Spontaneous emission enhancement and saturable absorption of colloidal quantum dots coupled to photonic crystal cavity.
We demonstrate spontaneous emission rate enhancement and saturable absorption of cadmium selenide colloidal quantum dots coupled to a nanobeam photonic crystal cavity. We perform time-resolved lifetime measurements and observe an average enhancement of 4.6 for the spontaneous emission rate of quantum dots located at the cavity as compared to those located on an unpatterned surface. We also demonstrate that the cavity linewidth narrows with increasing pump intensity due to quantum dot saturable absorption.


Profiling the thermodynamic softness of adenoviral promoters.
We showed previously that anharmonic DNA dynamical features correlate with transcriptional activity in selected viral promoters, and hypothesized that areas of DNA softness may represent loci of functional significance. The nine known promoters from human adenovirus type 5 were analyzed for inherent DNA softness using the Peyrard-Bishop-Dauxois model and a statistical mechanics approach, using a transfer integral operator. We found a loosely defined pattern of softness peaks distributed both upstream and downstream of the transcriptional start sites, and that early transcriptional regions tended to be softer than late promoter regions. When reported transcription factor binding sites were superimposed on our calculated softness profiles, we observed a close correspondence in many cases, which suggests that DNA duplex breathing dynamics may play a role in protein recognition of specific nucleotide sequences and protein-DNA binding. These results suggest that genetic information is stored not only in explicit codon sequences, but also may be encoded into local dynamic and structural features, and that it may be possible to access this obscured information using DNA dynamics calculations.


Deciphering the MSG controversy.
Monosodium glutamate (MSG), a common flavor enhancer in various canned food and stereotypically associated with food in Chinese restaurants, has been claimed and tested to have side effects including headache and dizziness. However, the mechanism behind MSG-induced headache was not clear. Using dissociated mouse neuronal culture and cell injury assays, we determined whether incubation of neurons with clinically relevant concentrations of MSG induces cell swelling or death, and whether any measure can be taken to prevent or reduce MSG effects. We demonstrated that (1) Treatment with MSG induces a dose-dependent swelling and death of mature neurons (12-14 days in culture) with little effect on young immature neurons (<1 week in culture). The threshold concentration of MSG for neuronal injury is 3 microM; (2) MSG only injures neurons with little effect on glial cells; (3) Boiling MSG does not affect its toxicity but the addition of Vitamin C provides significant protection against MSG toxicity; (4) Pretreatment of neurons with a low dose of MSG reduces subsequent injury by a large dose of MSG. Together, our studies suggest that the side effect of MSG may be mediated, at least in part, by its toxic effect on brain neurons. Pre-exposure to low doses of MSG or the use of Vitamin C may prevent or reduce the side effects of MSG.


Fluorosis: a new model and new insights.
Fluoride is an effective agent for the prevention of dental caries. However, the mechanism of how excessive fluoride exposure causes fluorosis remains uncertain. Zebrafish (Danio rerio) exhibit periodic tooth replacement throughout their lives, thereby providing continuous access to teeth at developmental stages susceptible to fluoride exposure. Zebrafish teeth do not contain true enamel, but consist of a hard enameloid surface. Therefore, we asked whether zebrafish could be used as a model organism for the study of dental fluorosis. Scanning electron microscopy of fluoride-treated teeth demonstrated that the enameloid was pitted and rough, and FTIR analysis demonstrated that the teeth also contained a significantly higher organic content when compared with untreated controls. Furthermore, we demonstrate for the first time that decreased expression of an important signaling molecule (Alk8) in tooth development may contribute to the observed fluorotic phenotype, and that increased cell apoptosis may also play a role in the mechanism of fluorosis.


How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.
Various factors have been proposed to be related to refractory chronic rhinosinusitis (CRS). Treatment for refractory CRS is challenging for ear, nose, and throat (ENT) surgeons. The aim of the study was to determine the clinical features associated with the severity of CRS that may necessitate revision surgery by eliminating the bias of the surgeons technique using standardizing surgical procedures. Sinus wall thickness and blood eosinophilia, which may represent the depth of inflammation in CRS, are associated with the need for revision surgery. We found that, when the thickness of the postero-lateral maxillary sinus wall is more than 3.03 mm, there is an increased probability for a need for revision surgery. CRS patients with thickened sinus walls were found to have poorer outcomes. Further research is needed in order to justify this type of surgical procedure for CRS.


Rate of protein synthesis in skeletal muscle of normal man and patients with muscular dystrophy: a reassessment.
1. Quadriceps muscle protein synthetic rate has been determined in healthy subjects in the post-absorptive (n = 18) and fed (n = 10) states and in patients with a variety of myopathies, by analysis of the enrichment of serial muscle biopsies taken during primed continuous infusion of L-[1-13C]leucine. 2. Quadriceps protein synthetic rates in normal subjects were (mean +/- SD) 0.046 +/- 0.012 and 0.075 +/- 0.014%/h in the post-absorptive and fed states respectively. These results are significantly lower than we previously reported (M. J. Rennie et al., Clinical Science, 1982, 63, 519-523 [1]) but show the same relative differences of direction and magnitude, confirming the effects of feeding previously reported. In patients with muscular dystrophy, muscle protein synthetic rate was, as previously reported [1], much lower in the fed state than in normal subjects. A new finding is that for patients with myotonic dystrophy the rate is also depressed in the post-absorptive state. 3. We suggest that the present estimates in post-absorptive and fed normal subjects be used as reference values for quadriceps mixed muscle protein synthetic rate.


Blind multichannel reconstruction of high-resolution images using wavelet fusion.
We developed an approach to the blind multichannel reconstruction of high-resolution images. This approach is based on breaking the image reconstruction problem into three consecutive steps: a blind multichannel restoration, a wavelet-based image fusion, and a maximum entropy image interpolation. The blind restoration step depends on estimating the two-dimensional (2-D) greatest common divisor (GCD) between each observation and a combinational image generated by a weighted averaging process of the available observations. The purpose of generating this combinational image is to get a new image with a higher signal-to-noise ratio and a blurring operator that is a coprime with all the blurring operators of the available observations. The 2-D GCD is then estimated between the new image and each observation, and thus the effect of noise on the estimation process is reduced. The multiple outputs of the restoration step are then applied to the image fusion step, which is based on wavelets. The objective of this step is to integrate the data obtained from each observation into a single image, which is then interpolated to give an enhanced resolution image. A maximum entropy algorithm is derived and used in interpolating the resulting image from the fusion step. Results show that the suggested blind image reconstruction approach succeeds in estimating a high-resolution image from noisy blurred observations in the case of relatively coprime unknown blurring operators. The required computation time of the suggested approach is moderate.


Interventions at caesarean section for reducing the risk of aspiration pneumonitis.
Aspiration pneumonitis is a syndrome resulting from the inhalation of gastric contents. The incidence in obstetric anaesthesia has fallen, largely due to improved anaesthetic techniques and the increased use of regional anaesthesia at caesarean section. However, aspiration pneumonitis is still a cause of maternal morbidity and mortality, and it is important to use effective prophylaxis. To determine whether interventions given prior to caesarean section reduce the risk of aspiration pneumonitis in women with an uncomplicated pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2009). Randomised controlled trials were included. Quasi-randomised trials were excluded. Authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data entry was checked. Twenty-two studies, involving 2658 women, are included, all having a caesarean section under general anaesthesia. The studies covered a number of comparisons, but were mostly small and of unclear or poor quality.When compared to no treatment or placebo, there was a significant reduction in the risk of intragastric pH < 2.5 with antacids (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.09 to 0.32, two studies, 108 women), H(2) antagonists (RR 0.09, 95% CI 0.05 to 0.18, two studies, 170 women) and proton pump antagonists (RR 0.26, 95% CI 0.14 to 0.46, one study 80 women). H(2) antagonists were associated with a reduced the risk of intragastric pH < 2.5 at intubation when compared with proton pump antagonists (RR 0.39, 95% CI 0.16 to 0.97, one study, 120 women), but compared with antacids the findings were unclear. The combined use of 'antacids plus H(2) antagonists' was associated with a significant reduction in the risk of intragastric pH < 2.5 at intubation when compared with placebo (RR 0.02, 95% CI 0.00 to 0.15, one study, 89 women) or compared with antacids alone (RR 0.12, 95% CI 0.02 to 0.92, one study, 119 women). The quality of the evidence was poor, but the findings suggest that the combination of antacids plus H(2) antagonists was more effective than no intervention, and superior to antacids alone in preventing low gastric pH. However, none of the studies assessed potential adverse effects or substantive clinical outcomes. These findings are relevant for all women undergoing caesarean section under general anaesthesia.


ON THE RELATION OF TETANY TO THE PARATHYROID GLANDS AND TO CALCIUM METABOLISM.
1. Tetany occurs spontaneously in many forms and may also be produced by the destruction of the parathyroid glands. Recent researches tend to demonstrate an intimate relation between the various forms of tetany and relative or absolute insufficiency of the parathyroid gland. 2. The parathyroid glands are independent organs with definite specific function. Whether or not this function is intimately related to that of other organs of internal secretion is not as yet proven. 3. The number and distribution of the parathyroid glands varies. Failure to produce tetany experimentally is probably due to the fact that some parathyroid tissue remains after an apparently complete extirpation. When extirpation is complete tetany appears, even in herbivora. Only a very small amount of parathyroid tissue is required to prevent this. 4. The effect of the extirpation of the parathyroid glands may be annulled by the reintroduction of an extract of these glands even from an animal of widely different character. The active principle is associated with a nucleo-proteid in the extract and may be separated with this nucleo-proteid from the remaining inert albuminous substances. Its effect in counteracting tetany appears some hours after injection and lasts several days. 5. The parathyroid glands contain no considerable amount of iodine. The parathyroid extract is not an iodine containing compound. 6. In tetany there is apparently some disturbance of the composition of the circulating fluids ordinarily prevented by the secretion of the parathyroid, which disarranges the balance of the mineral constituents of the tissues. Possibly this consists in the appearance of an injurious substance of an acid nature for such tetany may he relieved by extensive bleeding with replacement of the blood by salt solution. No actual poisonous material has, however, been demonstrated by the transference of the blood of a tetanic animal to the veins of a normal one. 7. Numerous researches have shown the important relation of the calcium salts to the excitability of the central nervous system. Their withdrawal leaves the nerve cells in a state of hyperexcitability which can be made to disappear by supplying them with a solution of a calcium salt. 8. Tetany may be regarded as an expression of hyperexcitability of the nerve cells from some such cause. 9. The injection of a solution of a salt of calcium into the circulation of an animal in tetany promptly checks all the symptoms and restores the animal to an apparently normal condition. 10. Injections of magnesium salts probably have a similar effect but these effects are masked by the toxic action of the salt. 11. The injection of sodium or potassium salts has no such beneficial effect but rather tends to intensify the symptoms. This is true also of the alkaline salts of sodium which were studied especially in respect to their basic properties. 12. The effect of calcium is of value in human therapeutics in combating the symptoms of spontaneous forms of tetany and in relieving the symptoms in cases of operative tetany and thus tiding over the period of acute parathyroid insufficiency until remnants of parathyroid tissue can recover their function or new parathyroid tissue can be transplanted. It is in this way an important and convenient ally of the method of injecting parathyroid extract. 13. Studies of the metabolism in parathyroidectomized animals show: 1. A marked reduction in the calcium content of the tissues especially of the blood and brain, during tetany. 2. An increased output of calcium in the urine and faeces on the development of tetany. 3. An increased output of nitrogen in the urine. 4. An increased output of ammonia in the urine with 4a. an increased ammonia ratio in the urine. 5. An increased amount of ammonia in the blood. Much of this affords evidence of the existence of some type of acid intoxication. Its effects are, however, not neutralized by the introduction of alkaline sodium salts and may perhaps be regarded as especially important in producing a drainage of calcium salts from the tissues which can be remedied by the reintroduction of calcium salts. 14. Emphasis must be laid upon the remarkable difference which exists between the alterations inmetabolism following thyroidectomy and those following parathyroidectomy. In myxoedema there is lowered metabolism, decreased respiratory changes and lowered nitrogen output with depression of body temperature. In tetany there is increased metabolism, probably increased respiratory changes, certainly increase in nitrogen output and elevation of the temperature. 15. It is important, therefore, that in any experiments upon metabolism in relation to the thyroid and parathyroid gland, these glands should be clearly distinguished as structures exercising very different and in large part contrary effects upon metabolism. 16. In general the role of the calcium salts in connection with tetany may be conceived of as follows: These salts have a moderating influence upon the nerve cells. The parathyroid secretion in some way controls the calcium exchange in the body. It may possibly be that in the absence of the parathyroid secretion, substances arise which can combine with calcium, abstract it from the tissues and cause its excretion and that the parathyroid secretion prevents the appearance of such bodies. The mechanism of the parathyroid action is not determined, but the result, the impoverishment of the tissues with respect to calcium and the consequent development of hyperexcitability of the nerve cells, and tetany is proven. Only the restoration of calcium to the tissues can prevent this. 17. This explanation is readily applicable to spontaneous forms of tetany in which there is a drain of calcium for physiological purposes, or in which some other condition causes a drain of calcium. In such cases the parathyroid glands may be relatively insufficient.


Stoichiometry and turnover of the bacterial flagellar switch protein FliN.
Some proteins in biological complexes exchange with pools of free proteins while the complex is functioning. Evidence is emerging that protein exchange can be part of an adaptive mechanism. The bacterial flagellar motor is one of the most complex biological machines and is an ideal model system to study protein dynamics in large multimeric complexes. Recent studies showed that the copy number of FliM in the switch complex and the fraction of FliM that exchanges vary with the direction of flagellar rotation. Here, we investigated the stoichiometry and turnover of another switch complex component, FliN, labeled with the fluorescent protein CyPet, in Escherichia coli. Our results confirm that, in vivo, FliM and FliN form a complex with stoichiometry of 1:4 and function as a unit. We estimated that wild-type motors contained 120 ± 26 FliN molecules. Motors that rotated only clockwise (CW) or counterclockwise (CCW) contained 114 ± 17 and 144 ± 26 FliN molecules, respectively. The ratio of CCW-to-CW FliN copy numbers was 1.26, very close to that of 1.29 reported previously for FliM. We also measured the exchange of FliN molecules, which had a time scale and dependence upon rotation direction similar to those of FliM, consistent with an exchange of FliM-FliN as a unit. Our work confirms the highly dynamic nature of multimeric protein complexes and indicates that, under physiological conditions, these machines might not be the stable, complete structures suggested by averaged fixed methodologies but, rather, incomplete rings that can respond and adapt to changing environments. Importance: The flagellum is one of the most complex structures in a bacterial cell, with the core motor proteins conserved across species. Evidence is now emerging that turnover of some of these motor proteins depends on motor activity, suggesting that turnover is important for function. The switch complex transmits the chemosensory signal to the rotor, and we show, by using single-cell measurement, that both the copy number and the fraction of exchanging molecules vary with the rotational bias of the rotor. When the motor is locked in counterclockwise rotation, the copy number is similar to that determined by averaged, fixed methodologies, but when locked in a clockwise direction, the number is much lower, suggesting that that the switch complex ring is incomplete. Our results suggest that motor remodeling is an important component in tuning responses and adaptation at the motor.


Inhibitory effect of silicon nanowires on the polymerase chain reaction.
The effect of nanomaterials on biological reactions has received much attention. We report herein that silicon nanowires (SiNWs) inhibit the polymerase chain reaction (PCR). The inhibitory effect was found to be concentration-dependent, with a minimum inhibitory concentration of about 0.4 mg ml(-1). DNA polymerase, restriction endonucleases, lysozyme and horseradish peroxidase maintained their bioactivities after exposure to SiNWs. Also the interaction of SiNWs with primers and dNTP did not lead to decreased PCR yield. Compared to primers and dNTP, template DNA showed 4.7-10.5-fold greater adsorption on SiNWs. Template bound to SiNWs was ineffective in the PCR, whereas addition of free template to the PCR system increased the yield. The results of this work suggest that the inhibitory effect of SiNWs on the PCR was due to the selective adsorption of double-stranded DNA on SiNWs, thereby decreasing the availability of template for the reaction.


Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.
Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.


A prospective investigation of the role of cognitive factors in persistent posttraumatic stress disorder (PTSD) after physical or sexual assault.
The effectiveness of psychological treatments for PTSD is likely to be enhanced by improved understanding of the factors involved in maintaining the disorder. Ehlers and Clark [A cognitive model of persistent posttraumatic stem disorder Behav. Res. Ther. 38 (2000) 319-345] recently proposed a cognitive model of maintenance. The current study aimed to investigate several cognitive factors highlighted in Ehlers and Clark's model using a prospective design. Fifty-seven victims of physical or sexual assault participated in the study. Cognitive factors were assessed within 4 months of assault and victims were followed-up 6 and 9 months after the assault. Cognitive variables which significantly predicted PTSD severity at both follow-ups were: cognitive processing style during assault (mental defeat, mental confusion, detachment); appraisal of assault sequelae (appraisal of symptoms, perceived negative responses of others, permanent change); negative beliefs about self and world; and maladaptive control strategies (avoidance/safety seeking). Relationships between early appraisals, control strategies, and processing styles and subsequent PTSD severity remained significant after statistically controlling for gender and perceived assault severity. These findings support the cognitive model of PTSD proposed by Ehlers and Clark and suggest that effective treatment will need to address these cognitive factors.


Hydrogen bonding and catalysis: a novel explanation for how a single amino acid substitution can change the pH optimum of a glycosidase.
The pH optima of family 11 xylanases are well correlated with the nature of the residue adjacent to the acid/base catalyst. In xylanases that function optimally under acidic conditions, this residue is aspartic acid, whereas it is asparagine in those that function under more alkaline conditions. Previous studies of wild-type (WT) Bacillus circulans xylanase (BCX), with an asparagine residue at position 35, demonstrated that its pH-dependent activity follows the ionization states of the nucleophile Glu78 (pKa 4.6) and the acid/base catalyst Glu172 (pKa 6.7). As predicted from sequence comparisons, substitution of this asparagine residue with an aspartic acid residue (N35D BCX) shifts its pH optimum from 5.7 to 4.6, with an approximately 20% increase in activity. The bell-shaped pH-activity profile of this mutant enzyme follows apparent pKa values of 3.5 and 5.8. Based on 13C-NMR titrations, the predominant pKa values of its active-site carboxyl groups are 3.7 (Asp35), 5.7 (Glu78) and 8.4 (Glu172). Thus, in contrast to the WT enzyme, the pH-activity profile of N35D BCX appears to be set by Asp35 and Glu78. Mutational, kinetic, and structural studies of N35D BCX, both in its native and covalently modified 2-fluoro-xylobiosyl glycosyl-enzyme intermediate states, reveal that the xylanase still follows a double-displacement mechanism with Glu78 serving as the nucleophile. We therefore propose that Asp35 and Glu172 function together as the general acid/base catalyst, and that N35D BCX exhibits a "reverse protonation" mechanism in which it is catalytically active when Asp35, with the lower pKa, is protonated, while Glu78, with the higher pKa, is deprotonated. This implies that the mutant enzyme must have an inherent catalytic efficiency at least 100-fold higher than that of the parental WT, because only approximately 1% of its population is in the correct ionization state for catalysis at its pH optimum. The increased efficiency of N35D BCX, and by inference all "acidic" family 11 xylanases, is attributed to the formation of a short (2.7 A) hydrogen bond between Asp35 and Glu172, observed in the crystal structure of the glycosyl-enzyme intermediate of this enzyme, that will substantially stabilize the transition state for glycosyl transfer. Such a mechanism may be much more commonly employed than is generally realized, necessitating careful analysis of the pH-dependence of enzymatic catalysis.


Emergence of group B streptococci in obstetric and perinatal infections.
A retrospective study of obstetric and perinatal illness due to group B streptococci during 1972-4 based on bacteriological referrals from Aberdeen Maternity Hospital and Special Nursery disclosed (1) a wide spectrum of maternal morbidity, particularly associated with amniotomy and a prolonged rupture-delivery interval, and (2) the emergence of the group B streptococcus as a major cause of serious neonatal infection in infants of low birth weight, often in the absence of maternal pyrexia. The group B isolates appeared to show a previously undocumented increased resistance to the aminoglycosides gentamicin and kanamycin. A prospective study of 369 random deliveries in Aberdeen Maternity Hospital showed a group B vaginal carriage rate of 49/1000; a neonatal colonization rate of 19/1000; maternal and neonatal morbidity rates of 16 and 2-7/1000, respectively; and an overall neonatal mortality of 1/1000 live births.


Psychophysical assessment of assistive devices for transferring patients/residents.
This article reports the psychophysical assessment of nine battery-powered lifts, a sliding board, a walking belt, and a baseline manual method for transferring nursing home patients/residents from a bed to a chair. A separate article reports the biomechanical evaluation of the same task and devices. The objectives of the psychophysical assessment were to investigate the effects of resident-transferring methods on the psychophysical stress to nursing assistants performing the transferring task, and to identify transfer methods that could reduce the psychophysical stress reported by nursing assistants. Nine nursing assistants served as test subjects. Two elderly persons participated as residents. The results indicated that the psychophysical stresses on nursing assistants were significantly lower when performing resident transfers with some of the assistive devices than when performing transfers with the baseline manual transfer method. The nursing assistants generally preferred the basket-sling lift and stand-up lift to other methods. The residents' comfort and security ratings indicated the comfort and security with most of the assistive devices were greater than or equal to the baseline manual method. Most of the comments of the nursing assistants and residents on the assistive devices were favourable.


Submicrometer radius and highly confined plasmonic ring resonator filters based on hybrid metal-oxide-semiconductor waveguide.
We numerically report the submicrometer radius (0.5 μm) and high confinement (mode area ~λ(2)/1200) plasmonic ring resonators for both all-pass and add-drop filters based on the hybrid metal-oxide-semiconductor (Ag-SiO(2)-Si) waveguide platform. The best tradeoff between the propagation length and the confinement of this hybrid plasmonic waveguide platform is also discussed and compared to the dielectric-loaded plasmonic waveguide counterpart. We show that the ring resonator all-pass filter features an extinction ratio as high as 23 dB with a transmission loss of 1.5 dB, and a wide free spectral range of 168 nm with a bandwidth of 14 nm. Moreover, the demonstrated add-drop filter achieves an extinction ratio larger than 12 dB with a channel isolation between the through and drop channels of 13.5 dB at the resonant wavelength. These demonstrated plasmonic devices reveal as potential building blocks for future nanoscale electronic-photonic integrated circuits.


Temporal evolution of oscillatory activity predicts performance in a choice-reaction time reaching task.
In this study, we characterized the patterns and timing of cortical activation of visually guided movements in a task with critical temporal demands. In particular, we investigated the neural correlates of motor planning and on-line adjustments of reaching movements in a choice-reaction time task. High-density electroencephalography (EEG, 256 electrodes) was recorded in 13 subjects performing reaching movements. The topography of the movement-related spectral perturbation was established across five 250-ms temporal windows (from prestimulus to postmovement) and five frequency bands (from theta to beta). Nine regions of interest were then identified on the scalp, and their activity was correlated with specific behavioral outcomes reflecting motor planning and on-line adjustments. Phase coherence analysis was performed between selected sites. We found that motor planning and on-line adjustments share similar topography in a fronto-parietal network, involving mostly low frequency bands. In addition, activities in the high and low frequency ranges have differential function in the modulation of attention with the former reflecting the prestimulus, top-down processes needed to promote timely responses, and the latter the planning and control of sensory-motor processes.


Effects of yoga on well-being and healthy ageing: study protocol for a randomised controlled trial (FitForAge).
Due to ageing populations worldwide, the burden of disability is increasing. It is therefore important to develop interventions that improve healthy ageing, reduce disability onset and enhance life quality. Physical activity can promote healthy ageing and help maintain independence, yet many older adults are inactive. Yoga is a form of physical activity that aims to improve health and may be particularly suitable for older adults. Research indicates positive effects of yoga on several health-related outcomes; however, empirical studies examining the benefits of yoga on well-being among the elderly remain scarce. This study protocol reports the methodology for a 12-week yoga programme aimed to improve health and well-being among physically inactive older adults. Three group parallel, single-blind randomised controlled trial. Two comparison groups are included: aerobic exercise and a non-active wait-list control. In total, 180 participants aged 65-85 years will be recruited. Assessments will be performed at baseline and postintervention (12-week follow-up). The primary outcome is subjective well-being. Secondary outcomes include physical activity/sedentary behaviour, mobility/fall risk, cognition, depression, anxiety, mood, stress, pain, sleep quality, social support and cardiometabolic risk factors. Data will be analysed using intention-to-treat analyses, with mixed linear modelling. This study is approved by the Ethical Review Board in Stockholm (2017/1862-31/2). All participants must voluntarily agree to participate and are free to withdraw from the study at any point. Written informed consent will be obtained from each participant prior to inclusion. Results will be available through research articles and conferences. A summary of key results will be publicly available through newspaper articles. DRKS00015093, U1111-1217-4248.


MutMap Approach Enables Rapid Identification of Candidate Genes and Development of Markers Associated With Early Flowering and Enhanced Seed Size in Chickpea (Cicer arietinum L.).
Globally terminal drought is one of the major constraints to chickpea (Cicer arietinum L.) production. Early flowering genotypes escape terminal drought, and the increase in seed size compensates for yield losses arising from terminal drought. A MutMap population for early flowering and large seed size was developed by crossing the mutant line ICC4958-M3-2828 with wild-type ICC 4958. Based on the phenotyping of MutMap population, extreme bulks for days to flowering and 100-seed weight were sequenced using Hi-Seq2500 at 10X coverage. On aligning 47.41 million filtered reads to the CDC Frontier reference genome, 31.41 million reads were mapped and 332,395 single nucleotide polymorphisms (SNPs) were called. A reference genome assembly for ICC 4958 was developed replacing these SNPs in particular positions of the CDC Frontier genome. SNPs specific for each mutant bulk ranged from 3,993 to 5,771. We report a single unique genomic region on Ca6 (between 9.76 and 12.96 Mb) harboring 31, 22, 17, and 32 SNPs with a peak of SNP index = 1 for low bulk for flowering time, high bulk for flowering time, high bulk for 100-seed weight, and low bulk for 100-seed weight, respectively. Among these, 22 SNPs are present in 20 candidate genes and had a moderate allelic impact on the genes. Two markers, Ca6EF10509893 for early flowering and Ca6HSDW10099486 for 100-seed weight, were developed and validated using the candidate SNPs. Thus, the associated genes, candidate SNPs, and markers developed in this study are useful for breeding chickpea varieties that mitigate yield losses under drought stress.


Enhancing NEMD with automatic shear rate sampling to model viscosity and correction of systematic errors in modeling density: Application to linear and light branched alkanes.
We perform molecular dynamics simulations to model density as a function of temperature for 74 alkanes with 5-10 carbon atoms and non-equilibrium molecular dynamics simulations in the NVT ensemble to model the kinematic viscosity of 10 linear alkanes as a function of molecular weight, pressure, and temperature. To model density, we perform simulations in the NPT ensemble before applying correction factors to exploit the systematic error in the SciPCFF force field and compare the results to experimental values, obtaining an average absolute deviation of 3.4 gl at 25 °C and of 7.2 gl at 100 °C. We develop a sampling algorithm that automatically selects good shear rates at which to perform viscosity simulations in the NVT ensemble and use the Carreau model with weighted least squares regression to extrapolate Newtonian viscosity. Viscosity simulations are performed at experimental densities and show an excellent agreement with experimental viscosities, with an average percent deviation of -1% and an average absolute percent deviation of 5%. Future plans to study and apply the sampling algorithm are outlined.


Intrauterine device may trigger typical attacks of familial Mediterranean fever: a case report.
Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by episodic, recurrent, self-limited attacks of fever and serositis (sterile peritonitis, pleuritis, arthritis, etc). The insufficiency in restriction of mild inflammation contributes this consequence in FMF.Intrauterine devices (IUDs) have been widely used in the world for contraception by gynecologists as an effective and safe method. Herein, we present a woman with FMF as the first case, whose attacks were triggered by copper-containing IUD. Our hypothesis in the present case was that sterile mild inflammation in the uterus caused by copper-containing IUD may be the initial source of systemic inflammatory response.In our opinion, clinicians should consider that the copper-containing IUDs may be another cause of FMF attacks in women using this contraceptive method.


Adherence to therapies for secondary prevention of cardiovascular disease: a focus on aspirin.
Suboptimal adherence to medications taken chronically for secondary prevention of cardiovascular disease (CVD, e.g., aspirin) continues to burden the healthcare system despite the well-established benefits of prevention. We conducted a literature search to examine patient adherence to medications for secondary prevention of CVD-as evaluated by prescription refill data, electronic medication monitors, pill counts, and physiologic markers-to better identify an unmet need for measures to improve patient adherence to these therapies. English-language articles were obtained from the PubMed database using the following key words or combinations thereof "adherence," "compliance," "secondary prevention," and "cardiovascular disease." Publications that provided adherence data only for primary prevention, lacked data on medication adherence (e.g., focus on guideline adherence), emphasized quality-of-care outcomes, or focused on outcomes of acute interventions were excluded. Multiple patient-, disease-, and treatment-related factors may contribute to poor adherence to treatment regimens, and therefore, a multifactorial approach will likely be needed to improve compliance with prescribed treatments for CVD. Although no magic bullet exists to assure full adherence, adherence programs coupled with patient counseling and education (inclusive of over-the-counter therapies), along with treatments that are less complex or avoid bothersome adverse effects, are more likely to be associated with successful outcomes. Given the burden of CVD to the community and the healthcare system, nonadherence to CVD-preventative medications such as aspirin remains a substantial area of unmet need and represents a key opportunity for the development of quality-of-care enhancement programs to improve health outcomes in this patient population.


Renal endothelial dysfunction in diabetic nephropathy.
Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN). Due to the heterogeneity of endothelial cells (ECs), it is difficult to generalize about endothelial responses to diabetic stimuli. At present, there are limited techniques fordirectly measuring EC function in vivo, so diagnosis of endothelial disorders still largely depends on indirect assessment of mediators arising from EC injury. In the kidney microcirculation, both afferent and efferent arteries, arterioles and glomerular endothelial cells (GEnC) have all been implicated as targets of diabetic injury. Both hyperglycemia per se, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in EC dysfunction. Impaired eNOS activity can occur at numerous levels, including enzyme uncoupling, post-translational modifications, internalization and decreased expression. Reduced nitric oxide (NO) bioavailability exacerbates oxidative stress, further promoting endothelial dysfunction and injury. The injured ECs may then function as active signal transducers of metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interact with adjacent cells, which may activate a cascade of inflammatory and proliferative and profibrotic responses in progressive DN. Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.


Case-finding effectiveness of partner notification and cluster investigation for sexually transmitted diseases/HIV.
To assess the case-finding effectiveness of partner notification(PN) and cluster investigation for sexually transmitted disease (STD)/human immunodeficiency virus (HIV). Literature review and quantitative summary. Since 1975, the median case-finding yield for syphilis, gonorrhea, and chlamydia PN reported in the literature is about 1 new case found for every 4 or 5 cases interviewed. The yield from HIV PN is approximately half as large, although there is substantial variability in yield across reports for each disease. Published reports underline the central role provider referral plays in effective PN and case-finding. Successful PN is more likely with index cases who are of majority ethnicity and detected through screening or spontaneous presentation for care with symptoms and with partners with whom index cases have had sexual contact that is recent, frequent, and of long duration. The case-finding yield for HIV PN also is much higher when cases are diagnosed through confidential, rather than anonymous, testing. Cluster investigation and related strategies tend to have lower case-finding yields than PN but can play a very useful case-finding role, especially in settings with high disease incidence. STD/HIV PN and cluster investigation can contribute meaningfully to case finding. More research is needed to strengthen the empiric foundation of PN and related strategies, including the impact they have on disease transmission.


Characterization of lung-to-finger circulation time in sleep study assessment: the Multi-Ethnic Study of Atherosclerosis.
Lung-to-finger circulation time (LFCT) measured from sleep studies may reflect underlying cardiac dysfunction. We aimed to examine the distribution of LFCT in community-dwelling men and women in order to better understand the factors determining LFCT between and within subjects. We included participants of the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep with polysomnography-based evidence of sleep apnea (defined by apnea hypopnea index >15 hr-1). In a randomly selected subset of the analytical dataset, we tested an automated LFCT measurement method against the visual method. Using the automated method we then scored LFCTs from all eligible respiratory events for all included participants. A multiple regression model was constructed to determine factors independently associated with average LFCT across subjects. We also explored factors that are associated with LFCT within subjects using linear mixed-effect models. In a subset of the cohort (N = 39) there was a high correlation in average LFCT obtained by automated and visual methods (r = 0.96). In the analysis of 596 participants, men [19.6 (2.8)] (vs. women [17.9 (2.7) s], p < 0.0001) and older age (> 69 (vs. ≤ 69) had longer average LFCT (19.4 [2.8] vs. 18.5 [2.9] s, p < 0.0001). These associations persisted in multivariable analysis. No association was found with body habitus. Within subject analysis revealed trivial associations between apnea/hypopnea duration, apnea (vs. hypopnea), nadir O2 saturation and sleep stages (NREM vs. REM) and individual LFCT. Automated LFCT measurement was highly correlated with visual-based LFCT measurement. In this group of community-dwelling adults, male sex and older age were associated with higher average LFCT.


Chronic hypoxia abolishes posthypoxia frequency decline in the anesthetized rat.
In anesthetized rats, increases in phrenic nerve amplitude and frequency during brief periods of hypoxia are followed by a reduction in phrenic nerve burst frequency [posthypoxia frequency decline (PHFD)]. We investigated the effects of chronic exposure to hypoxia on PHFD and on peripheral and central O2-sensing mechanisms. In Inactin-anesthetized (100 mg/kg) Sprague-Dawley rats, phrenic nerve discharge and arterial pressure responses to 10 s N2 inhalation were recorded after exposure to hypoxia (10 +/- 0.5% O2) for 6-14 days. Compared with rats maintained at normoxia, PHFD was abolished in chronic hypoxic rats. Because of inhibition of PHFD, the increased phrenic burst frequency and amplitude after N2 inhalation persisted for 1.8-2.8 times longer in chronic hypoxic (70 s) compared with normoxic (25-40 s) rats (P < 0.05). After acute bilateral carotid body denervation, N2 inhalation produced a short depression of phrenic nerve discharge in both chronic hypoxic and normoxic rats. However, the degree and duration of depression of phrenic nerve discharge was smaller in chronic hypoxic compared with normoxic rats (P < 0.05). We conclude that after exposure to chronic hypoxia, a reduction in PHFD contributes to an increased duration of the acute hypoxic ventilatory response in anesthetized rats. Furthermore, after exposure to chronic hypoxia, the central network responsible for respiration is more resistant to the depressant effects of acute hypoxia in anesthetized rats.


Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma.
Survivors of Hodgkin lymphoma and other patients who receive neck irradiation are at increased risk of thyroid cancer. Ultrasonography provides an inexpensive and non-invasive method of thyroid screening, but the clinical significance of thyroid nodules detected by ultrasound screening is uncertain. We reviewed the demographics, clinical characteristics, method of detection, and outcome of patients who developed thyroid nodules after treatment for pediatric Hodgkin lymphoma at our institution. One radiologist reviewed all imaging studies. Sixty-seven children treated for Hodgkin lymphoma from 1962 to 2001 developed thyroid nodules. The study group represented 9,024 person-years of follow-up after the diagnosis of Hodgkin lymphoma and 581 person-years after diagnosis of a thyroid nodule. A median of 10.5 years (range, 0.2-24.8 years) elapsed between the diagnoses of Hodgkin lymphoma and thyroid nodule(s). All but one patient had received neck irradiation for Hodgkin lymphoma, with a median thyroid radiation dose of 35 Gy (range, 12-45 Gy). Thyroid nodules were found to be malignant in seven patients (10%), at a median of 16.2 years (range, 8.4-23.7 years) after diagnosis of Hodgkin lymphoma. Only one malignancy was found through screening ultrasonography. All patients with thyroid cancer remained disease-free at 0.4-16.2 years of follow-up. Thyroid nodules are common in Hodgkin lymphoma survivors treated with neck irradiation, but the majority of these lesions have an indolent clinical course and do not undergo malignant transformation. Only patients with a palpable mass or clinical symptoms need more extensive evaluation, including Doppler-flow ultrasonography and fine-needle aspiration.


Region-specific diversification of the highly virulent serotype 1 Streptococcus pneumoniae.
Serotype 1 Streptococcus pneumoniae is a leading cause of invasive pneumococcal disease (IPD) worldwide, with the highest burden in developing countries. We report the whole-genome sequencing analysis of 448 serotype 1 isolates from 27 countries worldwide (including 11 in Africa). The global serotype 1 population shows a strong phylogeographic structure at the continental level, and within Africa there is further region-specific structure. Our results demonstrate that region-specific diversification within Africa has been driven by limited cross-region transfer events, genetic recombination and antimicrobial selective pressure. Clonal replacement of the dominant serotype 1 clones circulating within regions is uncommon; however, here we report on the accessory gene content that has contributed to a rare clonal replacement event of ST3081 with ST618 as the dominant cause of IPD in the Gambia.


Saccadic suppression and stimulus uncertainty.
Saccadic suppression is a decline in detectability of a weak flash presented during a saccadic eye movement. We examined the hypothesis of Matin [Psychol. Bull. 81, 899 (1974)] that saccadic suppression may be due to increased stimulus uncertainty during the saccade. Uncertainty could arise from variability and inhomogeneities in the visual frame of reference translation that must accompany a saccade. We measured an average 0.6-log-unit suppression for a brief foveal 1 degree flash in a light-adapted detection task. Receiver-operating-characteristic (ROC) slopes for flash detection during saccades, compared with those when fixating, were reduced, indicating the presence of increased uncertainty. The magnitude of this uncertainty change was estimated and found to be consistent with that required to account for the measured detectability decline. When a flashed pedestal was employed to reduce the effect of uncertainty, there was no saccadic suppression and no ROC slope change. Also, spatially separate flashed markers, intended to reduce uncertainty, led to a significant reduction in saccadic suppression for one of two subjects. Our results are consistent with the hypothesis that a saccade leaves the observer with increased uncertainty as to which subjective visual direction to attend for a stimulus of fixed retinal locus. The magnitude of this uncertainty change can account fully for the saccadic suppression measured.


Training opportunities in thoracic ultrasound for respiratory trainees: are current guidelines practical?
Respiratory trainees in the UK face challenges in meeting current Royal College of Radiologists (RCR) Level 1 training requirements for thoracic ultrasound (TUS) competence, specified as attending 'at least one session per week over a period of no less than 3 months, with approximately five scans per session performed by the trainee (under supervision of an experienced practitioner)'. We aimed to clarify where TUS training opportunities currently exist for respiratory registrars. Data were collected (over a 4-week period) to clarify the number of scans (and therefore volume of training opportunities) within radiology departments and respiratory services in hospitals in the South West, North West deaneries and Oxford. 14 hospitals (including three tertiary pleural centres) provided data. Of 964 scans, 793 (82.3%) were conducted by respiratory teams who performed a mean of 17.7 scans per week, versus 3.1 TUS/week in radiology departments. There was no radiology session in any hospital with ≥5 TUS performed, whereas 8/14 (86%) of respiratory departments conducted such sessions. Almost half (6/14) of radiology departments conducted no TUS scans in the period surveyed. The currently recommended exposure of regularly attending a list or session to undertake five TUS is not achievable in radiology departments. The greatest volume of training opportunities exists within respiratory departments in a variety of scheduled and unscheduled settings. Revision of the competency framework in TUS, and where this is delivered, is required.


In planta secretion of a calreticulin by migratory and sedentary stages of root-knot nematode.
Esophageal secretions from endoparasitic sedentary nematodes are thought to play key roles throughout plant parasitism, in particular during the invasion of the root tissue and the initiation and maintenance of the nematode feeding site (NFS) essential for nematode development. The secretion in planta of esophageal cell-wall-degrading enzymes by migratory juveniles has been shown, suggesting a role for these enzymes in the invasion phase. Nevertheless, the secretion of an esophageal gland protein into the NFS by nematode sedentary stages has never been demonstrated. The calreticulin Mi-CRT is a protein synthesized in the esophageal glands of the root-knot nematode Meloidogyne incognita. After three-dimensional modeling of the Mi-CRT protein, a surface peptide was selected to raise specific antibodies. In planta immunolocalization showed that Mi-CRT is secreted by migratory and sedentary stage nematodes, suggesting a role for Mi-CRT throughout parasitism. During the maintenance of the NFS, the secreted Mi-CRT was localized outside the nematode at the tip of the stylet. In addition, Mi-CRT accumulation was observed along the cell wall of the giant cells that compose the feeding site, providing evidence for a nematode esophageal protein secretion into the NFS.


Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study.
Microalbuminuria is associated with excess cardiovascular mortality in both diabetic and nondiabetic subjects. Patients with NIDDM and microalbuminuria are more insulin resistant than those without microalbuminuria. However, the relationship between insulin resistance and microalbuminuria in patients with NIDDM could be due to hyperglycemia, which can cause both insulin resistance and an increase in albumin excretion rate. Little is known about microalbuminuria and insulin resistance in nondiabetic subjects. Therefore, we examined, cross-sectionally, the relationship of insulin sensitivity (S(I) x 10(-4) min x microU(-1) x ml(-1)), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and fasting plasma insulin concentration, to microalbuminuria (albumin-to-creatinine ratio > or = 2 mg/mmol) in 982 nondiabetic subjects aged 40-69 years. Altogether, 15% of the subjects had microalbuminuria, and 32% had hypertension. Subjects with microalbuminuria had a lower degree of insulin sensitivity (means +/- SE, 1.70 +/- 0.11 vs. 2.25 +/- 0.07, P = 0.003) and higher fasting insulin concentrations (17.4 +/- 1.1 vs. 15.7 +/- 0.5 mU/l, P = 0.059) compared with subjects without microalbuminuria. In logistic regression analysis, an increasing degree of insulin sensitivity was related to a decreasing prevalence of microalbuminuria (odds ratio = 0.86, 95% CI: 0.79-0.94, P < 0.001). Although this relationship attenuated after adjustment for age, sex, ethnicity, hypertension, fasting glucose, and BMI, it still remained significant. The association between insulin sensitivity and microalbuminuria was shown not to be different between normotensive and hypertensive subjects. Our results suggest a relationship between insulin resistance and microalbuminuria in nondiabetic subjects that is partially dependent on blood pressure, glucose levels, and obesity.


Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.


Development of generic Taqman PCR and RT-PCR assays for the detection of DNA and mRNA of β-actin-encoding sequences in a wide range of animal species.
As a member of the European Virus Archive (EVA) consortium, our laboratory is developing and maintaining a large collection of viruses. This collection implies the use of a panel of cell lines originating from various animal species. In order to make easier the handling of such a large panel of cell lines, wide spectrum real-time PCR and RT-PCR assays were developed to allow the detection and the quantification of DNA and mRNA of β-actin, one of the most commonly used eukaryotic housekeeping genes. By using two degenerated primers and a unique probe, these two assays were shown to detect nucleic acids of a panel of vertebrate and invertebrate cell lines commonly used in animal virology. This panel included human, monkey, rodent, dog, pig, fish, batrachian, mosquito and tick cell lines. Additionally, the two assays amplified successfully β-actin-encoding sequences of sandflies. Sensitivity evaluation performed on synthetic DNA and RNA sequences showed that the two assays were very sensitive and suitable for accurate quantification. The two assays constitute together a convenient method suitable for multiple purposes. They can be used for instance to estimate the amount of contaminating cellular genetic material prior to sequence-independent amplification of viral genomes achieved before high-throughput sequencing, to evaluate the efficiency of DNase and/or RNase treatments performed on cellular extract and to check nucleic acid extraction by using β-actin-encoding sequences as endogenous control. This assay will constitute a precious tool for virologists working with multiple cell lines or animal models.


Multicomponent assembly of proposed DNA precursors in water.
We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and β-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from β-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form.


Weak acid-concentration Atot and dissociation constant Ka of plasma proteins in racehorses.
The plasma proteins are a significant contributor to the total weak acid concentration as a net anionic charge. Due to potential species difference, species-specific values must be confirmed for the weak acid anionic concentrations of proteins (Atot) and the effective dissociation constant for plasma weak acids (Ka). We studied the net anion load Atot of equine plasma protein in 10 clinically healthy mature Standardbred horses. A multi-step titration procedure, using a tonometer covering a titration range of PCO2 from 25 to 145 mmHg at 37 degrees C, was applied on the plasma of these 10 horses. Blood gases (pH, PCO2) and electrolytes required to calculate the strong ion difference ([SID] = [(Na(+) + K(+) + Ca(2+) + Mg(2+))-(Cl(-) + Lac(-) + PO4(2-))]) were simultaneously measured over a physiological pH range from 6.90-7.55. A nonlinear regression iteration to determine Atot and Ka was performed using polygonal regression curve fitting applied to the electrical neutrality equation of the physico-chemical system. The average anion-load Atot for plasma protein of 10 Standardbred horses was 14.89 +/- 0.8 mEq/l plasma and Ka was 2.11 +/- 0.50 x 10(-7) Eq/l (pKa = 6.67). The derived conversion factor (iterated Atot concentration/average plasma protein concentration) for calculation of Atot in plasma is 0.21 mEq/g protein (protein-unit: g/l). This value compares closely with the 0.24 mEq/g protein determined by titration of Van Slyke et al. (1928) and 0.22 mEq/g protein recently published by Constable (1997) for horse plasma. The Ka value compares closely with the value experimentally determined by Constable in 1997 (2.22 x 10(7) Eq/l). Linear regression of a set of experimental data from 5 Thoroughbred horses on a treadmill exercise test, showed excellent correlation with the regression lines not different from identity for the calculated and measured variables pH, HCO3 and SID. Knowledge of Atot and Ka for the horse is useful especially in exercise studies and in clinical conditions to quantify the mechanisms of the acid-base disturbances occurring.


Injection-locked semiconductor laser array using a graded-index rod: a computational model.
We describe a computation which models the coupling among five widely separated laser emitters in a single monolithic array due to a GRIN rod lens. Individual emitter modes are characterized as to nearfield rectangular beam waist sizes by using an effective index waveguide calculation. The differential equations describing ray propagation in a medium with nonuniform index of refraction are solved using a Runge-Kutta algorithm. A ray bundle originating at each emitter is traced through free space, the GRIN rod, and back to the array. The fraction of (1/e**2) power entering an emitter from the front then defines the coupling from the source diode to the target diode. Provisions for describing array distances, offsets, and tilts are included. The model was tested for an array with 6-microm stripes on 250-microm centers. An array position and orientation was found which coupled all five laser elements together. The computed coupling coefficients were commensurate with values reqired to fully couple the array elements. Previous experimental results are now interpreted as a result of injection locking facilitated by the rod lens as opposed to an external cavity configuration.


White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients.
HIV associated dementia (HAD) is the most advanced stage of central nervous system disease caused by HIV infection. Previous studies have demonstrated that patients with HAD exhibit greater cerebral and basal ganglia atrophy than non-demented HIV+ (HND) patients. However, the extent to which white matter is affected in HAD patients compared to HND patients remains elusive. This study is designed to address the potential white matter abnormalities through the utilization of diffusion tensor imaging (DTI) in both HND and HAD patients. DTI and T1-weighted images were acquired from 18 healthy controls, 21 HND and 8 HAD patients. T1 image-based registration was performed to 1) parcellate the whole brain white matter into major white matter regions, including frontal, parietal, temporal and occipital white matter, corpus callosum and internal capsule for statistical comparisons of the mean DTI values, and 2) warp all DTI parametric images towards the common template space for voxel-based analysis. The statistical comparisons were performed with four DTI parameters including fractional anisotropy (FA), mean (MD), axial (AD), and radial (RD) diffusivities. With Whitney U tests on the mean DTI values, both HND and HAD demonstrated significant differences from the healthy control in multiple white matter regions. In addition, HAD patients exhibited significantly elevated MD and RD in the parietal white matter when compared to HND patients. In the voxel-based analysis, widespread abnormal regions were identified for both HND and HAD patients, although a much larger abnormal volume was observed in HAD patients for all four DTI parameters. Furthermore, both region of interest (ROI) based and voxel-based analyses revealed that RD was affected to a much greater extent than AD by HIV infection, which may suggest that demyelination is the prominent disease progression in white matter.


Population structure of a microparasite infecting Daphnia: spatio-temporal dynamics.
Detailed knowledge of spatial and temporal variation in the genetic population structure of hosts and parasites is required for understanding of host - parasite coevolution. As hot-spots of contemporary coevolution in natural systems are difficult to detect and long-term studies are restricted to few systems, additional population genetic data from various host - parasite systems may provide important insights into the topic. This is particularly true for parasites, as these players have been under-investigated so far due to the lower availability of suitable molecular markers. Here, we traced genetic variation (based on sequence variants in the internal transcribed spacer region, ITS) among seven geographically isolated populations of the ichthyosporean Caullerya mesnili, a common microparasite of the cladoceran Daphnia (here, the D. longispina hybrid complex). At three sites, we also studied parasite genetic variation over time (three to four sampling points) and tested for associations between parasite genotypes and host species. Parasite (and host) populations were significantly structured across space, indicating limited dispersal. Moreover, the frequency of parasite genotypes varied significantly over time, suggesting rapid evolutionary change in Caullerya. However, the distribution of parasite genotypes was similar across different host species, which might in turn have important consequences for parasite epidemiology. The approach proposed here can be applied to track spatial and temporal changes in the population structure of other microparasite species for which sequence variation in the ITS or other highly variable genome regions has been documented but other types of polymorphic markers are lacking. Screening of parasite sequence variants allows for reliable detection of cross-species infections and, using advanced sequencing techniques in the near future, for detailed studies of parasite evolution in natural host - parasite systems.


Ion Channel Based Bio-Synthetic Modulator for Diffusive Molecular Communication.
In diffusion-based molecular communication (DMC), a transmitter nanomachine is responsible for signal modulation. Thereby, the transmitter has to be able to control the release of the signaling molecules employed for representing the transmitted information. In nature, an important class of control mechanisms for releasing molecules from cells utilizes ion channels which are pore-forming proteins across the cell membrane. The opening and closing of the ion channels is controlled by a gating parameter. In this paper, an ion channel based modulator for DMC is proposed which controls the rate of molecule release from the transmitter by modulating a gating parameter signal. Exploiting the capabilities of the proposed modulator, an on-off keying modulation technique is introduced and the corresponding average modulated signal, i.e., the average release rate of the molecules from the transmitter, is analyzed. However, since the modulated signal is random in nature, it may deviate from its average. Therefore, the concept of modulator noise is introduced and the statistics of the modulated signal are investigated. Finally, by assuming a simple transparent receiver, the performance of the proposed on-off keying modulation format is studied. The derived analytical expressions for the average modulated signal are confirmed with particle based simulations. Our numerical results reveal that performance estimates of DMC systems obtained based on the assumption of instantaneous molecule release at the transmitter may substantially deviate from the performance achieved with practical modulators.


Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma.
We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.


Baseline thyroid indices and the subsequent response to citalopram treatment, a pilot study.
The lack of reliable outcome predictors and the delayed onset of therapeutic response to antidepressants are among the clinical challenges in the treatment of depression. Identifying clinical correlates associated with antidepressant response would reduce symptom severity and morbidity for patients with depression. Twenty-three subjects with major depression were treated with citalopram 20 mg/day in a 6-week open trial and were also simultaneously randomized to either adjunctive triiodothyronine (T3) 25 μg BID (n = 7), pindolol 5 mg BID (n = 8), or placebo (n = 8). Baseline thyroid-stimulating hormone (TSH), FT4, FT3, and TT3 were measured for potential relationships to treatment response across groups. In males only, there was a significant inverse correlation between baseline free T4 and time to response (r = -0.7, P = 0.034). In both males and females across all treatment conditions, as measured by Kaplan-Meier (K-M) maintenance failure time, baseline TSH below the mean (1.5 ng/dL) was associated with a shorter time to response (50% reduction in Montgomery and Asberg Depression Rating Scale [MADRS] score) (χ(2) = 4.53, df = 1, P = 0.03). Patients with baseline TSH above the mean were less likely to reach full remission (MADRS ≤ 7) (χ(2) = 4.38, df = 1, P = 0.03). No significant differences between groups emerged in the mean response time. Baseline thyroid function, as measured by serum free T4 and TSH, may predict a patient's response time to antidepressant treatment with citalopram.


Crystal structure of the phosphoenolpyruvate-binding enzyme I-domain from the Thermoanaerobacter tengcongensis PEP: sugar phosphotransferase system (PTS).
Enzyme I (EI), the first component of the phosphoenolpyruvate (PEP):sugar phosphotransferase system (PTS), consists of an N-terminal protein-binding domain (EIN) and a C-terminal PEP-binding domain (EIC). EI transfers phosphate from PEP by double displacement via a histidine residue on EIN to the general phosphoryl carrier protein HPr. Here, we report the 1.82A crystal structure of the homodimeric EIC domain from Thermoanaerobacter tengcongensis, a saccharolytic eubacterium that grows optimally at 75 degrees C. EIC folds into a (betaalpha)(8) barrel with three large helical insertions between beta2/alpha2, beta3/alpha3 and beta6/alpha6. The large amphipathic dimer interface buries 3750A(2) of accessible surface area per monomer. A comparison with pyruvate phosphate dikinase (PPDK) reveals that the active-site residues in the empty PEP-binding site of EIC and in the liganded PEP-binding site of PPDK have almost identical conformations, pointing to a rigid structure of the active site. In silico models of EIC in complex with the Z and E-isomers of chloro-PEP provide a rational explanation for their difference as substrates and inhibitors of EI. The EIC domain exhibits 54% amino acid sequence identity with Escherichia coli and 60% with Bacillus subtilis EIC, has the same amino acid composition but contains additional salt-bridges and a more complex salt-bridge network than the homology model of E.coli EIC. The easy crystallization of EIC suggests that T.tengcongensis can serve as source for stable homologs of mesophilic proteins that are too labile for crystallization.


Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in Indonesian Papua.
Chloroquine remains the first-line therapy for uncomplicated malaria in Indonesia. Among a series of trials of chloroquine for malaria on this archipelago conducted since 1990, we now report the highest risk of therapeutic failure yet observed. A clinical trial of standard chloroquine therapy for uncomplicated malaria at Arso PIR V in northeastern Indonesian Papua was conducted during 1995. We enrolled 104 non-immune subjects infected with Plasmodium falciparum (n = 55), P. vivax (n = 29), or P. falciparum plus P. vivax (n = 20) and administered supervised standard chloroquine therapy (10 + 10 + 5 mg/kg at 24-hour intervals). The 28-day cumulative incidence of therapeutic failure was 95% for P. falciparum, 84% for P. vivax, and 100% for mixed infections. Only one subject each for P. falciparum and P. vivax remained free of parasites at day 28. All recurrent parasitemias occurred with whole blood levels of chloroquine plus desethylchloroquine exceeding 100 ng/ml. These findings document almost complete failure of chloroquine against P. falciparum or P. vivax near the northeastern coast of Indonesian Papua.


A closed-loop control "playback" smoking machine for generating mainstream smoke aerosols.
A first generation smoking machine capable of reading and replicating detailed puffing behavior from recorded smoking topography data is presented. Unlike standard smoking machines, which model human puffing behavior as a steady periodic waveform with a fixed puff frequency, volume, and duration, this novel machine generates a mainstream smoke aerosol by automatically "playing-back" puff topography recordings. Because combustion chemistry is highly non-linear, representing real smoking behavior with a smoothed periodic waveform may result in a tobacco smoke aerosol with a significantly different chemical composition and physical properties than that generated by a smoker. The machine presented here utilizes a rapid closed-loop control algorithm coded in Labview to generate smoke aerosols for toxicological assessment and inhalation studies. To illustrate its use, dry particulate matter and carbon monoxide yields generated using the playback and equivalent periodic puffing regimens are compared for a single smoking session by a 26-year-old male narghile water-pipe smoker. It was found that the periodic puffing regimen yielded 20% less carbon monoxide (CO) than the played-back smoking session, indicating that steady periodic smoking regimens, which are widely used in tobacco smoke research, may not produce realistic smoke aerosols.


A home-based comprehensive care model in patients with Multiple Sclerosis: A study pre-protocol.
Background Disability is prevalent in individuals with multiple sclerosis (MS), leading to difficulty in care access, significant caregiver burden, immense challenges in self-care and great societal burden. Without highly coordinated, competent and accessible care, individuals living with progressive MS experience psychological distress, poor quality of life, suffer from life-threatening complications, and have frequent but avoidable healthcare utilizations. Unfortunately, current healthcare delivery models present severe limitations in providing easily accessible, patient-centered, coordinated comprehensive care to those with progressive MS. We propose a home-based comprehensive care model (MAHA) to address the unmet needs, challenges, and avoidable complications in individuals with progressive MS with disabling disease. Objective The article aims to describe the study design and methods used to implement and evaluate the proposed intervention. Method The study will use a randomized controlled design to evaluate the feasibility of providing a 24-month, home-based, patient-centered comprehensive care program to improve quality of life, reduce complications and healthcare utilizations overtime (quarterly) for 24 months. A transdisciplinary team led by a MS-Comprehensivist will carry out this project. Fifty MS patients will be randomly assigned to the intervention and usual care program using block randomization procedures. We hypothesize that patients in the intervention group will have fewer complications, higher quality of life, greater satisfaction with care, and reduced healthcare utilization. The proposed project is also expected to be financially sustainable in fee-for-service models but best suited for and gain financial success in valued-based care systems. Discussion This is the first study to examine the feasibility and effectiveness of a home-based comprehensive care management program in MS patients living with progressive disability. If successful, it will have far-reaching implications in research, education and practice in terms of providing high quality but affordable care to population living with severe complex, disabling conditions.


Antioxidant and Antidiabetic Activity of Algae.
Currently, algae arouse a growing interest in the pharmaceutical and cosmetic area due to the fact that they have a great diversity of bioactive compounds with the potential for pharmacological and nutraceutical applications. Due to lifestyle modifications brought on by rapid urbanization, diabetes mellitus, a metabolic illness, is the third largest cause of death globally. The hunt for an efficient natural-based antidiabetic therapy is crucial to battling diabetes and the associated consequences due to the unfavorable side effects of currently available antidiabetic medications. Finding the possible advantages of algae for the control of diabetes is crucial for the creation of natural drugs. Many of algae's metabolic processes produce bioactive secondary metabolites, which give algae their diverse chemical and biological features. Numerous studies have demonstrated the antioxidant and antidiabetic benefits of algae, mostly by blocking carbohydrate hydrolyzing enzyme activity, such as α-amylase and α-glucosidase. Additionally, bioactive components from algae can lessen diabetic symptoms in vivo. Therefore, the current review concentrates on the role of various secondary bioactive substances found naturally in algae and their potential as antioxidants and antidiabetic materials, as well as the urgent need to apply these substances in the pharmaceutical industry.


Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.
The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.


Analysis of bakery products by laser-induced breakdown spectroscopy.
In this study, we focused on the detection of Na in bakery products by using laser-induced breakdown spectroscopy (LIBS) as a quick and simple method. LIBS experiments were performed to examine the Na at 589 nm to quantify NaCl. A series of standard bread sample pellets containing various concentrations of NaCl (0.025-3.5%) were used to construct the calibration curves and to determine the detection limits of the measurements. Calibration graphs were drawn to indicate functions of NaCl and Na concentrations, which showed good linearity in the range of 0.025-3.5% NaCl and 0.01-1.4% Na concentrations with correlation coefficients (R(2)) values greater than 0.98 and 0.96. The obtained detection limits for NaCl and Na were 175 and 69 ppm, respectively. Performed experimental studies showed that LIBS is a convenient method for commercial bakery products to quantify NaCl concentrations as a rapid and in situ technique.


Associations between specific technologies and adolescent sleep quantity, sleep quality, and parasomnias.
We tested the hypothesis that weekday bedtime use of six technologies would be significantly associated with eight sleep parameters studied relating to sleep quantity, sleep quality, and parasomnias. In our cross-sectional study, we previously administered validated age-appropriate questionnaires (School Sleep Habits Survey, Technology Use Questionnaire). Participating adolescents (n=738; 54.5% boys) were aged 11-13 years and were from the Midlands region of the United Kingdom in 2010. Frequent use of all technology types was significantly inversely associated with weekday sleep duration (hours). Frequent music listeners and video gamers had significantly prolonged sleep onset (β=7.03 [standard error {SE}, 2.66]; P<.01 and β=6.17 [SE, 2.42]; P<.05, respectively). Frequent early awakening was significantly associated with frequent use of all technology types. The greatest effect was observed in frequent television viewers (odds ratio [OR], 4.05 [95% confidence interval {CI}, 2.06-7.98]). Difficulty falling asleep was significantly associated with frequent mobile telephone use, video gaming, and social networking, with music listeners demonstrating the greatest effect (OR, 2.85 [95%CI, 1.58-5.13]). Music listeners were at increased risk for frequent nightmares (OR, 2.02 [95% CI, 1.22-3.45]). Frequent use of all technologies except for music and mobile telephones was significantly associated with greater cognitive difficulty in shutting off. Frequent television viewers were almost four times more likely to report higher sleepwalking frequency (OR, 3.70 [95% CI, 1.89-7.27]). Frequent weekday technology use at bedtime was associated with significant adverse effects on multiple sleep parameters. If confirmed in other samples and longitudinally, improving sleep hygiene through better management of technology could enhance the health and well-being of adolescent populations.


Effect of artificial aging regimens on the performance of self-etching adhesives.
This in vitro study was performed to compare the microtensile bond strengths (MTBS) of current self-etching adhesives to dentin and to evaluate the effects of artificial aging [(thermocycling (TC) and/or mechanic loading (ML)] on MTBS and on nanoleakage of self-etching adhesives. Two-step (AdheSE Bond, Clearfil Protect Bond, Clearfil SE Bond, Optibond Self-Etch) and one-step (Hybrid Bond, G-bond, Clearfil Tri-S Bond, and Adper Prompt L-Pop) self-etching adhesives were tested. Resin composite build-ups were created, and the specimens were subjected to 10(4) TC, 10(5) ML, and 10(4)/10(5) TC/ML. Non-aged specimens served as controls. In the control group, no significant differences were found among the MTBS of the one-step self-etching adhesives and among those of three two-step self-etching adhesives (AdheSE Bond, Clearfil Protect Bond, and Clearfil SE Bond) (p > 0.05). The MTBS of AdheSE Bond and Clearfil Protect Bond were higher than were those of all one-step self-etching adhesives and than those of Optibond Self-Etch. The MTBS of Clearfil SE Bond was higher than were those of two one-step self-etching adhesives (Adper Prompt L-Pop, G-bond) (p < 0.05). Compared with the non-aged controls, TC did not decrease (p > 0.05), but ML and TC/ML significantly decreased the MTBS of the adhesives tested (p < 0.05). Two-step self-etching adhesives tended to fail more cohesively in dentin. Transmission electron microscopy revealed different nanoleakage patterns in the adhesive and hybrid layers of all adhesives examined, and signs of additional silver-filled water channels were more readily detectable after TC/ML.


Practical dosing of praziquantel for schistosomiasis in preschool-aged children.
Schistosomiasis is known to occur in preschool-aged children, but achieving accurate dosing of praziquantel in its current form is challenging. While waiting for a paediatric formulation, there is a need to develop a means for using the available products to treat this age group. Current 600-mg tablets are differently scored to give units of 150 mg (a quarter of a tablet) or 300 mg (half a tablet). We examined several dosing schemes to dose accurately (40-60 mg/kg) children aged 3-72 months (weight range 4-25 kg, based on available weight-for-age growth references from sub-Saharan Africa and Brazil, n = 106,230). Adequate dosing can be achieved with formulations that can be split into four 150 mg quarters for children weighing 5 kg or more, and with tablets than can be split into two 300 mg halves for children weighing 10 kg or more. Giving ½ tablet for 5-7 kg; ¾ tablet for 8-10 kg; 1 tablet for 11-15 kg; 1 ½ tablet for 16-21 kg; and two tablets for 22-25 kg will have 100% of subjects correctly dosed within the target 40-60 mg/kg range. Formulations that can be divided into four parts (to give 150 mg increments) are preferred for children weighing less than 11 kg; the same dosing can be applied with 600 mf praziquantel formulations that can be divided into four quarters or two halves from 11 kg body weight.


The use of respondent-driven sampling to assess malaria knowledge, treatment-seeking behaviours and preventive practices among mobile and migrant populations in a setting of artemisinin resistance in Western Cambodia.
Multi-drug-resistant Plasmodium falciparum threatens malaria elimination efforts in Cambodia and the Greater Mekong Subregion (GMS). Malaria burden in the GMS is higher among certain high-risk demographic groups in Cambodia, especially among migrant and mobile populations (MMPs). This respondent driven sampling (RDS) study was conducted in order to determine malaria knowledge, treatment-seeking behaviours and preventive practices among two MMP groups in Western Cambodia. An RDS survey of MMPs was implemented in four purposively-selected communes along the Thai-Cambodia border; two in Veal Veang District and two in Pailin Province, chosen due to their sizeable MMP groups, their convenience of access, and their proximity to Thailand, which allowed for comparison with RDS studies in Thailand. There were 764 participants in Pailin Province and 737 in Veal Veang District. Health messages received in Veal Veang were most likely to come from billboards (76.5%) and family and friends (57.7%), while in Pailin they were most likely to come from sources like radio (57.1%) and television (31.3%). Knowledge of malaria transmission by mosquito and prevention by bed net was above 94% in both locations, but some misinformation regarding means of transmission and prevention methods existed, predominantly in Veal Veang. Ownership of treated bed nets was lower in Pailin than in Veal Veang (25.3% vs 53.2%), while reported use the night before the survey was higher in Pailin than in Veal Veang (57.1% vs 31.6%). Use of private sector health and pharmaceutical services was common, but 81.1% of patients treated for malaria in Pailin and 86.6% in Veal Veang had received a diagnostic test. Only 29.6% of patients treated in Pailin and 19.6% of those treated in Veal Veng reported receiving the indicated first-line treatment. Barriers in access to malaria prevention and case management were common among MMPs, with marked variation by site. Resolving both nation-wide and MMP-specific challenges will require targeted interventions that take into account this heterogeneity.


Sociodemographic determinants of oral anticoagulant prescription in patients with atrial fibrillations: findings from the PINNACLE registry using machine learning.
Current risk scores that are solely based on clinical factors have shown modest predictive ability for understanding of factors associated with gaps in real-world prescription of oral anticoagulation (OAC) in patients with atrial fibrillation (AF). In this study, we sought to identify the role of social and geographic determinants, beyond clinical factors associated with variation in OAC prescriptions using a large national registry of ambulatory patients with AF. Between January 2017 and June 2018, we identified patients with AF from the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) Registry. We examined associations between patient and site-of-care factors and prescription of OAC across U.S. counties. Several machine learning (ML) methods were used to identify factors associated with OAC prescription. Among 864,339 patients with AF, 586,560 (68%) were prescribed OAC. County OAC prescription rates ranged from 26.8% to 93%, with higher OAC use in the Western United States. Supervised ML analysis in predicting likelihood of OAC prescriptions and identified a rank order of patient features associated with OAC prescription. In the ML models, in addition to clinical factors, medication use (aspirin, antihypertensives, antiarrhythmic agents, lipid modifying agents), and age, household income, clinic size, and U.S. region were among the most important predictors of an OAC prescription. In a contemporary, national cohort of patients with AF underuse of OAC remains high, with notable geographic variation. Our results demonstrated the role of several important demographic and socioeconomic factors in underutilization of OAC in patients with AF.


Autoimmune thyroid disease in rheumatoid arthritis: a global perspective.
Objective. To determine the prevalence and impact of autoimmune thyroid disease (AITD) in patients with rheumatoid arthritis (RA). Methods. Eight-hundred patients were included. The association between AITD and RA was analyzed was analyzed by bivariate and multivariate analysis. In addition, a literature review was done focusing on geographical variations. Results. In our cohort the prevalence of AITD was 9.8% while the presence of antibodies was 37.8% for antithyroperoxidase enzyme (TPOAb) and 20.8% for antithyroglobulin protein (TgAb). The presence of type 2 diabetes, thrombosis, abnormal body mass index, and a high educational level was positively associated with AITD. The literature review disclosed a geographical variation of AITD in RA ranging from 0.5% to 27%. Autoantibody prevalence ranges from 6% to 31% for TgAb, 5% to 37% for TPOAb, and from 11.4% to 32% for the presence of either of the two. Conclusion. AITD is not uncommon in RA and should be systematically assessed since it is a risk factor for developing diabetes and cardiovascular disease. These results may help to further study the common mechanisms of autoimmune diseases, to improve patients' outcome, and to define public health policies. An international consensus to accurately diagnose AITD is warranted.


Association of traditional cardiovascular risk factors with coronary plaque sub-types assessed by 64-slice computed tomography angiography in a large cohort of asymptomatic subjects.
Although prior studies have shown that traditional cardiovascular (CV) risk factors are associated with the burden of coronary atherosclerosis, less is known about the relationship of risk factors with coronary plaque sub-types. Coronary computed tomography angiography (CCTA) allows an assessment of both, total disease burden and plaque characteristics. In this study, we investigate the relationship between traditional CV risk factors and the presence and extent of coronary plaque sub-types in a large group of asymptomatic individuals. The study population consisted of 1015 asymptomatic Korean subjects (53+/-10 years; 64% were males) free of known CV disease who underwent 64-slice CCTA as part of a health screening evaluation. We analyzed plaque characteristics on a per-segment basis according to the modified American Heart Association classification. Plaques in which calcified tissue occupied more than 50% of the plaque area were classified as calcified (CAP), <50% calcified area as mixed (MCAP), and plaques without any calcium as non-calcified (NCAP). A total of 215 (21%) subjects had coronary plaque while 800 (79%) had no identifiable disease. Multivariate regression analysis demonstrated that increased age (per decade) and gender are the strongest predictors for the presence of any coronary plaque or the presence of at least one segment of CAP and MCAP (any plaque-age: OR 2.89; 95% CI 2.34, 3.56; male gender: OR 5.21; 95% CI 3.20, 8.49; CAP-age: OR 2.75; 95% CI 2.12, 3.58; male gender: 4.78; 95% CI 2.48, 9.23; MCAP-age: OR 2.62; 95% CI 2.02, 3.39; male gender: OR 4.15; 95% CI 2.17, 7.94). The strongest predictors for the presence of any NCAP were gender (OR 3.56; 95% CI 1.96-6.55) and diabetes mellitus (OR 2.87; 95% CI 1.63-5.08). When looking at the multivariate association between the presence of >/=2 coronary segments with a plaque sub-type and CV risk factors, male gender was the strongest predictor for CAP (OR 7.31; 95% CI 2.12, 25.20) and MCAP (OR 5.54; 95% CI 1.84, 16.68). Alternatively, smoking was the strongest predictor for the presence of >/=2 coronary segments with NCAP (OR 4.86; 95% CI 1.68, 14.07). Low-density lipoprotein cholesterol (LDL-C) was only a predictor for the presence and extent of mixed coronary plaque. Age and gender are overall the strongest predictors of atherosclerosis as assessed by CCTA in this large asymptomatic Korean population and these two risk factors are not particularly associated with a specific coronary plaque sub-type. Smoking is a strong predictor of NCAP, which has been suggested by previous reports as a more vulnerable lesion. Whether a specific plaque sub-type is associated with a worse prognosis is yet to be determined by future prospective studies.


Stem cells as delivery vehicles for oncolytic adenoviral virotherapy.
Glioblastoma multiforme is the most common primary intracranial tumor in humans. Despite continued advances in cancer therapy, the outcome for patients diagnosed with this disease remains bleak. Novel treatments involving the use of conditionally replicating adenoviruses (CRAds) to target malignant brain tumors have undergone extensive research and proven to be a promising mode of glioblastoma therapy. CRAds are genetically manipulated to replicate within tumor cells, exhibiting a high degree of infectivity, cytotoxicity, and transgene expression. While the use of various CRAds has been deemed safe for intracranial injection in preclinical trials, a significant therapeutic effect has yet to be seen in patients. This shortcoming stems from the distribution limitations involved with local delivery of virolytic agents. To enhance this modality of treatment, stem cells have been explored as cellular vehicles in virotherapy applications, given that they possess an intrinsic tropism for malignant brain tumors. Stem cell loaded CRAd delivery offers a more specific and effective method of targeting disseminated tumor cells and forms the basis for this review.


Phenotyping of subjects for large scale studies on patients with IBS.
Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity, immunity, epithelial permeability and gastrointestinal microflora. Such complexity means there is currently no specific reliable biomarker for IBS, and thus IBS continues to be diagnosed and classified according to symptom based criteria, the Rome Criteria. Carefully phenotyping and characterisation of a 'large' pool of IBS patients across Europe and even the world however, might help identify sub-populations with accuracy and consistency. This will not only aid future research but improve tailoring of treatment and health care of IBS patients. The aim of this position paper is to discuss the requirements necessary to standardize the process of selecting and phenotyping IBS patients and how to organise the collection and storage of patient information/samples in such a large multi-centre pan European/global study. We include information on general demographics, gastrointestinal symptom assessment, psychological factors, quality of life, physiological evaluation, genetic/epigenetic and microbiota analysis, biopsy/blood sampling, together with discussion on the organisational, ethical and language issues associated with implementing such a study. The proposed approach and documents selected to be used in such a study was the result of a thoughtful and thorough four-year dialogue amongst experts associated with the European COST action BM1106 GENIEUR (www.GENIEUR.eu).