual wavelength, high-quality images at 10 frames / s with a maximum 20 deg imaging field-of-view with any desired combination of wavelengths in the visible spectrum. We demonstrate SLO-based dual-wavelength oximetry in vessels down to 50 μm in diameter. Reproducibility was demonstrated by performing three different imaging sessions of the same volunteer, 8 min apart. Finally, by performing a wavelength sweep between 485 and 608 nm, we determined, for our SLO geometry, an approximately linear relationship between the effective path length of photons through the blood vessels and the vessel diameter.


Single-nucleotide base excision repair DNA polymerase activity in C. elegans in the absence of DNA polymerase β.
The base excision DNA repair (BER) pathway known to occur in Caenorhabditis elegans has not been well characterized. Even less is known about the DNA polymerase (pol) requirement for the gap-filling step during BER. We now report on characterization of in vitro uracil-DNA initiated BER in C. elegans. The results revealed single-nucleotide (SN) gap-filling DNA polymerase activity and complete BER. The gap-filling polymerase activity was not due to a DNA polymerase β (pol β) homolog, or to another X-family polymerase, since computer-based sequence analyses of the C. elegans genome failed to show a match for a pol β-like gene or other X-family polymerases. Activity gel analysis confirmed the absence of pol β in the C. elegans extract. BER gap-filling polymerase activity was partially inhibited by both dideoxynucleotide and aphidicolin. The results are consistent with a combination of both replicative polymerase(s) and lesion bypass/BER polymerase pol θ contributing to the BER gap-filling synthesis. Involvement of pol θ was confirmed in experiments with extract from pol θ null animals. The presence of the SN BER in C. elegans is supported by these results, despite the absence of a pol β-like enzyme or other X-family polymerase.


Simulated microgravity facilitates cell migration and neuroprotection after bone marrow stromal cell transplantation in spinal cord injury.
Recently, cell-based therapy has gained significant attention for the treatment of central nervous system diseases. Although bone marrow stromal cells (BMSCs) are considered to have good engraftment potential, challenges due to in vitro culturing, such as a decline in their functional potency, have been reported. Here, we investigated the efficacy of rat BMSCs (rBMSCs) cultured under simulated microgravity conditions, for transplantation into a rat model of spinal cord injury (SCI). rBMSCs were cultured under two different conditions: standard gravity (1G) and simulated microgravity attained by using the 3D-clinostat. After 7 days of culture, the rBMSCs were analyzed morphologically, with RT-PCR and immunostaining, and were used for grafting. Adult rats were used for constructing SCI models by using a weight-dropping method and were grouped into three experimental groups for comparison. rBMSCs cultured under 1 g and simulated microgravity were transplanted intravenously immediately after SCI. We evaluated the hindlimb functional improvement for 3 weeks. Tissue repair after SCI was examined by calculating the cavity area ratio and immunohistochemistry. rBMSCs cultured under simulated microgravity expressed Oct-4 and CXCR4, in contrast to those cultured under 1 g conditions. Therefore, rBMSCs cultured under simulated microgravity were considered to be in an undifferentiated state and thus to possess high migration ability. After transplantation, grafted rBMSCs cultured under microgravity exhibited greater survival at the periphery of the lesion, and the motor functions of the rats that received these grafts improved significantly compared with the rats that received rBMSCs cultured in 1 g. In addition, rBMSCs cultured under microgravity were thought to have greater trophic effects on reestablishment and survival of host spinal neural tissues because cavity formations were reduced, and apoptosis-inhibiting factor expression was high at the periphery of the SCI lesion. Here we show that transplantation of rBMSCs cultured under simulated microgravity facilitates functional recovery from SCI rather than those cultured under 1 g conditions.


Mucositis grades and yeast species.
Surgically treated patients with oral, head and neck cancer commonly develop mucositis during additional irradiation therapy. Oral mucosa inflammation other than irradiation is mostly caused by Candida albicans, yeast of Candida genus. This study evaluated possible connection between grades of oral mucositis and oral yeast profile in irradiated patients before, during and after irradiation. In 25 examined patients mucosits grades "0" to "2" before irradiation with 20% positive smears and only two different species of yeasts (C. krusei 4%, C. albicans 16%) during the irradiation changed into "0" to "4" and 36% positive smears with five different species of oral yeasts (C. albicans 12%, C. glabrata 12%, C. parapsilosis 4%, C. guilliermondii 4% and Saccharomyces cerevisiae 4%). Three weeks after irradiation was finished mucositis decreased into "1" to "3" with 20% positive smears and again only two species of yeasts (C. albicans 16%, C. guilliermondii 4%). Mucositis grades was increased significantly (p = 0.0037) with changes in fungi profile.


An overview of the safety of sucralose.
Sucralose is a non-nutritive sweetener used in a broad range of foods and beverages and is the non-nutritive sweetener in retail SPLENDA Sweetening Products, composed of sucralose and common food ingredients. A review of the extensive body of evidence that supports the safety of sucralose is provided. The results of an independent review of a new study investigating the safety of a sucralose-mixture retail product, Granulated SPLENDA No Calorie Sweetener, are also discussed. The collective evidence supports the conclusion that the ingredient, sucralose, is safe for use in food and that the sucralose-mixture product, Granulated SPLENDA No Calorie Sweetener, is also safe for its intended use.


Clinical spectrum of tuberculous optic neuropathy.
Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette-Guerin. However, this condition is not well described in the ophthalmic literature. Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.


Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury.
Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.


Low-frequency noise in multilayer MoS2 field-effect transistors: the effect of high-k passivation.
Diagnosing of the interface quality and the interactions between insulators and semiconductors is significant to achieve the high performance of nanodevices. Herein, low-frequency noise (LFN) in mechanically exfoliated multilayer molybdenum disulfide (MoS2) (~11.3 nm-thick) field-effect transistors with back-gate control was characterized with and without an Al2O3 high-k passivation layer. The carrier number fluctuation (CNF) model associated with trapping/detrapping the charge carriers at the interface nicely described the noise behavior in the strong accumulation regime both with and without the Al2O3 passivation layer. The interface trap density at the MoS2-SiO2 interface was extracted from the LFN analysis, and estimated to be Nit ~ 10(10) eV(-1) cm(-2) without and with the passivation layer. This suggested that the accumulation channel induced by the back-gate was not significantly influenced by the passivation layer. The Hooge mobility fluctuation (HMF) model implying the bulk conduction was found to describe the drain current fluctuations in the subthreshold regime, which is rarely observed in other nanodevices, attributed to those extremely thin channel sizes. In the case of the thick-MoS2 (~40 nm-thick) without the passivation, the HMF model was clearly observed all over the operation regime, ensuring the existence of the bulk conduction in multilayer MoS2. With the Al2O3 passivation layer, the change in the noise behavior was explained from the point of formation of the additional top channel in the MoS2 because of the fixed charges in the Al2O3. The interface trap density from the additional CNF model was Nit = 1.8 × 10(12) eV(-1) cm(-2) at the MoS2-Al2O3 interface.


Comparative Analysis of the Effects of Olive Oil Hydroxytyrosol and Its 5-S-Lipoyl Conjugate in Protecting Human Erythrocytes from Mercury Toxicity.
Oxidative stress is one of the underlying mechanisms of the toxic effects exerted by mercury (Hg) on human health. Several antioxidant compounds, including the olive oil phenol hydroxytyrosol (HT), were investigated for their protective action. Recently, we have reported that 5-S-lipoylhydroxytyrosol (Lipo-HT) has shown increased antioxidant activities compared to HT and exerted potent protective effects against reactive oxygen species (ROS) generation and oxidative damage in human hepatocellular carcinoma HepG2 cell lines. In this study, the effects of Lipo-HT and HT on oxidative alterations of human erythrocytes induced by exposure to 40 μM HgCl2 were comparatively evaluated. When administered to the cells, Lipo-HT (5-20 μM) proved nontoxic and it decreased the Hg-induced generation of ROS, the hemolysis, and the depletion of intracellular GSH levels. At all tested concentrations, Lipo-HT exhibited higher ability to counteract Hg-induced cytotoxicity compared to HT. Model studies indicated the formation of a mercury complex at the SH group of Lipo-HT followed by a redox reaction that would spare intracellular GSH. Thus, the enhanced erythrocyte protective action of Lipo-HT from Hg-induced damage with respect to HT is likely due to an effective chelating and reducing ability toward mercury ions. These findings encourage the use of Lipo-HT in nutraceutical strategies to contrast heavy metal toxicity in humans.


Design and Validation of Probes and Sensors for the Characterization of Magneto-Ionic Radio Wave Propagation on Near Vertical Incidence Skywave Paths.
This article describes the design and validation of deployable low-power probes and sensors to investigate the influence of the ionosphere and the Earth's magnetic field on radio wave propagation below the plasma frequency of the ionosphere, known as Near Vertical Incidence Skywave (NVIS) propagation. The propagation of waves that are bent downward by the ionosphere is dominated by a bi-refractive mechanism called 'magneto-ionic propagation'. The polarization of both downward waves depends on the spatial angle between the Earth's magnetic field and the direction of propagation of the radio wave. The probes and sensors described in this article are needed to simultaneously investigate signal fading and polarization dynamics on six radio wave propagation paths. The 1-Watt probes realize a 57 dB signal-to-noise ratio. The probe polarization is controlled using direct digital synthesis and the cross-polarization is 25-35 dB. The intermodulation-free dynamic range of the sensor exceeds 100 dB. Measurement speed is 3000 samples/second. This publication covers design, practical realization and deployment issues. Research performed with these devices will be shared in subsequent publications.


Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.
Down syndrome (trisomy 21) is the most common cause of mental retardation in children and leads to marked deficits in contextual learning and memory. In rodents, these tasks require the hippocampus and are mediated by several inputs, particularly those originating in the locus coeruleus. These afferents mainly use norepinephrine as a transmitter. To explore the basis for contextual learning defects in Down syndrome, we examined the Ts65Dn mouse model. These mice, which have three copies of a fragment of mouse chromosome 16, exhibited significant deficits in contextual learning together with dysfunction and degeneration of locus coeruleus neurons. However, the postsynaptic targets of innervation remained responsive to noradrenergic receptor agonists. Indeed, despite advanced locus coeruleus degeneration, we were able to reverse contextual learning failure by using a prodrug for norepinephrine called l-threo-3,4-dihydroxyphenylserine, or xamoterol, a beta(1)-adrenergic receptor partial agonist. Moreover, an increased gene dosage of App, in the context of Down syndrome, was necessary for locus coeruleus degeneration. Our findings raise the possibility that restoring norepinephrine-mediated neurotransmission could reverse cognitive dysfunction in Down syndrome.


Venus: absence of a phase effect at a 2-centimeter wavelength.
Observations of Venus made during 1967 and 1968 at a frequency of 15.4 gigahertz set an upper limits of 5 percent for the variation of brightness temperature with phase. This negative result appears to contradict earlier detections of a phase effect. By comparison with Virg A (3C 274), which has an assumed flux density of 29 x 10(-26) watt per square meter per hertz, the brightness temperature of Venus at this frequency is 485 + 60, -40 degrees K (mean error).


The management of hyperlipidaemia: are specialist lipid clinics needed?
A survey of all general practitioners in Oxfordshire was undertaken to determine what use they wanted to make of a district lipid clinic, and to assess how effectively it met their needs. The response rate was 85% (288/340) but some respondents failed to answer each section of every question. One hundred and eighty-five general practitioners (64%) had previously referred patients to the clinic. Most respondents selectively asked for blood cholesterol measurements in patients with major cardiovascular risk factors (94%, 266/283), and few routinely asked for cholesterol as part of a health check (17%, 43/258). Most thought that referral to a clinic was appropriate for children (65%, 149/229), for patients aged 20 to 39 (85%, 209/247), and for older patients aged up to 60 (77%, 186/243). Ninety-four per cent (260/277) wanted access to specialist advice for patients with a cholesterol concentration exceeding 8.0 mmol l-1, and 73% (197/270) wanted specialist advice before starting treatment with a lipid-lowering drug. Although most respondents rated the service provided by the clinic favourably, more than half would have liked more information on prognosis, drug treatment, long-term follow-up, and screening of family members. We conclude that general practitioners would like access to specialist advice for the management of severe hyperlipidaemias, and that cardiovascular screening programmes in primary care have important resource implications for specialist services.


Histoplasmosis: Up-to-Date Evidence-Based Approach to Diagnosis and Management.
Histoplasmosis is the most common endemic mycosis in the North America, Central America, and many countries of South America and also occurs in China, India, Southeast Asia, Africa, Australia, and Europe. Clinical syndromes are not specific and histoplasmosis often is overlooked in the evaluation of patients with community-acquired pneumonia, chronic cavitary pneumonia resembling tuberculosis or anaerobic infection, granulomatous inflammatory diseases such as sarcoidosis or Crohn disease, and malignancy. The diagnosis depends on understanding the geographic distribution, common clinical presentations, and tests used for diagnosis of histoplasmosis. While histoplasmosis resolves without treatment in most patients, treatment is indicated in all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease. Treatment is appropriate in most patients with acute pulmonary disease but rarely in those with other pulmonary or mediastinal manifestations. The preferred agents include liposomal amphotericin B for more severe cases and itraconazole for milder cases and "step-down" therapy following response to amphotericin B.


Characterization of membrane progestin receptor α (mPRα) of the medaka and role in the induction of oocyte maturation.
Oocyte maturation in medaka is induced by the maturation-inducing hormone (MIH) via its membrane receptor. The most likely candidates for the membrane receptor are membrane progestin receptors (mPRs). In order to characterize the mPRα subtype of medaka, a human cell line expressing the mPRα gene of medaka was established and its steroid binding property was assessed. The α subtype exhibited high binding affinity for 17,20β-DHP, the MIH in medaka. Treatment with a morpholino antisense oligonucleotide to mPRα blocked oocyte maturation in vivo. These results suggest that the medaka mPRα protein acts as an intermediary during MIH-induced oocyte maturation in medaka in a manner similar to that described previously for fish species.


Self-consistent learning of the environment.
We study the Bayesian process to estimate the features of the environment. We focus on two aspects of the Bayesian process: how estimation error depends on the prior distribution of features and how the prior distribution can be learned from experience. The accuracy of the perception is underestimated when each feature of the environment is considered independently because many different features of the environment are usually highly correlated and the estimation error greatly depends on the correlations. The self-consistent learning process renews the prior distribution of correlated features jointly with the estimation of the environment. Here, maximum a posteriori probability (MAP) estimation decreases the effective dimensions of the feature vector. There are critical noise levels in self-consistent learning with MAP estimation, that cause hysteresis behaviors in learning. The self-consistent learning process with stochastic Bayesian estimation (SBE) makes the presumed distribution of environmental features converge to the true distribution for any level of channel noise. However, SBE is less accurate than MAP estimation. We also discuss another stochastic method of estimation, SBE2, which has a smaller estimation error than SBE without hysteresis.


Highly sensitive spectroscopic detection of heme-protein submonolayer films by channel integrated optical waveguide.
A highly sensitive technique based on optical absorption using a single-mode, channel integrated optical waveguide is described for broad spectral band detection and analysis of heme-containing protein films at a glass/water interface. Fabrication steps and device characteristics of optical waveguides suitable for operation in the wavelength range of 400 - 650 nm are described. Experimental results reported here show a limit of detection smaller than 100 pg/cm(2) for a submonolayer of ferricytochrome c by probing the Soret transition band with a 406-nm semiconductor diode laser propagating in a single-mode, ion-exchanged channel waveguide. By taking advantage of the exceptionally low limit of detection, we examined the adsorption isotherm of cytochrome c on a glass surface with unprecedented detail. Unlike other surface-specific techniques (e.g. SPR, integrated optic Mach-Zehnder interferometer) that probe local refractive-index changes and therefore are very susceptible to temperature fluctuations, the integrated optical waveguide absorption technique probes molecular-specific transition bands and is expected to be less vulnerable to environmental perturbations.


The properties and regulation of functional acetylcholine receptors on chick ciliary ganglion neurons.
The properties of acetylcholine receptor (AChR) channels on chick ciliary ganglion neurons in culture were examined using patch-clamp recording techniques. Acetylcholine (ACh) was applied by rapid microperfusion. Whole-cell current noise analysis revealed a single class of functional receptors on the neurons. Dose-response studies indicated a Kd of about 36 microM and a Hill coefficient of 1.5-1.7, predicting 2 ACh binding sites per receptor. Both fast and slow components of receptor desensitization were observed. Single-channel recordings from excised outside-out patches of soma membrane exposed to 2-5 microM ACh indicated a single-channel conductance of 40 pS, a reversal potential of -9 mV, a mean open duration of 1 msec, and an opening probability of 0.34. The kinetic behavior of the channels was provisionally described by a 3-closed, 1-open state model for receptor activation. In all of these properties, AChRs of ciliary ganglion neurons resemble those on skeletal muscle fibers. Growing the neurons in an elevated K+ concentration produced a 2-3-fold decrease in peak whole-cell currents induced by ACh under standard test conditions, without altering any of the single-channel properties described above. Neither changes in cholinesterase activity nor receptor distribution accounted for the decrease. Instead, calculations indicated that elevated K+ reduced the ACh response by decreasing the number of functional AChRs on the neurons. No K+-dependent decrease is observed, however, in the number of total receptors on the neurons detected either by a monoclonal antibody specific for the receptor or by an alpha-neurotoxin that binds to the receptor and blocks its function. Moreover, the number of receptors detected by the 2 probes is at least 10-fold greater than the calculated number of functional receptors. The findings suggest that only a small fraction of the AChRs on the neuronal surface is functional and that the cell can alter the ratio of functional and nonfunctional receptors in response to growth conditions.


Cell entry mechanism of enzymatic bacterial colicins: porin recruitment and the thermodynamics of receptor binding.
Binding of enzymatic E colicins to the vitamin B12 receptor, BtuB, is the first stage in a cascade of events that culminate in the translocation of the cytotoxic nuclease into the Escherichia coli cytoplasm and release of its tightly bound immunity protein. A dogma of colicin biology is that the toxin coiled-coil connecting its functional domains must unfold or unfurl to span the periplasm, with recent reports claiming this reaction is initiated by receptor binding. We report isothermal titration calorimetry data of BtuB binding the endonuclease toxin ColE9 and a disulfide form (ColE9S-S) where unfolding of the coiled-coil is prevented and, as a consequence, the toxin is biologically inactive. Contrary to expectation, the thermodynamics of receptor binding, characterized by large negative values for TDeltaS, are identical for the two colicins, arguing against any form of BtuB-induced unfolding. We go on to delineate key features of the "colicin translocon" that assembles at the cell surface after BtuB binding by using a complex of histidine-tagged Im9 bound to ColE9S-S. First, we show that the porin OmpF is recruited directly to the BtuB.colicin complex to form the translocon. Second, recruitment is through the natively unfolded region of the colicin translocation domain, with this domain likely having two contact points for OmpF. Finally, the immunity protein is not released during its assembly. Our study demonstrates that although colicin unfolding is undoubtedly a prerequisite for E. coli cell death, it must occur after assembly of the translocon.


Economies through Application of Nonmedical Primary-Preventative Health: Lessons from the Healthy Country Healthy People Experience of Australia's Aboriginal People.
The World Health Organization reports noncommunicable disease as a global pandemic. While national and international health research/policy bodies, such as the World Health Organization and the Australian Institute of Health and Welfare, emphasize the importance of preventative health, there is a continuing distortion in the allocation of resources to curative health as a result of government failure. Government failure is, in part, the result of a political response to individual preference for certainty in receiving treatment for specific health conditions, rather than the uncertainty of population-based preventative intervention. This has led to a failure to engage with those primary causative factors affecting chronic disease, namely the psychosocial stressors, in which the socioeconomic determinants are an important component. Such causal factors are open to manipulation through government policies and joint government-government, government-private cooperation through application of nonmedical primary-preventative health policies. The health benefits of Aboriginal people in traditional land management, or caring-for-country, in remote to very remote Australia, is used to exemplify the social benefits of nonmedical primary-preventative health intervention. Such practices form part of the "healthy country, health people" concept that is traditionally relied upon by Indigenous peoples. Possible health and wider private good and public good social benefits are shown to occur across multiple disciplines and jurisdictions with the possibility of substantial economies. General principles in the application of nonmedical primary-preventative health activities are developed through consideration of the experience of Afboriginal people participation in traditional caring-for-country.


Treating the traumatic memories of patients with dissociative identity disorder.
The author uses clinical experience informed by research findings to suggest approaches to the treatment of the traumatic memories of patients with dissociative identity disorder. Recent findings in the treatment of patients with this disorder and current considerations with regard to memories of childhood trauma are used to develop recommended approaches. Treatment of traumatic memories appears crucial in the recovery of patients with dissociative identity disorder, even though the reported memories may not be historically accurate. Criteria are available for determining whether a patient with the disorder is able to undertake such efforts, and methods such as fractionated abreaction have been developed to make the process less unsettling. Despite the difficulties posed by the vulnerability of patients with dissociative identity disorder to decompensation when working with traumatic material and the vicissitudes of autobiographical memory, modern therapeutic approaches allow the processing of such patients' traumatic material in a manner that reduces the likelihood of disruptive events and the misuse of recovered material.


Antithrombin use during pediatric cardiac extracorporeal membrane oxygenation admission: insights from a national database.
The frequency of extracorporeal membrane oxygenation in pediatric patients continues to increase, especially in patients with complex congenital heart disease. Providing adequate anticoagulation is necessary for patients on extracorporeal membrane oxygenation and is achieved with adequate heparin administration. Antithrombin is administered to potentiate heparin's effects. However, the efficacy of antithrombin supplementation is unclear and a clear clinical benefit has not been established. We present a large retrospective study examining the effects of antithrombin on pediatric patients receiving extracorporeal membrane oxygenation. Data for this study were obtained from the Pediatric Health Information System and Pediatric Health Information System+ databases from 2004 to 2015. Pediatric patients receiving extracorporeal membrane oxygenation with a congenital heart disease diagnosis were included and divided into groups that did or did not utilize antithrombin. For all admissions, the following were captured: age of admission, gender, year of admission, length of stay, billed charges, inpatient mortality, the presence of specific congenital malformations of the heart, specific cardiac surgeries, and comorbidities. A total of 9,193 admissions were included and 865 (9.4%) utilized antithrombin. Between groups, there were significantly different frequencies of co-morbidities, cardiac lesion types and antithrombin usage over the study period. There were significantly lower odds in the antithrombin group of venous thrombosis. Antithrombin was not significantly associated with hemorrhage; however, antithrombin was associated with increased inpatient mortality and a decrease in length of stay and billed charges. Antithrombin administration is associated with increased mortality, a shorter length of stay, and decreased billing cost. Recently, antithrombin usage has been decreasing-potentially due to the reported lack of clinical benefit. Together, these results reinforce that antithrombin may not be indicated for all pediatric extracorporeal membrane oxygenation patients.


An instrument to measure nurses' knowledge in palliative care: Validation of the Spanish version of Palliative Care Quiz for Nurses.
Palliative care is nowadays essential in nursing care, due to the increasing number of patients who require attention in final stages of their life. Nurses need to acquire specific knowledge and abilities to provide quality palliative care. Palliative Care Quiz for Nurses is a questionnaire that evaluates their basic knowledge about palliative care. The Palliative Care Quiz for Nurses (PCQN) is useful to evaluate basic knowledge about palliative care, but its adaptation into the Spanish language and the analysis of its effectiveness and utility for Spanish culture is lacking. To report the adaptation into the Spanish language and the psychometric analysis of the Palliative Care Quiz for Nurses. The Palliative Care Quiz for Nurses-Spanish Version (PCQN-SV) was obtained from a process including translation, back-translation, comparison with versions in other languages, revision by experts, and pilot study. Content validity and reliability of questionnaire were analyzed. Difficulty and discrimination indexes of each item were also calculated according to Item Response Theory (IRT). Adequate internal consistency was found (S-CVI = 0.83); Cronbach's alpha coefficient of 0.67 and KR-20 test result of 0,72 reflected the reliability of PCQN-SV. The questionnaire had a global difficulty index of 0,55, with six items which could be considered as difficult or very difficult, and five items with could be considered easy or very easy. The discrimination indexes of the 20 items, show us that eight items are good or very good while six items are bad to discriminate between good and bad respondents. Although in shows internal consistency, reliability and difficulty indexes similar to those obtained by versions of PCQN in other languages, a reformulation of the items with lowest content validity or discrimination indexes and those showing difficulties with their comprehension is an aspect to take into account in order to improve the PCQN-SV. The PCQN-SV is a useful Spanish language instrument for measuring Spanish nurses' knowledge in palliative care and it is adequate to establish international comparisons.


Frontoparietal connectivity correlates with working memory performance in multiple sclerosis.
Working Memory (WM) impairment is the most common cognitive deficit of patients with Multiple Sclerosis (MS). However, evidence of its neurobiological mechanisms is scarce. Here we recorded electroencephalographic activity of twenty patients with relapsing-remitting MS and minimal cognitive deficit, and 20 healthy control (HC) subjects while they solved a WM task. In spite of similar performance, the HC group demonstrated both a correlation between temporoparietal theta activity and memory load, and a correlation between medial frontal theta activity and successful memory performances. MS patients did not show theses correlations leading significant differences between groups. Moreover, cortical connectivity analyses using granger causality and phase-amplitude coupling between theta and gamma revealed that HC group, but not MS group, presented a load-modulated progression of the frontal-to-parietal connectivity. This connectivity correlated with working memory capacity in MS groups. This early alterations in the oscillatory dynamics underlaying working memory could be useful for plan therapeutic interventions.


7-Deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist.
Cyclic ADP-ribose (cADPR) is a putative second messenger that has been demonstrated to mobilize Ca2+ in many cell types. Its postulated role as the endogenous regulator of ryanodine-sensitive Ca2+ release channels has been greatly supported by the advent and use of specific cADPR receptor antagonists such as 8-NH2-cADPR (Walseth, T. F., and Lee, H. C. (1993) Biochim. Biophys. Acta 1178, 235-242). However, investigations of the role of cADPR in physiological responses, such as fertilization, stimulus-secretion coupling, and excitation-contraction coupling, have been hindered by the susceptibility of cADPR receptor antagonists to hydrolysis and the need to introduce these molecules into cells by microinjection or patch clamp techniques. We have recently reported on the discovery of a poorly hydrolyzable analogue of cADPR, 7-deaza-cADPR (Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., and Potter, B. V. L. (1997) Chem. Biol. 4, 41-51) but this, like cADPR, is an agonist of ryanodine-sensitive Ca2+ release channels. We therefore explored the possibility of combining antagonistic activity with that of hydrolytic resistance and now report on the biological properties of the first hydrolysis-resistant cADPR receptor antagonist, 7-deaza-8-bromo-cADPR. In addition this compound has the advantage of being membrane-permeable. Together these properties make this hybrid molecule the most powerful tool to date for studying cADPR-mediated Ca2+ signaling in intact cells.


Nebulised salbutamol without oxygen in severe acute asthma: how effective and how safe?
Thirty two patients with severe acute asthma, all of whom were hypoxaemic, entered a double blind comparative assessment of three doses of salbutamol (1.25, 2.5, and 5 mg) nebulised by an electrically operated air compressor. The study lasted for two hours, during which oxygen and corticosteroid treatment were withheld. All patients were observed in an intensive care area during this period. Four patients had to be withdrawn from the study. Two became distressed immediately after receiving salbutamol and were excluded from further analysis. Two other patients were withdrawn, one with persistent respiratory distress and an unchanged one second forced expiratory volume (FEV1) and the other because of the development of profound hypoxaemia and a deteriorating FEV1 within 60 minutes of treatment. No significant differences were observed between the three dosage groups. In the 28 patients completing the study there were only small increases in mean FEV1 (0.8 to 1.1 l) and forced vital capacity (FVC) (1.3 to 1.8 l) over the two hours. There was a fall in the mean pulse rate at 120 minutes of 15 beats per minute (117-102). No significant change in oxygen tension (PaO2) was observed at 15 or 60 minutes after administration of nebulised salbutamol in any of the three groups. Salbutamol nebulised in air, in a single dose of 5 mg, produces only slight relief of airflow obstruction and no worsening of hypoxaemia in severe acute asthma.


Assessment of environmental water demands (EWD) of forests for two distinct Indian ecosystems.
Sustainable use of water and land resources requires that these scarce resources be appropriately allocated among various competing human activities. Worldwide, there is a realization now that sustainable river basin management should be accorded the highest priority, because it deals not only with technical, but also with ecological and socioeconomic aspects, and thus calls for a multidisciplinary and integrated approach. However, most of the policy and planning documents have either remained silent, or have made only implicit reference to the importance of environmental water demand (EWD) and its quantification. Therefore, in the light of its importance, a methodology has been evolved in this article for quantifying EWD for various forested areas in two distinctly different Indian river basins: Brahmani (humid zone) and Sabarmati (dry zone). The article analyzes and discusses EWD estimates at three different spatial levels: river basins, states, and districts within them, and finally presents a comparative analysis of all these results. Findings of the present study will be immensely useful in understanding various ecological issues connected with water resource projects and proposals in these river basins.


Resistance, susceptibility, and immunity to Eimeria tenella in major histocompatibility (B) complex congenic lines.
The major histocompatibility (B) complex influence on resistance, susceptibility, and immunity to Eimeria tenella was examined in UCD B complex congenic chicken lines. In Experiment 1, 6-wk-old chicks from 12 UCD congenic lines were weighed and assigned to either challenge or control groups. The challenge group received a dose of 10,000 E. tenella oocysts. Response to challenge was evaluated by body weight gain and cecal lesion scores. Cecal lesion scores in B3B3 chickens were significantly lower than those of all other genotypes. Genotype B2B2 had the highest lesion scores, which were significantly different from the lesion scores calculated for B3B3, B18B18, and B21B21 chickens but were not significantly different from B14B14, B15B15, B17B17, B19B19, B24B24, BCBC, BJBJ, and BQBQ genotypes. The B21B21 chickens had significantly lower lesion scores than B2B2, B14B14, and BCBC chickens. No other significant lesion score differences were found among the remaining lines. The highest weight gain found in B19B19 chickens was significantly different from that of B3B3, B14B14, B15B15, B17B17, B18B18, B24B24, and BCBC chickens. The B15B15 chickens had the lowest weight gain, which was significantly different from that of B2B2, B19B19, B21B21, B24B24, BJBJ, and BQBQ chickens. Experiment 2 tested the immune response to E. tenella after low dose oocyst immunization. Chicks from 10 UCD 003 congenic lines were divided into three groups: control, challenge, and immune. At 5 wk of age, the immune group was immunized with 500 E. tenella oocysts for 5 consecutive d. Fourteen days after the last immunization all chicks were weighed, and 10,000 E. tenella oocysts were administered to the challenge and immune groups. Significant lesion score differences existed among all three treatments: control (0), immune (2.14 +/- 0.1); challenge (3.13 +/- 0.1). Among immune birds, B3B3 and BQBQ chickens had significantly lower lesion scores than B19B19, B24B24, B14B14, and B2B2 chickens. Neither B19B19 nor B24B24 chickens were well-protected, as indicated by their higher lesion scores. No significant differences in weight gain were found in immune birds. The B complex affected resistance and susceptibility as well as the immune response to E. tenella. Cecal lesion scores following challenge in naive birds or after immunization were influenced by the B complex, whereas weight gain was affected in naive birds only. These effects may be manifested through differences in immune competence at the time of challenge or immunization, the amount of parasite antigen production, or the threshold doses for effective immunization.


Anti-dementia drugs and changes in gait: a pre-post quasi-experimental pilot study.
Anti-dementia drugs may improve gait performance. No comparison between acetylcholinesterase inhibitors (CEIs) and memantine-related changes in gait variability has been reported. The objectives of this study were to 1) quantify and compare the mean values and coefficients of variation (CoV) of stride time in demented patients with Alzheimer's disease and related disorders (ADRD) before and after the use of CEIs or memantine, and in age- and gender-matched controls patients with ADRD using no anti-dementia drugs; and 2) to determine whether changes in CoV of stride time differed between CEIs or memantine. A total of 120 demented patients with mild-to-moderate ADRD were prospectively included in this pre-post quasi-experimental study with two intervention groups (43 patients taking CEIs, and 41 taking memantine) and a control group (36 age- and gender matched patients without any anti-dementia drugs). CoV of stride time and walking speed were measured with GAITRite® system while usual walking at steady state. Age, gender, number of drugs daily taken, use of psychoactive drugs, body mass index and time between the two visits were also recorded. There was no difference between groups for the time between baseline and follow-up assessments (232.9 ± 103.7 days for patients without anti-dementia drugs, 220.0 ± 67.5 days for patients with CEIs, 186.7 ± 96.2 days for patients with memantine, P = 0.062). Patients with memantine had a lower (i.e., better) CoV of stride time at follow-up assessment compared to those with CEIs (4.2 ± 2.4% versus 5.8 ± 4.2%, P = 0.010). Patients with memantine had a greater decrease in CoV of stride time compared to those with CEIs (-1.90% versus 0.93%, P = 0.010) and mixed-effects linear regressions showed that this decrease was specifically explained by memantine (P = 0.028). Our results showed that patients with ADRD and treated with memantine, but not those with CEIs, decreased their gait variability, and thus improved their gait safety (Trial registration number: NCT01315704).


Prevalence, incidence and risk factors for pharyngeal chlamydia in the community based Health in Men (HIM) cohort of homosexual men in Sydney, Australia.
To determine the prevalence, incidence and risk factors for pharyngeal Chlamydia trachomatis in the community based Health in Men (HIM) cohort of HIV negative homosexual men in Sydney, Australia. From January 2003, all HIM participants were offered annual screening for pharyngeal chlamydia using BD ProbeTec nucleic acid amplification testing (NAAT). Detailed sexual behavioural data were collected every 6 months, and risk factors for infection and hazard ratios were calculated using Cox regression. Among 1427 participants enrolled, the prevalence of pharyngeal chlamydia on initial testing was 1.06% and the incidence rate was 0.58 per 100 person-years. More than 50% of all infections were identified on baseline testing and 68% of men with pharyngeal infection had no evidence of concurrent anogenital chlamydia. There was no association of pharyngeal chlamydia with sore throat. Infection was significantly associated with increasing frequency of receptive penile-oral sex with ejaculation with casual partners (p = 0.009), although approximately half of infections occurred in participants not reporting this risk behaviour. Neither kissing nor oro-anal practices were associated with infection. The incidence of pharyngeal chlamydia infection in the HIM study was relatively low; however, the relatively high prevalence on baseline testing compared to incidence suggests a long duration of infection. Occasional screening for pharyngeal chlamydia in homosexual men who frequently practise receptive oral sex with ejaculation may be warranted.


Differential Profiles of Gut Microbiota and Metabolites Associated with Host Shift of Plutella xylostella.
Evolutionary and ecological forces are important factors that shape gut microbial profiles in hosts, which can help insects adapt to different environments through modulating their metabolites. However, little is known about how gut microbes and metabolites are altered when lepidopteran pest species switch hosts. In the present study, using 16S-rDNA sequencing and mass spectrometry-based metabolomics, we analyzed the gut microbiota and metabolites of three populations of Plutella xylostella: one feeding on radish (PxR) and two feeding on peas (PxP; with PxP-1 and PxP-17 being the first and 17th generations after host shift from radish to peas, respectively). We found that the diversity of gut microbes in PxP-17 was significantly lower than those in PxR and PxP-1, which indicates a distinct change in gut microbiota after host shift. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the functions of energy metabolism, signal transduction, and xenobiotics biodegradation and metabolism were increased in PxP-17, suggesting their potential roles in host adaptation. Metabolic profiling showed a significant difference in the abundance of gut metabolites between PxR and PxP-17, and significant correlations of gut bacteria with gut metabolites. These findings shed light on the interaction among plants, herbivores, and symbionts, and advance our understanding of host adaptation associated with gut bacteria and metabolic activities in P. xylostella.


Lack of association between PCK1 polymorphisms and obesity, physical activity, and fitness in European Youth Heart Study (EYHS).
Phosphoenolpyruvate carboxykinase-1 (PCK1) is the rate-limiting enzyme in the hepatic gluconeogenic pathway. Studies have shown that overexpression of Pck1 in mice results in obesity-related traits and higher levels of physical activity (PA). Therefore, our aims were to investigate whether common genetic variation in the PCK1 gene influences obesity-related traits, PA, and fitness, and to examine whether PA and fitness attenuate the influence of the PCK1 polymorphisms on obesity in children. Analyses were undertaken on data from Danish and Estonian children (958 boys and 1,104 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of children (mean ± s.d. age: 9.6 ± 0.4 years) and adolescents (15.5 ± 0.5 years). We genotyped eight polymorphisms that captured the common genetic variations in the PCK1 gene. The association between the PCK1 polymorphisms and BMI, waist circumference (WC), sum of four skinfolds, PA, and fitness was tested using an additive model adjusted for age, age-group, gender, maturity, and country. Interactions were tested by including interaction terms in the model. None of the polymorphisms were significantly associated with BMI, WC, sum of four skinfolds, PA, and fitness, and also with the risk of being overweight or obese (P > 0.05). The interactions between the polymorphisms and age-group, gender, PA, and fitness were not statistically significant. This is the first study to comprehensively examine the association of PCK1 polymorphisms with obesity, PA, and fitness. Despite strong evidence from animal studies, our study in the EYHS cohort failed to identify an association of PCK1 polymorphisms with obesity, PA, and fitness.


HIV prevalence among high school learners - opportunities for schools-based HIV testing programmes and sexual reproductive health services.
Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners. Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables. The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p = 0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups. The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services.


Violation of the 12/23 rule of genomic V(D)J recombination is common in lymphocytes.
V(D)J genomic recombination joins single gene segments to encode an extensive repertoire of antigen receptor specificities in T and B lymphocytes. This process initiates with double-stranded breaks adjacent to conserved recombination signal sequences that contain either 12- or 23-nucleotide spacer regions. Only recombination between signal sequences with unequal spacers results in productive coding genes, a phenomenon known as the "12/23 rule." Here we present two novel genomic tools that allow the capture and analysis of immune locus rearrangements from whole thymic and splenic tissues using second-generation sequencing. Further, we provide strong evidence that the 12/23 rule of genomic recombination is frequently violated under physiological conditions, resulting in unanticipated hybrid recombinations in ∼10% of Tcra excision circles. Hence, we demonstrate that strict adherence to the 12/23 rule is intrinsic neither to recombination signal sequences nor to the catalytic process of recombination and propose that nonclassical excision circles are liberated during the formation of antigen receptor diversity.


Structural insights into the signalling mechanisms of two-component systems.
Two-component systems reprogramme diverse aspects of microbial physiology in response to environmental cues. Canonical systems are composed of a transmembrane sensor histidine kinase and its cognate response regulator. They catalyse three reactions: autophosphorylation of the histidine kinase, transfer of the phosphoryl group to the regulator and dephosphorylation of the phosphoregulator. Elucidating signal transduction between sensor and output domains is highly challenging given the size, flexibility and dynamics of histidine kinases. However, recent structural work has provided snapshots of the catalytic mechanisms of the three enzymatic reactions and described the conformation and dynamics of the enzymatic moiety in the kinase-competent and phosphatase-competent states. Insight into signalling mechanisms across the membrane is also starting to emerge from new crystal structures encompassing both sensor and transducer domains of sensor histidine kinases. In this Progress article, we highlight such important advances towards understanding at the molecular level the signal transduction mechanisms mediated by these fascinating molecular machines.


A genomic timescale for the origin of eukaryotes.
Genomic sequence analyses have shown that horizontal gene transfer occurred during the origin of eukaryotes as a consequence of symbiosis. However, details of the timing and number of symbiotic events are unclear. A timescale for the early evolution of eukaryotes would help to better understand the relationship between these biological events and changes in Earth's environment, such as the rise in oxygen. We used refined methods of sequence alignment, site selection, and time estimation to address these questions with protein sequences from complete genomes of prokaryotes and eukaryotes. Eukaryotes were found to evolve faster than prokaryotes, with those eukaryotes derived from eubacteria evolving faster than those derived from archaebacteria. We found an early time of divergence (approximately 4 billion years ago, Ga) for archaebacteria and the archaebacterial genes in eukaryotes. Our analyses support at least two horizontal gene transfer events in the origin of eukaryotes, at 2.7 Ga and 1.8 Ga. Time estimates for the origin of cyanobacteria (2.6 Ga) and the divergence of an early-branching eukaryote that lacks mitochondria (Giardia) (2.2 Ga) fall between those two events. We find support for two symbiotic events in the origin of eukaryotes: one premitochondrial and a later mitochondrial event. The appearance of cyanobacteria immediately prior to the earliest undisputed evidence for the presence of oxygen (2.4-2.2 Ga) suggests that the innovation of oxygenic photosynthesis had a relatively rapid impact on the environment as it set the stage for further evolution of the eukaryotic cell.


Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study.
Among elderly people without dementia, the apolipoprotein E epsilon4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex. In a community-dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70-74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT). Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes. Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.


Fabrication of Novel Hydrogel with Berberine-Enriched Carboxymethylcellulose and Hyaluronic Acid as an Anti-Inflammatory Barrier Membrane.
An antiadhesion barrier membrane is an important biomaterial for protecting tissue from postsurgical complications. However, there is room to improve these membranes. Recently, carboxymethylcellulose (CMC) incorporated with hyaluronic acid (HA) as an antiadhesion barrier membrane and drug delivery system has been reported to provide excellent tissue regeneration and biocompatibility. The aim of this study was to fabricate a novel hydrogel membrane composed of berberine-enriched CMC prepared from bark of the P. amurense tree and HA (PE-CMC/HA). In vitro anti-inflammatory properties were evaluated to determine possible clinical applications. The PE-CMC/HA membranes were fabricated by mixing PE-CMC and HA as a base with the addition of polyvinyl alcohol to form a film. Tensile strength and ultramorphology of the membrane were evaluated using a universal testing machine and scanning electron microscope, respectively. Berberine content of the membrane was confirmed using a UV-Vis spectrophotometer at a wavelength of 260 nm. Anti-inflammatory property of the membrane was measured using a Griess reaction assay. Our results showed that fabricated PE-CMC/HA releases berberine at a concentration of 660 μg/ml while optimal plasticity was obtained at a 30 : 70 PE-CMC/HA ratio. The berberine-enriched PE-CMC/HA had an inhibited 60% of inflammation stimulated by LPS. These results suggest that the PE-CMC/HA membrane fabricated in this study is a useful anti-inflammatory berberine release system.


Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody.
Monoclonal antibodies (mAbs) labeled with alpha-emitting radionuclides such as (211)At, (212)Bi, (213)Bi, and (212)Pb (which decays by beta-emission to its alpha-emitting daughter, (212)Bi) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. In this study, we attached various radionuclides that result in alpha-emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of (125)I- and (111)In-labeled T101. T101 was labeled with (211)At, (125)I, (205,6)Bi, (111)In, and (203)Pb. CD5 antigen-positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for 1 h at 4 degrees C for surface labeling. Unbound activity was removed and 1 mL medium added. The cells were then incubated at 37 degrees C for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and non-protein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, (205,6)Bi, (203)Pb, and (111)In radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, (211)At and (125)I were released from cells rapidly ((211)At < (125)I) and most of the radioactivity in the supernatant was in a non-protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. (211)At catabolism and release from cells were somewhat similar to that of (125)I, whereas (205,6)Bi and (203)Pb showed prolonged cell retention similar to that of (111)In. These catabolism differences may be important in the selection of alpha-radionuclides for radioimmunotherapy.


Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection.
There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1(-/-)-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2(-/-)-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.


Small conductance Ca2+-activated K+ channels and calmodulin.
Small conductance Ca(2+)-activated K(+) channels (SK channels) contribute to the long lasting afterhyperpolarization (AHP) that follows an action potential in many central neurones. The biophysical and pharmacological attributes of cloned SK channels strongly suggest that one or more of them underlie the medium component of the AHP that regulates interspike interval and plays an important role in setting tonic firing frequency. The cloned SK channels comprise a distinct subfamily of K(+) channels. Heterologously expressed SK channels recapitulate the biophysical and pharmacological hallmarks of native SK channels, being gated solely by intracellular Ca(2+) ions with no voltage dependence to their gating, small unitary conductance values and sensitivity to the bee venom peptide toxin, apamin. Molecular, biochemical and electrophysiological studies have revealed that Ca(2+) gating in SK channels is due to heteromeric assembly of the SK alpha pore-forming subunits with calmodulin (CaM). Ca(2+) binding to the N-terminal E-F hands of CaM is responsible for SK channel gating. Crystallographic studies suggest that SK channels gate as a dimer-of-dimers, and that the physical gate of SK channels resides at or near the selectivity filter of the channels. In addition, Ca(2+)-independent interactions between the SK channel alpha subunits and CaM are necessary for proper membrane trafficking.


Endocannabinoid system as a regulator of tumor cell malignancy - biological pathways and clinical significance.
The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy.


Survey of RF exposure levels from mobile telephone base stations in Australia.
This paper reports the results of an exposure level survey of radiofrequency electromagnetic energy originating from mobile telephone base station antennas. Measurements of CDMA800, GSM900, GSM1800, and 3G(UMTS) signals were performed at distances ranging over 50 to 500 m from 60 base stations in five Australian cities. The exposure levels from these mobile telecommunications base stations were found to be well below the general public exposure limits of the ICNIRP guidelines and the Australian radiofrequency standard (ARPANSA RPS3). The highest recorded level from a single base station was 7.8 x 10(-3) W/m(2), which translates to 0.2% of the general public exposure limit.


Using bicistronic constructs to evaluate the chaperone activities of heat shock proteins in cells.
Heat shock proteins (Hsps) are molecular chaperones that prevent the aggregation of client proteins by facilitating their refolding, or trafficking them for degradation. The chaperone activities of Hsps are dependent on dynamic protein-protein interactions, including their oligomerisation into large multi-subunit complexes. Thus, tagging Hsps with fluorescent proteins can interfere with their chaperone activity. To overcome this limitation, we have exploited bicistronic constructs for the concurrent expression of a non-tagged Hsp and fluorescent reporter from a single mRNA in cells. We used the Hsp-encoding bicistronic constructs in a cell-based model of protein aggregation, using a destabilised (mutant) form of firefly luciferase (mFluc) that forms inclusion bodies in cells. Expression of Hsp40, Hsp70, or Hsp40 and Hsp70 in cells expressing mFluc decreased the formation of inclusion bodies by 25-46% compared to controls. Moreover, there was a concentration-dependent decrease in the proportion of cells with inclusions when Hsp70, or Hsp40 and Hsp70 were co-expressed with mFluc in cells. The Hsp-encoding bicistronic constructs enable transfection efficiencies and concentration-dependent effects of Hsp expression to be determined using fluorescence based techniques, without the need to tag the Hsp with a fluorescent protein.


Viral-induced systemic necrosis in plants involves both programmed cell death and the inhibition of viral multiplication, which are regulated by independent pathways.
Resistant plants respond rapidly to invading avirulent plant viruses by triggering a hypersensitive response (HR). An HR is accompanied by a restraint of virus multiplication and programmed cell death (PCD), both of which have been observed in systemic necrosis triggered by a successful viral infection. Here, we analyzed signaling pathways underlying the HR in resistance genotype plants and those leading to systemic necrosis. We show that systemic necrosis in Nicotiana benthamiana, induced by Plantago asiatica mosaic virus (PlAMV) infection, was associated with PCD, biochemical features, and gene expression patterns that are characteristic of HR. The induction of necrosis caused by PlAMV infection was dependent on SGT1, RAR1, and the downstream mitogen-activated protein kinase (MAPK) cascade involving MAPKKKalpha and MEK2. However, although SGT1 and RAR1 silencing led to an increased accumulation of PlAMV, silencing of the MAPKKKalpha-MEK2 cascade did not. This observation indicates that viral multiplication is partly restrained even in systemic necrosis induced by viral infection, and that this restraint requires SGT1 and RAR1 but not the MAPKKKalpha-MEK2 cascade. Similarly, although both SGT1 and MAPKKKalpha were essential for the Rx-mediated HR to Potato virus X (PVX), SGT1 but not MAPKKKalpha was involved in the restraint of PVX multiplication. These results suggest that systemic necrosis and HR consist of PCD and a restraint of virus multiplication, and that the latter is induced through unknown pathways independent from the former.


The development of postgraduate anaesthesia and intensive care training at the University of the West Indies.
The one-year Diploma in Anaesthetics (DA) was the first postgraduate programme offered by the then Faculty of Medicine of The University of the West Indies (UWI). It was instituted in 1966, when the need for trained physician anaesthetists became paramount. Over 200 physicians have been awarded the DA which was discontinued in 1994. The four-year Doctor of Medicine in Anaesthetics [DM (Anaesthetics)] was commenced in 1974 and continues to train most of the region's physician anaesthetists. The majority of the 119 graduates (as of December 2011) are providing invaluable services to the people of the Caribbean. The time has come for the establishment of a regional certifying body, the Caribbean College of Anaesthetists. This college would determine the standards for the training and clinical practice of anaesthetists as perioperative physicians including: the conduct of anaesthesia, critical care, acute and chronic pain management. It would also facilitate continuing medical education and recertification of all practising anaesthetists within the region.


Spatial foraging segregation by close neighbours in a wide-ranging seabird.
Breeding seabirds are central-place foragers and therefore exploit food resources most intensively nearer their colonies. When nesting aggregations are close to one another density-dependent competition is likely to be high, potentially promoting foraging segregation (i.e. neighbouring colonies may segregate to search for food in different areas). However, little is known about spatial segregation in foraging behaviour between closely adjacent colonies, particularly in species that are wide-ranging foragers. Here, we tested for foraging segregation between two sub-colonies of a wide-ranging seabird, Cory's shearwater Calonectris borealis, separated by only 2 km, on a small Island in the North Atlantic. During the 2010 chick-rearing period, 43 breeding adults of both sexes were simultaneously sampled at both sub-colonies. A GPS logger was deployed on each individual and removed after several foraging trips at sea. Blood samples (plasma and red blood cells) were collected from each tracked individual for stable isotope analysis. Results indicated partial spatial segregation between the two sub-colonies during local foraging trips (i.e. those of ≤1 day duration and 216 km from the colony) accounting for 84.2% of all trips recorded. The location of the breeding sub-colony influenced the direction of travel of birds during local trips resulting in sub-colony-specific foraging areas. Although the oceanographic conditions associated with the foraging range of the two sub-colonies differed, no differences were found in the habitat exploited and in their estimated diets. This suggests that birds concentrated their feeding activity in patches of similar habitat and prey during the chick-rearing period.