Simulation-based quantification of native T1 and T2 of the myocardium using a modified MOLLI scheme and the importance of Magnetization Transfer.
Quantitative cardiovascular Magnetic Resonance Imaging techniques are gaining wide acceptance within the MR community due to their potential to diagnose non-localized disease, guide therapy and improve patient outcome. During the last decade, there has been an increasing interest for developing new techniques that allow for simultaneous quantification of both T1 and T2 maps of myocardium. Newer studies demonstrated that the incorporation of MRI simulations could yield similar results to conventional mapping techniques in the myocardium. However, these simulation-based quantitative MR techniques usually compare the in-vivo T1 estimates against less accurate T1 techniques, whereas they present inconsistencies between simulation studies, phantom and in-vivo measurements. Moreover, these studies do not investigate the effect of Magnetization Transfer on the myocardial T1 and T2 estimates but are usually validated on phantoms where the MT effect is small. The main aim of this study was to perform simultaneous mapping of the native T1 and T2 of the myocardium through the utilization of a modified MOLLI pulse sequence and the incorporation of advanced MR simulations through the SQUAREMR framework. A second aim of this study was to investigate the effect of MT on simulation-based quantitative MR techniques. A conventional MOLLI pulse sequence was modified so as to present combined high T2 sensitivity and low MT effect. The new technique was applied in healthy volunteers and demonstrated an improved T1 accuracy compared to the conventional MOLLI and a T2 accuracy similar to the one provided by the T2prep-bSSFP method. The effect of MT on T1 and T2 estimates was also investigated in the current study. Phantoms with an increasing MT effect as well as phantoms without an MT effect were included in this work whereas several variants of the modified-MOLLI that introduce different amounts of T2 modulation on the MR signal and induce different MT effects were applied on the phantoms. The proposed simulation-based quantitative MR technique for simultaneous T1 and T2 mapping of the myocardium does not require the incorporation of a complicated custom designed pulse sequence and does not require a complicated reconstruction workflow. Moreover, the current study demonstrates for the first time that MT plays an important role in the simulation-based quantitative MR studies and points out the necessity of incorporating the study of MT in future techniques.


A robust algorithm for segmenting and tracking clustered cells in time-lapse fluorescent microscopy.
We present herein a robust algorithm for cell tracking in a sequence of time-lapse 2-D fluorescent microscopy images. Tracking is performed automatically via a multiphase active contours algorithm adapted to the segmentation of clustered nuclei with obscure boundaries. An ellipse fitting method is applied to avoid problems typically associated with clustered, overlapping, or dying cells, and to obtain more accurate segmentation and tracking results. We provide quantitative validation of results obtained with this new algorithm by comparing them to the results obtained from the established CellProfiler, MTrack2 (plugin for Fiji), and LSetCellTracker software.


Effects of 16-week consumption of caffeinated and decaffeinated instant coffee on glucose metabolism in a randomized controlled trial.
Objective. Observational studies have shown a protective association between coffee consumption and type 2 diabetes mellitus whereas caffeine or caffeinated coffee acutely deteriorates glucose tolerance. We investigated the effects of chronic drinking of instant coffee on glucose and insulin concentrations during a 75 g oral glucose tolerance test. Methods. Overweight men with a mild-to-moderate elevation of fasting plasma glucose were randomly allocated to a 16-week intervention of consuming 5 cups of caffeinated (n = 17) or decaffeinated (n = 15) instant coffee per day or no coffee (n = 13). Results. The caffeinated coffee group showed statistically significant decreases in the 2-hour concentrations and the area under the curve of glucose while neither decaffeinated coffee nor coffee group showed such a change. Waist circumstance decreased in the caffeinated coffee group, increased in the decaffeinated coffee group, and did not change in the noncoffee group (P = 0.002). With adjustment for the change in waist circumference, caffeinated and decaffeinated coffee consumption were associated with a modest decrease in the postload glucose levels. Conclusion. Both caffeinated and decaffeinated coffee may be protective against deterioration of glucose tolerance.


Stability of cefuroxime axetil oral suspension at different temperature storage conditions.
Stability testing of an active substance or finished product provides information of the variation of drug substance or final product with time influenced by a variety of environmental factors such as temperature, humidity and light. Knowledge gained from stability studies enables understanding of the effects of the environment on the drugs. The aim of our study was to determine the stability of cefuroxime axetil oral suspension at different temperature storage conditions (stored at room /20 degrees C/ and refrigerated /5 degrees C/ conditions). Determination of cefuroxime (as cefuroxime axetil) was performed by dissolution testing. Fractions of the released cefuroxime axetil were compared using f2 value. After interpolating data for dissolution profiles at room and refrigerated conditions the following f2values were obtained: 62,56; 56,32 and 36,18 on 3rd, 6th and 10th day, respectively. These values indicate similarities in drug release from analyzed cefuroxime axetil oral suspension on 3rd, 6th day, and differences on 10th day. Based on our results, we may assume that cefuroxime axetil oral suspension preserves its stability for 10 days after reconstitution under room and refrigerated conditions. It is obvious, according to the f2 value obtained on the 10th day, that there is a difference between the released cefuroxime axetil from oral suspension at room (87,68%) and refrigerated (92,35%) conditions. Concentration changes can be caused by the mechanisms associated with drug release and hydrolytical decomposition of the sample and higher temperatures during longer period of storage.


Comparative growth of ectomycorrhizal basidiomycetes (Hebeloma spp.) on organic and inorganic nitrogen.
In the largely organic soils in which ectomycorrhizas are commonly found, a preference for absorbing organic nitrogen over mineral forms is likely to be an advantage, especially where mineralisation rates are low. To determine rates of both independent and preferential growth of ectomycorrhizal basidiomycetes on organic and inorganic nitrogen, strains of Hebeloma were grown on nutrient agar media containing either NH4+ or glutamic acid as the sole source of nitrogen, on both single medium and split plate Petri dishes. Growth rates on the split plate Petri dishes, where the fungi had access to both nitrogen sources, were generally greater than on the single medium dishes. Growth on glutamic acid was at least equal to, and usually greater than, that on NH4+. In some cases growth on NH4+ alone appeared severely inhibited, a condition that was partially alleviated by access to glutamic acid on the split plates Petri dishes. This highlights a potential pitfall of single nitrogen source growth studies. The greater growth of most strains on glutamic acid suggests an adaptation to organic nitrogen utilisation in these strains. If this is so in soils with low mineralisation rates, direct uptake of amino acids by ectomycorrhizal plants could by-pass the bottle neck that requires mineral nitrogen to be made available for plant uptake.


How spike generation mechanisms determine the neuronal response to fluctuating inputs.
This study examines the ability of neurons to track temporally varying inputs, namely by investigating how the instantaneous firing rate of a neuron is modulated by a noisy input with a small sinusoidal component with frequency (f). Using numerical simulations of conductance-based neurons and analytical calculations of one-variable nonlinear integrate-and-fire neurons, we characterized the dependence of this modulation on f. For sufficiently high noise, the neuron acts as a low-pass filter. The modulation amplitude is approximately constant for frequencies up to a cutoff frequency, fc, after which it decays. The cutoff frequency increases almost linearly with the firing rate. For higher frequencies, the modulation amplitude decays as C/falpha, where the power alpha depends on the spike initiation mechanism. For conductance-based models, alpha = 1, and the prefactor C depends solely on the average firing rate and a spike "slope factor," which determines the sharpness of the spike initiation. These results are attributable to the fact that near threshold, the sodium activation variable can be approximated by an exponential function. Using this feature, we propose a simplified one-variable model, the "exponential integrate-and-fire neuron," as an approximation of a conductance-based model. We show that this model reproduces the dynamics of a simple conductance-based model extremely well. Our study shows how an intrinsic neuronal property (the characteristics of fast sodium channels) determines the speed with which neurons can track changes in input.


Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1.
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc-/- (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 x 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.


Pumpkin seed oil (prostafit) or prazosin? Which one is better in the treatment of symptomatic benign prostatic hyperplasia.
To assess the efficacy of drugs containing herbal extracts in the treatment of Benign Prostatic Hyperplasia. The clinical trial study was performed in 2011-2012 at Imam Reza Hospital, Mashhad, Iran. One hundred patients with Benign Prostatic Hyperplasia were randomly divided into 2 equal groups receiving prostafit and prazosin, respectively. Quality of life and International Prostatic Symptom Score questionnaire were filled and prostate specific antigen level, uroflowmetry and prostate volume were measured at baseline, 3 and 6 months after the medication. The data was analysed using SPSS 15 and repeated measure analysis of variance. No complications were observed during and after the treatment. International Prostatic Symptom Score had significant differences at baseline and 6 months after the treatment in both groups, specially in group 2 18 vs 22 (36% versus 44%). Quality of life was better in group 2, 25.5 vs 31.5 (51% versus 63%). prostate specific antigen level did not change after the treatment and there was no remarkable difference in either group. Prostafit is an effective and safe treatment in Benign Prostatic Hyperplasia but not as much as prozasin.


Viroimmunotherapy of Thoracic Cancers.
Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases remain as some of the poorest of any cancers. Recent advances in immunotherapy, specifically immune checkpoint inhibitors, have begun to help a small population of patients with advanced lung cancer. People who respond to these immune therapies generally have a durable response and many see dramatic decreases in their disease. However, response to immune therapies remains relatively low. Therefore, intense research is now underway to rationally develop combination therapies to expand the range of patients who will respond to and benefit from immune therapy. One promising approach is with oncolytic viruses. These oncolytic viruses (OVs) have been found to be selective for or have been engineered to preferentially infect and kill cancer cells. In pre-clinical models of different thoracic cancers, it has been found that these viruses can induce immunogenic cell death, increase the number of immune mediators brought into the tumor microenvironment and broaden the neoantigen-specific T cell response. We will review here the literature regarding the application of virotherapy toward augmenting immune responses in thoracic cancers.


The implications of trace metal-nitrilotriacetetic acid speciation on its environmental impact and toxicology.
Substitution of nitrilotriacetic acid (NTA) for polyphosphates in detergents has brought questions concerning its potential toxicity and impact on trace metal distribution in the environment. A calculation based upon metal ligand equilibria, known environmental concentrations of NTA following extensive detergent usage, and the presence of competitive metal-binding ligands and trace elements demonstrates that NTA will be present almost completely as the calcium and magnesium chelates. An analogous estimate of the speciation of NTA in various toxicity studies demonstrates that the onset of chronic toxicity in feeding studies is coincident with the presence of significant concentrations of "free" NTA in the gastrointestinal tract. Massive doses of NTA over long periods of time cause reproducible renal tumors in rats, but dosages of 7500 ppm administered indefinitely are without measurable effect.


Inbreeding and parasite sex ratios.
The breeding system of parasitic protozoa affects the evolution of drug resistance and virulence, and is relevant to disease diagnosis and the development of chemo- and immunotherapy. A major group of protozoan parasites, the phylum Apicomplexa, that includes the aetiological agents of malaria, toxoplasmosis and coccidiosis, all have dimorphic sexual stages. The sex ratio (proportion of males produced by parasites) is predicted to depend upon the inbreeding rate, and it has been suggested that sex-ratio data offer a relatively cheap and easy method for indirectly estimating inbreeding rates. Here, we exploit a new theoretical machinery to show that there are generally valid relationships between f, Wright's coefficient of inbreeding, and sex ratio, z(*), the generality being with respect to population structure. To focus the discussion, we concentrate on malaria and show that the previously derived result, f = 1 - 2z(*), does not depend on the artificial assumptions about population structure that were previously made. Not only does this justify the use of sex ratio as an indirect measure of f, but also we argue that it may actually be preferable to measure f by measuring sex ratios, rather than by measuring departures from Hardy-Weinberg genotypic proportions both in malaria and parasites more generally.


High-intensity interval exercise training before abdominal aortic aneurysm repair (HIT-AAA): protocol for a randomised controlled feasibility trial.
In patients with large abdominal aortic aneurysm (AAA), open surgical or endovascular aneurysm repair procedures are often used to minimise the risk of aneurysm-related rupture and death; however, aneurysm repair itself carries a high risk. Low cardiopulmonary fitness is associated with an increased risk of early post-operative complications and death following elective AAA repair. Therefore, fitness should be enhanced before aneurysm repair. High-intensity interval exercise training (HIT) is a potent, time-efficient strategy for enhancing cardiopulmonary fitness. Here, we describe a feasibility study for a definitive trial of a pre-operative HIT intervention to improve post-operative outcomes in patients undergoing elective AAA repair. A minimum of 50 patients awaiting elective repair of a 5.5-7.0 cm infrarenal AAA will be allocated by minimisation to HIT or usual care control in a 1:1 ratio. The patients allocated to HIT will complete three hospital-based exercise sessions per week, for 4 weeks. Each session will include 2 or 4 min of high-intensity stationary cycling followed by the same duration of easy cycling or passive recovery, repeated until a total of 16 min of high-intensity exercise is accumulated. Outcomes to be assessed before randomisation and 24-48 h before aneurysm repair include cardiopulmonary fitness, maximum AAA diameter and health-related quality of life. In the post-operative period, we will record destination (ward or critical care unit), organ-specific morbidity, mortality and the durations of critical care and hospital stay. Twelve weeks after the discharge, participants will be interviewed to reassess quality of life and determine post-discharge healthcare utilisation. The costs associated with the exercise intervention and healthcare utilisation will be calculated. Ethics approval was secured through Sunderland Research Ethics Committee. The findings of the trial will be disseminated through peer-reviewed journals, and national and international presentations. Current Controlled Trials ISRCTN09433624.


Imbalance in individual researcher's peer review activities quantified for four British Ecological Society journals, 2003-2010.
Researchers contribute to the scientific peer review system by providing reviews, and "withdraw" from it by submitting manuscripts that are subsequently reviewed. So far as we are aware, there has been no quantification of the balance of individual's contributions and withdrawals. We compared the number of reviews provided by individual researchers (i.e., their contribution) to the number required by their submissions (i.e. their withdrawals) in a large and anonymised database provided by the British Ecological Society. The database covered the Journal of Ecology, Journal of Animal Ecology, Journal of Applied Ecology, and Functional Ecology from 2003-2010. The majority of researchers (64%) did not have balanced contributions and withdrawals. Depending on assumptions, 12% to 44% contributed more than twice as much as required; 20% to 52% contributed less than half as much as required. Balance, or lack thereof, varied little in relation to the number of years a researcher had been active (reviewing or submitting). Researchers who contributed less than required did not lack the opportunity to review. Researchers who submitted more were more likely to accept invitations to review. These finding suggest overall that peer review of the four analysed journals is not in crisis, but only due to the favourable balance of over- and under-contributing researchers. These findings are limited to the four journals analysed, and therefore cannot include researcher's other peer review activities, which if included might change the proportions reported. Relatively low effort was required to assemble, check, and analyse the data. Broader analyses of individual researcher's peer review activities would contribute to greater quality, efficiency, and fairness in the peer review system.


Wild bitter gourd protects against alcoholic fatty liver in mice by attenuating oxidative stress and inflammatory responses.
Bitter gourd (Momordica charantia L.) is a common vegetable grown widely in Asia that is used as a traditional medicine. The objective of this study was to investigate whether wild bitter gourd possessed protective effects against chronic alcohol-induced liver injury in mice. C57BL/6 mice were fed an alcohol-containing liquid diet for 4 weeks to induce alcoholic fatty liver. Meanwhile, mice were treated with ethanol extracts from four different wild bitter gourd cultivars: Hualien No. 1', Hualien No. 2', Hualien No. 3' and Hualien No. 4'. The results indicated that the daily administration of 500 mg kg body weight(-1) of a Hualien No. 3' extract (H3E) or a Hualien No. 4' extract (H4E) markedly reduced the steatotic alternation of liver histopathology. In addition, the activation of serum aminotransferases (AST and ALT) and the accumulation of hepatic TG content caused by alcohol were ameliorated. The hepatoprotective effects of H3E and H4E involved the enhancement of the antioxidant defence system (GSH, GPx, GRd, CAT and SOD), inhibition of lipid peroxidation (MDA) and reduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the liver. Moreover, H3E and H4E supplementation suppressed the alcohol-induced elevation of CYP2E1, SREBP-1, FAS and ACC protein expression. These results demonstrated that ethanol extracts of Hualien No. 3' and Hualien No. 4' have beneficial effects against alcoholic fatty liver, in which they attenuate oxidative stress and inflammatory responses.


The Relationship Between Accuracy of Numerical Magnitude Comparisons and Children's Arithmetic Ability: A Study in Iranian Primary School Children.
The relationship between children's accuracy during numerical magnitude comparisons and arithmetic ability has been investigated by many researchers. Contradictory results have been reported from these studies due to the use of many different tasks and indices to determine the accuracy of numerical magnitude comparisons. In the light of this inconsistency among measurement techniques, the present study aimed to investigate this relationship among Iranian second grade children (n = 113) using a pre-established test (known as the Numeracy Screener) to measure numerical magnitude comparison accuracy. The results revealed that both the symbolic and non-symbolic items of the Numeracy Screener significantly correlated with arithmetic ability. However, after controlling for the effect of working memory, processing speed, and long-term memory, only performance on symbolic items accounted for the unique variances in children's arithmetic ability. Furthermore, while working memory uniquely contributed to arithmetic ability in one-and two-digit arithmetic problem solving, processing speed uniquely explained only the variance in single-digit arithmetic skills and long-term memory did not contribute to any significant additional variance for one-digit or two-digit arithmetic problem solving.


A dual program for translation regulation in cellular proliferation and differentiation.
A dichotomous choice for metazoan cells is between proliferation and differentiation. Measuring tRNA pools in various cell types, we found two distinct subsets, one that is induced in proliferating cells, and repressed otherwise, and another with the opposite signature. Correspondingly, we found that genes serving cell-autonomous functions and genes involved in multicellularity obey distinct codon usage. Proliferation-induced and differentiation-induced tRNAs often carry anticodons that correspond to the codons enriched among the cell-autonomous and the multicellularity genes, respectively. Because mRNAs of cell-autonomous genes are induced in proliferation and cancer in particular, the concomitant induction of their codon-enriched tRNAs suggests coordination between transcription and translation. Histone modifications indeed change similarly in the vicinity of cell-autonomous genes and their corresponding tRNAs, and in multicellularity genes and their tRNAs, suggesting the existence of transcriptional programs coordinating tRNA supply and demand. Hence, we describe the existence of two distinct translation programs that operate during proliferation and differentiation.


Epidemic Wave Dynamics Attributable to Urban Community Structure: A Theoretical Characterization of Disease Transmission in a Large Network.
Multiple waves of transmission during infectious disease epidemics represent a major public health challenge, but the ecological and behavioral drivers of epidemic resurgence are poorly understood. In theory, community structure—aggregation into highly intraconnected and loosely interconnected social groups—within human populations may lead to punctuated outbreaks as diseases progress from one community to the next. However, this explanation has been largely overlooked in favor of temporal shifts in environmental conditions and human behavior and because of the difficulties associated with estimating large-scale contact patterns. The aim was to characterize naturally arising patterns of human contact that are capable of producing simulated epidemics with multiple wave structures. We used an extensive dataset of proximal physical contacts between users of a public Wi-Fi Internet system to evaluate the epidemiological implications of an empirical urban contact network. We characterized the modularity (community structure) of the network and then estimated epidemic dynamics under a percolation-based model of infectious disease spread on the network. We classified simulated epidemics as multiwave using a novel metric and we identified network structures that were critical to the network's ability to produce multiwave epidemics. We identified robust community structure in a large, empirical urban contact network from which multiwave epidemics may emerge naturally. This pattern was fueled by a special kind of insularity in which locally popular individuals were not the ones forging contacts with more distant social groups. Our results suggest that ordinary contact patterns can produce multiwave epidemics at the scale of a single urban area without the temporal shifts that are usually assumed to be responsible. Understanding the role of community structure in epidemic dynamics allows officials to anticipate epidemic resurgence without having to forecast future changes in hosts, pathogens, or the environment.


Concurrent estimation of total body and exchangeable body sodium in hypertension.
1. Total-body neutron-activation analysis in vivo was carried out in 11 hypertensive subjects to measure simultaneously the total body content of sodium, chlorine, calcium, phosphorus and nitrogen. 2. There was a highly significant correlation between total body sodium measured by activation analysis and total exchangeable sodium measured by a standard isotope-dilution technique (r = 0.92, P less than 0.001). Exchangeable sodium averaged 80.3% of total body sodium. 3. The measured values of chlorine, calcium, phosphorus and nitrogen were similar to those for healthy subjects reported by others. 4. Activation analysis in vivo appears promising as an additional tool for investigating sodium metabolism in hypertension, as it is the only method available for determining the total body content of this element. The radiation dose (1 rem) is sufficiently low to permit repeated measurements in the same subject.


Mixed Flavonoid Supplementation Attenuates Postexercise Plasma Levels of 4-Hydroxynonenal and Protein Carbonyls in Endurance Athletes.
This double-blinded, placebo controlled, randomized crossover trial investigated the influence of 2-week mixed flavonoid versus placebo supplementation on oxinflammation markers after a 75-km cycling time trial in 22 cyclists (42.3 ± 1.7 years). Blood samples were collected before and after the 2-week supplementation, and then 0 hr, 1.5 hr, and 21 hr post 75-km cycling (176 ± 5.4 min, 73.4 ±2.0% maximal oxygen consumption). The supplement provided 678-mg flavonoids with quercetin (200 mg), green tea catechins (368 mg, 180-mg epigallocatechin gallate), and anthocyanins (128 mg) from bilberry extract, with caffeine, vitamin C, and omega-3 fatty acids added as adjuvants. Blood samples were analyzed for blood leukocyte counts, oxinflammation biomarkers, including 4-hydroxynonenal, protein carbonyls, and peripheral blood mononuclear mRNA expression for cyclooxygenease-2 and glutathione peroxidase. Each of the blood biomarkers was elevated postexercise (time effects, all ps < .01), with lower plasma levels for 4-hydroxynonenal (at 21-hr postexercise) in flavonoid versus placebo (interaction effect, p = .008). Although elevated postexercise, no trial differences for the neutrophil/lymphocyte ratio (p = .539) or peripheral blood mononuclear mRNA expression for cyclooxygenease-2 (p = .322) or glutathione peroxidase (p = .839) were shown. Flavonoid supplementation prior to intensive exercise decreased plasma peroxidation and oxidative damage, as determined by 4-hydroxynonenal. Postexercise increases were similar between the flavonoid and placebo trials for peripheral blood mononuclear mRNA expression for cyclooxygenease-2 and the nuclear factor erythroid 2-related factor 2 related gene glutathione peroxidase (NFE2L2). The data support the strategy of flavonoid supplementation to mitigate postexercise oxidative stress in endurance athletes.


Mechanistic insight into the attenuation of gouty inflammation by Taiwanese green propolis via inhibition of the NLRP3 inflammasome.
Dysregulation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including gouty arthritis. Activation of the NLRP3 inflammasome requires priming and activation signals: the priming signal controls the expression of NLRP3 and interleukin (IL)-1β precursor (proIL-1β), while the activation signal leads to the assembly of the NLRP3 inflammasome and to caspase-1 activation. Here, we reported the effects of the alcoholic extract of Taiwanese green propolis (TGP) on the NLRP3 inflammasome in vitro and in vivo. TGP inhibited proIL-1β expression by reducing nuclear factor kappa B activation and reactive oxygen species (ROS) production in lipopolysaccharide-activated macrophages. Additionally, TGP also suppressed the activation signal by reducing mitochondrial damage, ROS production, lysosomal rupture, c-Jun N-terminal kinases 1/2 phosphorylation and apoptosis-associated speck-like protein oligomerization. Furthermore, we found that TGP inhibited the NLRP3 inflammasome partially via autophagy induction. In the in vivo mouse model of uric acid crystal-induced peritonitis, TGP attenuated the peritoneal recruitment of neutrophils, and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 in lavage fluids. As a proof of principle, in this study, we purified a known compound, propolin G, from TGP and identified this compound as a potential inhibitor of the NLRP3 inflammasome. Our results indicated that TGP might be useful for ameliorating gouty inflammation via inhibition of the NLRP3 inflammasome.


BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.
B-cell lymphoma 6 (BCL6) is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with a BCL6 inhibitor revealed induction of BCL6-repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitors induced apoptosis and decreased colony-forming capacity, which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in a significant reduction of leukemia-initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal hematopoietic stem cells. Treatment with cytarabine further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to cytarabine. Treatment of AML patient-derived xenografts with BCL6 inhibitor plus cytarabine suggested enhanced antileukemia activity with this combination. Hence, pharmacologic inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.


The Catalytic Site Atlas: a resource of catalytic sites and residues identified in enzymes using structural data.
The Catalytic Site Atlas (CSA) provides catalytic residue annotation for enzymes in the Protein Data Bank. It is available online at http://www.ebi.ac.uk/thornton-srv/databases/CSA. The database consists of two types of annotated site: an original hand-annotated set containing information extracted from the primary literature, using defined criteria to assign catalytic residues, and an additional homologous set, containing annotations inferred by PSI-BLAST and sequence alignment to one of the original set. The CSA can be queried via Swiss-Prot identifier and EC number, as well as by PDB code. CSA Version 1.0 contains 177 original hand- annotated entries and 2608 homologous entries, and covers approximately 30% of all EC numbers found in PDB. The CSA will be updated on a monthly basis to include homologous sites found in new PDBs, and new hand-annotated enzymes as and when their annotation is completed.


Sulforaphane Inhibits HIV Infection of Macrophages through Nrf2.
Marburg virus, the Kaposi's sarcoma-associated herpesvirus (KSHV) and Dengue virus all activate, and benefit from, expression of the transcription regulator nuclear erythroid 2-related factor 2 (Nrf2). The impact of Nrf2 activation on human immunodeficiency virus (HIV) infection has not been tested. Sulforaphane (SFN), produced in cruciferous vegetables after mechanical damage, mobilizes Nrf2 to potently reprogram cellular gene expression. Here we show for the first time that SFN blocks HIV infection in primary macrophages but not in primary T cells. Similarly SFN blocks infection in PMA-differentiated promonocytic cell lines, but not in other cell lines tested. siRNA-mediated depletion of Nrf2 boosted HIV infectivity in primary macrophages and reduced the anti-viral effects of SFN treatment. This supports a model in which anti-viral activity is mediated through Nrf2 after it is mobilized by SFN. We further found that, like the type I interferon-induced cellular anti-viral proteins SAMHD1 and MX2, SFN treatment blocks infection after entry, but before formation of 2-LTR circles. Interestingly however, neither SAMHD1 nor MX2 were upregulated. This shows for the first time that Nrf2 action can potently block HIV infection and highlights a novel way to trigger this inhibition.


Role of alpha-actinin-3 in contractile properties of human single muscle fibers: a case series study in paraplegics.
A common nonsense polymorphism in the ACTN3 gene results in the absence of α-actinin-3 in XX individuals. The wild type allele has been associated with power athlete status and an increased force output in numeral studies, though the mechanisms by which these effects occur are unclear. Recent findings in the Actn3(-/-) (KO) mouse suggest a shift towards 'slow' metabolic and contractile characteristics of fast muscle fibers lacking α-actinin-3. Skinned single fibers from the quadriceps muscle of three men with spinal cord injury (SCI) were tested regarding peak force, unloaded shortening velocity, force-velocity relationship, passive tension and calcium sensitivity. The SCI condition induces an 'equal environment condition' what makes these subjects ideal to study the role of α-actinin-3 on fiber type expression and single muscle fiber contractile properties. Genotyping for ACTN3 revealed that the three subjects were XX, RX and RR carriers, respectively. The XX carrier's biopsy was the only one that presented type I fibers with a complete lack of type II(x) fibers. Properties of hybrid type II(a)/II(x) fibers were compared between the three subjects. Absence of α-actinin-3 resulted in less stiff type II(a)/II(x) fibers. The heterozygote (RX) exhibited the highest fiber diameter (0.121±0.005 mm) and CSA (0.012±0.001 mm(2)) and, as a consequence, the highest peak force (2.11±0.14 mN). Normalized peak force was similar in all three subjects (P = 0.75). Unloaded shortening velocity was highest in R-allele carriers (P<0.001). No difference was found in calcium sensitivity. The preservation of type I fibers and the absence of type II(x) fibers in the XX individual indicate a restricted transformation of the muscle fiber composition to type II fibers in response to long-term muscle disuse. Lack of α-actinin-3 may decrease unloaded shortening velocity and increase fiber elasticity.


Molecular characterization of the interaction between siRNA and PAMAM G7 dendrimers by SAXS, ITC, and molecular dynamics simulations.
A prerequisite for the use of dendrimers as drug delivery vehicles is the detailed molecular understanding of the drug interaction. The purpose of this study was to characterize the self-assembly process between siRNA and generation 7 poly(amidoamine) dendrimers and the resulting dendriplexes in aqueous solution using structural and calorimetric methods combined with molecular dynamics simulations. Complexes with a length scale of 150 nm showed a decreasing size with increasing amine-to-phosphate ratio by dynamic light scattering. At the molecular level, individual dendrimers studied by small-angle X-ray scattering (SAXS) showed no change in size upon siRNA binding, suggesting a rigid sphere behavior. Isothermal titration calorimetry (ITC) demonstrated exothermic binding with a concentration-dependent collapse of complexes. Both the experimentally determined ΔH(bind) and size were in close accordance with molecular dynamics simulations. This study demonstrates the unique complementarity of SAXS, ITC, and modeling for the detailed description of the molecular interactions between dendrimers and siRNA during dendriplex formation.


Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals.
Despite effective and widely available suppressive anti-HIV therapy, the prevalence of mild neurocognitive dysfunction continues to increase. HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with sustained central nervous system inflammation and immune activation as prominent features. Inflammatory macrophages, HIV-infected and uninfected, play a central role in the development of HIV dementia. There is a critical need to identify biomarkers and to better understand the molecular mechanisms leading to cognitive dysfunction in HAND. In this regard, we identified through a subtractive hybridization strategy osteopontin (OPN, SPP1, gene) an inflammatory marker, as an upregulated gene in HIV-infected primary human monocyte-derived macrophages. Knockdown of OPN in primary macrophages resulted in a threefold decrease in HIV-1 replication. Ectopic expression of OPN in the TZM-bl cell line significantly enhanced HIV infectivity and replication. A significant increase in the degradation of the NF-κB inhibitor, IκBα and an increase in the nuclear-to-cytoplasmic ratio of NF-κB were found in HIV-infected cells expressing OPN compared to controls. Moreover, mutation of the NF-κB binding domain in the HIV-LTR abrogated enhanced promoter activity stimulated by OPN. Interestingly, compared to cerebrospinal fluid from normal and multiple sclerosis controls, OPN levels were significantly higher in HIV-infected individuals both with and without neurocognitive disorder. OPN levels were highest in HIV-infected individuals with moderate to severe cognitive impairment. Moreover, OPN was significantly elevated in brain tissue from HIV-infected individuals with cognitive disorder versus those without impairment. Collectively, these data suggest that OPN stimulates HIV-1 replication and that high levels of OPN are present in the CNS compartment of HIV-infected individuals, reflecting ongoing inflammatory processes at this site despite anti-HIV therapy.


Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy.
High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.


Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin.
Luteolin, a common dietary flavonoid, has been found to have antitumor properties and therefore poses special interest for the development of preventive and/or therapeutic agent for cancers. E-cadherin, a marker of epithelial cells, mediates cell-cell adhesion. Decreased expression of E-cadherin results in a loss of cell-cell adhesion and an increased cell invasion. Many studies have shown the antiproliferative activities of luteolin on cancer cells. However, the effects of luteolin on invasion of cancer cells remain unclear. In this article, we show that luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. We found that Luteolin induced expression of E-cadherin through mdm2. Overexpression of mdm2 or knockdown of E-cadherin could restore invasion of PC3 cells after luteolin treatment. Luteolin inhibits mdm2 through AKT and overexpression of active AKT attenuated luteolin-induced expression of E-cadherin, suggesting that luteolin regulates E-cadherin through AKT/mdm2 pathway. The in vivo experiments showed that luteolin inhibited spontaneous lung metastasis of PC3 cells implanted onto the nude mice. These findings provide a new sight into the mechanisms that luteolin is against cancer cells, and suggest that molecular targeting of E-cadherin by luteolin may be a useful strategy for treatment of invasive prostate cancers.


Antiepileptic drugs and intrauterine death: A prospective observational study from EURAP.
To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.


Acupuncture for acute non-specific low back pain: a randomised, controlled, double-blind, placebo trial.
To assess the efficacy of Yamamoto's acupuncture method on pain, drug intake, functional capacity and quality of life for the treatment of acute non-specific low back pain (ANLBP). A prospective, randomised, parallel-group, double-blind, placebo-controlled trial was performed in 80 men and women with ANLBP who were randomly assigned to five acupuncture sessions (intervention group (IG), n=40) and to five non-penetrating acupuncture sessions (sham group (SG), n=40). Patients were evaluated at baseline and at 3, 7, 14, 21 and 28 days. The measurements used were: visual analogue scale (VAS) for cumulative pain (before intervention, VAS1) and immediate pain (after intervention, VAS2); function (Roland-Morris Disability Questionnaire (RM)); quality of life (SF-36); improvement rating; and number of anti-inflammatory tablets taken. The primary endpoint was a decrease of at least 2 cm in VAS1. Pain VAS improved significantly in the IG from day 14 onwards compared with the SG, but the difference did not reach the prespecified clinically relevant value of 2 cm. The IG was significantly superior to the SG in the following outcomes: cumulative pain, function, pain (SF-36) and vitality (SF-36) at days 14, 21 and 28 (p<0.05); limitation in physical aspects (SF-36) at all times (p=0.007 and p=0.02); and functional capacity (SF-36) at days 21 and 28 (p<0.05). The IG also took significantly fewer anti-inflammatory tablets than the SG (p=0.004) at all evaluation times and the improvement rating was better than the SG (p<0.001). Yamamoto's new scalp acupuncture was more effective than sham treatment with regard to decrease in pain and anti-inflammatory intake as well as improving functional status and quality of life for patients with ANLBP. NCT 01124955.


A comparative transcriptomic, fluxomic and metabolomic analysis of the response of Saccharomyces cerevisiae to increases in NADPH oxidation.
Redox homeostasis is essential to sustain metabolism and growth. We recently reported that yeast cells meet a gradual increase in imposed NADPH demand by progressively increasing flux through the pentose phosphate (PP) and acetate pathways and by exchanging NADH for NADPH in the cytosol, via a transhydrogenase-like cycle. Here, we studied the mechanisms underlying this metabolic response, through a combination of gene expression profiling and analyses of extracellular and intracellular metabolites and 13 C-flux analysis. NADPH oxidation was increased by reducing acetoin to 2,3-butanediol in a strain overexpressing an engineered NADPH-dependent butanediol dehydrogenase cultured in the presence of acetoin. An increase in NADPH demand to 22 times the anabolic requirement for NADPH was accompanied by the intracellular accumulation of PP pathway metabolites consistent with an increase in flux through this pathway. Increases in NADPH demand were accompanied by the successive induction of several genes of the PP pathway. NADPH-consuming pathways, such as amino-acid biosynthesis, were upregulated as an indirect effect of the decrease in NADPH availability. Metabolomic analysis showed that the most extreme modification of NADPH demand resulted in an energetic problem. Our results also highlight the influence of redox status on aroma production. Combined 13 C-flux, intracellular metabolite levels and microarrays analyses revealed that NADPH homeostasis, in response to a progressive increase in NADPH demand, was achieved by the regulation, at several levels, of the PP pathway. This pathway is principally under metabolic control, but regulation of the transcription of PP pathway genes can exert a stronger effect, by redirecting larger amounts of carbon to this pathway to satisfy the demand for NADPH. No coordinated response of genes involved in NADPH metabolism was observed, suggesting that yeast has no system for sensing NADPH/NADP+ ratio. Instead, the induction of NADPH-consuming amino-acid pathways in conditions of NADPH limitation may indirectly trigger the transcription of a set of PP pathway genes.


[Does evidence-b(i)ased psychiatry have its limitations?].
Evidence-based medicine (EBM) is an algorithm that integrates information technology and the results of outcome research into clinical work. EBM, if well understood, is a valuable and critical bottom-up method that promotes a dialectical process by which the practitioner is able to arrive at an informed treatment choice; the method starts from the individual patient and involves discussion with the patient and critical reading of the relevant literature. However, there is a risk that EBM will become an ideology unless we are aware of its assumptions and epistemology. It is not valuefree, but is driven by an implicit objectivist view of man. EBM attaches greater value to biomedical sciences that to the humanities, to empiricism than to hermeneutics and to quantitative research than to qualitative research. EBM focuses on internal validity, but is in danger of neglecting factors such as qualitative changes that are difficult to measure, ecological validity and effectiveness and may hinder the generalisation of research results to clinical practice. The limitations of EBM are even more poignant in psychiatry, because psychiatry is highly sensitive to context and values. EBM is a blessing if we use it critically and remain aware of its limitations and underlying philosophy and if we supplement it with strategies such as value-based medicine (VBM). EBM, however, does not teach us what is useful or valuable, whereas VBM helps us to explain and weigh up the values that are at stake.


Muscle Dysmorphia: An Overview of Clinical Features and Treatment Options.
An increasing public and empirical focus on male body image indicates that muscularity is a preeminent concern among boys and men. For some, these concerns develop into a complex and disabling psychiatric disorder termed muscle dysmorphia (MD), the hallmark of which is an intense preoccupation regarding one's (subjectively) insufficient muscularity. Treatment of MD is critical; however, evidence to inform treatment approaches is sorely lacking. The purpose of this article is twofold. First, we provide an overview of the clinical features of MD, drawing particular attention to the preoccupation, functional impairment and psychiatric comorbidity associated with the disorder. Second, we discuss and recommend potential treatment directions for MD, including techniques that have demonstrated efficacy in the treatment of related disorders, namely, body dysmorphic disorder and eating disorders (and anorexia nervosa in particular). Psychotherapeutic techniques, including cognitive restructuring of deleterious perfectionistic and egosyntonic beliefs, and dialectical behavioral techniques to improve the repertoire of emotion regulation skills available to afflicted individuals, are discussed, in addition to psychopharmacological approaches.


Gastric cancer histology: clinicopathologic characteristics and prognostic value.
Gastric cancer can be divided into two major histologic categories, that is, differentiated and undifferentiated types. In the present study, we sought to clarify the prognoses and clinicopathologic characteristics of signet ring cell carcinoma and mucinous carcinoma, both of which are mucin-producing tumors of the undifferentiated type. We retrospectively reviewed medical records of 2,275 patients who underwent gastric resection. Cases were divided into four histologic groups: differentiated carcinoma (well differentiated and moderately differentiated, WMD), poorly differentiated (PD), signet ring cell carcinoma (SRC), and mucinous carcinoma (MC). The overall cumulative 5-year survival rates for patients were 67% for WMD, 54% for PD, 65% for SRC, and 48% for MC. The outcome of SRC was similar to that of WMD, whereas that of MC was similar to that of PD. Stage-stratified analysis revealed that histologic type was not statistically related to survival in patients with stage I, II, or III. On the other hand, histologic type in patients with stage IV disease was found to be significantly associated with survival. Histologic classifications of mucin-producing gastric cancers should separately be considered from other histologic types.


Image-size differences worsen stereopsis independent of eye position.
With the eyes in forward gaze, stereo performance worsens when one eye's image is larger than the other's. Near, eccentric objects naturally create retinal images of different sizes. Does this mean that stereopsis exhibits deficits for such stimuli? Or does the visual system compensate for the predictable image-size differences? To answer this, we measured discrimination of a disparity-defined shape for different relative image sizes. We did so for different gaze directions, some compatible with the image-size difference and some not. Magnifications of 10-15% caused a clear worsening of stereo performance. The worsening was determined only by relative image size and not by eye position. This shows that no neural compensation for image-size differences accompanies eye-position changes, at least prior to disparity estimation. We also found that a local cross-correlation model for disparity estimation performs like humans in the same task, suggesting that the decrease in stereo performance due to image-size differences is a byproduct of the disparity-estimation method. Finally, we looked for compensation in an observer who has constantly different image sizes due to differing eye lengths. She performed best when the presented images were roughly the same size, indicating that she has compensated for the persistent image-size difference.


delta-Aminolaevulinic acid in plasma, cerebrospinal fluid, saliva and erythrocytes: studies in normal, uraemic and porphyric subjects.
delta-Aminolaevulinic acid (ALA) was determined by g.l.c. with electron-capture detection. Normal plasma level was 92 nmol/l (SD = 39, n = 89, range 24-270 nmol/l). ALA was undetectable in 35 of 53 samples of normal cerebrospinal fluid (limit of assay 2 nmol/l). The mean of the other 18 samples was 19 nmol/l (SD = 10, range 6-36 nmol/l). Salivary ALA was generally only 10-30% of the plasma level in normal and porphyric subjects. Erythrocytes of normal and porphyric subjects contained no detectable ALA and were impermeable to its entry. ALA clearance correlated closely with that of creatinine, consistent with it being excreted by glomerular filtration with limited tubular reabsorption. In chronic renal failure, serum ALA was elevated to a maximum of three to four times the normal, but its urinary excretion was reduced, in keeping with lessened production. In two cases of acute intermittent porphyria with overwhelming neuropathy the maximum plasma levels of ALA were 9 and 12 mumol/l. Haematin infusion decreased the ALA levels but without obvious clinical benefit. Limited neurological recovery occurred without major reduction in plasma levels of ALA. One subject's attack was precipitated by pregnancy. The neonate was apparently normal, despite high levels of ALA in maternal plasma throughout gestation and a high level of ALA in the cord blood. The observations described here do not support the view that ALA may be directly neurotoxic.


High average power diamond Raman laser.
We report a pulsed Raman laser at 1193 nm based on synthetic diamond crystals with a record output power of 24.5 W and a slope efficiency of 57%. We compared the performance of an anti-reflection coated crystal at normal incidence with a Brewster cut sample. Raman oscillation was achieved at both room temperature and under cryogenic operation at 77 K. Modeling of these experiments allowed us to confirm the value of Raman gain coefficient of diamond, which was found to be 13.5 ± 2.0 cm/GW for a pump wavelength of 1030 nm.


microRNA as a potential vector for the propagation of robustness in protein expression and oscillatory dynamics within a ceRNA network.
microRNAs (miRNAs) are small noncoding RNAs that are important post-transcriptional regulators of gene expression. miRNAs can induce thresholds in protein synthesis. Such thresholds in protein output can be also achieved by oligomerization of transcription factors (TF) for the control of gene expression. First, we propose a minimal model for protein expression regulated by miRNA and by oligomerization of TF. We show that miRNA and oligomerization of TF generate a buffer, which increases the robustness of protein output towards molecular noise as well as towards random variation of kinetics parameters. Next, we extend the model by considering that the same miRNA can bind to multiple messenger RNAs, which accounts for the dynamics of a minimal competing endogenous RNAs (ceRNAs) network. The model shows that, through common miRNA regulation, TF can control the expression of all proteins formed by the ceRNA network, even if it drives the expression of only one gene in the network. The model further suggests that the threshold in protein synthesis mediated by the oligomerization of TF can be propagated to the other genes, which can increase the robustness of the expression of all genes in such ceRNA network. Furthermore, we show that a miRNA could increase the time delay of a "Goodwin-like" oscillator model, which may favor the occurrence of oscillations of large amplitude. This result predicts important roles of miRNAs in the control of the molecular mechanisms leading to the emergence of biological rhythms. Moreover, a model for the latter oscillator embedded in a ceRNA network indicates that the oscillatory behavior can be propagated, via the shared miRNA, to all proteins formed by such ceRNA network. Thus, by means of computational models, we show that miRNAs could act as vectors allowing the propagation of robustness in protein synthesis as well as oscillatory behaviors within ceRNA networks.


Identification of a single amino acid residue which is critical for the interaction between HSV-1 inner tegument proteins pUL36 and pUL37.
The herpes simplex virus type 1 (HSV-1) structural tegument proteins pUL36 and pUL37 are essential for secondary envelopment during the egress of viral particles. For this study, scanning alanine mutagenesis of HSV-1 pUL37, in combination with yeast two-hybrid, identified pUL37 residue D631 as a major determinant for binding of pUL36. Further analysis of the binding of this pUL37 mutant to pUL36 by coimmunoprecipitation assay confirmed the role of pUL37 D631 in mediating binding of pUL36. A trans-complementation assay using pUL37 deletion virus FRΔUL37 was then carried out, where pUL37 wild type or D631A were provided in trans. For pUL37 D631A, a significant reduction in virus titer was observed compared to that seen when pUL37 wild type was present. The results presented here underline the crucial role of the pUL36/pUL37 interaction in replication of HSV-1 and indicate a critical role for pUL37 D631 in mediating this interaction.


Cancer--approaching a universal molecular mechanism?
Accumulating evidence strongly suggests that cancer is a genetic disease, arising from mutations in DNA. These mutations alter the function or synthesis of two groups of proteins, which are the products of either proto-oncogenes or anti-oncogenes. Of the more than 30 proto-oncogenes identified, ras proto-oncogenes are most frequently found to be mutationally activated (to oncogenes) in human tumours. Developments leading to current understanding of the function of ras proto-oncogenes and of the retinoblastoma anti-oncogene are reviewed. Based on the involvement of all known oncogenes and anti-oncogenes in cellular signal transduction pathways, it is suggested that a general model for cancer at the molecular level may become a reality.


Effectiveness of conventional versus virtual reality based vestibular rehabilitation in the treatment of dizziness, gait and balance impairment in adults with unilateral peripheral vestibular loss: a randomised controlled trial.
Unilateral peripheral vestibular loss results in gait and balance impairment, dizziness and oscillopsia. Vestibular rehabilitation benefits patients but optimal treatment remains unknown. Virtual reality is an emerging tool in rehabilitation and provides opportunities to improve both outcomes and patient satisfaction with treatment. The Nintendo Wii Fit Plus® (NWFP) is a low cost virtual reality system that challenges balance and provides visual and auditory feedback. It may augment the motor learning that is required to improve balance and gait, but no trials to date have investigated efficacy. In a single (assessor) blind, two centre randomised controlled superiority trial, 80 patients with unilateral peripheral vestibular loss will be randomised to either conventional or virtual reality based (NWFP) vestibular rehabilitation for 6 weeks. The primary outcome measure is gait speed (measured with three dimensional gait analysis). Secondary outcomes include computerised posturography, dynamic visual acuity, and validated questionnaires on dizziness, confidence and anxiety/depression. Outcome will be assessed post treatment (8 weeks) and at 6 months. Advances in the gaming industry have allowed mass production of highly sophisticated low cost virtual reality systems that incorporate technology previously not accessible to most therapists and patients. Importantly, they are not confined to rehabilitation departments, can be used at home and provide an accurate record of adherence to exercise. The benefits of providing augmented feedback, increasing intensity of exercise and accurately measuring adherence may improve conventional vestibular rehabilitation but efficacy must first be demonstrated. Clinical trials.gov identifier: NCT01442623.


A complete mitochondrial genome sequence of Ogura-type male-sterile cytoplasm and its comparative analysis with that of normal cytoplasm in radish (Raphanus sativus L.).
Plant mitochondrial genome has unique features such as large size, frequent recombination and incorporation of foreign DNA. Cytoplasmic male sterility (CMS) is caused by rearrangement of the mitochondrial genome, and a novel chimeric open reading frame (ORF) created by shuffling of endogenous sequences is often responsible for CMS. The Ogura-type male-sterile cytoplasm is one of the most extensively studied cytoplasms in Brassicaceae. Although the gene orf138 has been isolated as a determinant of Ogura-type CMS, no homologous sequence to orf138 has been found in public databases. Therefore, how orf138 sequence was created is a mystery. In this study, we determined the complete nucleotide sequence of two radish mitochondrial genomes, namely, Ogura- and normal-type genomes, and analyzed them to reveal the origin of the gene orf138. Ogura- and normal-type mitochondrial genomes were assembled to 258,426-bp and 244,036-bp circular sequences, respectively. Normal-type mitochondrial genome contained 33 protein-coding and three rRNA genes, which are well conserved with the reported mitochondrial genome of rapeseed. Ogura-type genomes contained same genes and additional atp9. As for tRNA, normal-type contained 17 tRNAs, while Ogura-type contained 17 tRNAs and one additional trnfM. The gene orf138 was specific to Ogura-type mitochondrial genome, and no sequence homologous to it was found in normal-type genome. Comparative analysis of the two genomes revealed that radish mitochondrial genome consists of 11 syntenic regions (length >3 kb, similarity >99.9%). It was shown that short repeats and overlapped repeats present in the edge of syntenic regions were involved in recombination events during evolution to interconvert two types of mitochondrial genome. Ogura-type mitochondrial genome has four unique regions (2,803 bp, 1,601 bp, 451 bp and 15,255 bp in size) that are non-syntenic to normal-type genome, and the gene orf138 was found to be located at the edge of the largest unique region. Blast analysis performed to assign the unique regions showed that about 80% of the region was covered by short homologous sequences to the mitochondrial sequences of normal-type radish or other reported Brassicaceae species, although no homology was found for the remaining 20% of sequences. Ogura-type mitochondrial genome was highly rearranged compared with the normal-type genome by recombination through one large repeat and multiple short repeats. The rearrangement has produced four unique regions in Ogura-type mitochondrial genome, and most of the unique regions are composed of known Brassicaceae mitochondrial sequences. This suggests that the regions unique to the Ogura-type genome were generated by integration and shuffling of pre-existing mitochondrial sequences during the evolution of Brassicaceae, and novel genes such as orf138 could have been created by the shuffling process of mitochondrial genome.


Effects of implant diameter, insertion depth, and loading angle on stress/strain fields in implant/jawbone systems: finite element analysis.
To investigate the interactions of implant diameter, insertion depth, and loading angle on stress/strain fields in a three-dimensional finite element implant/jawbone system and to determine the influence of the loading angle on stress/strain fields while varying the implant diameter and insertion depth. Four finite element models were created, which corresponded to two implant diameters and two insertion depths. The jawbone was composed of cortical and cancellous bone and modeled as a linearly elastic medium; the implant had a detailed screw structure and was modeled as an elastic-plastic medium. Static loading was applied to the coronal surface of the implant with a maximum load of 200 N for all the models. Loading directions were varied, with buccolingually applied loading angles ranging from 0 to 85 degrees. Increases in the angle of force application caused not only increased maximum stress/strain values but worsened stress/strain distribution patterns in the bone and implant. The maximum stress in the bone always occurred at the upper edge of the cortical bone on the lingual side adjacent to the implant. The use of a larger-diameter implant or an increased insertion depth significantly reduced the maximum stress/strain values, improved the stress/strain distribution patterns and, in particular, decreased the stress/strain sensitivity to loading angle. A narrow-diameter implant, when inserted into jawbone with a shallow insertion depth and loaded with an oblique loading angle, is most unfavorable for stress distribution in both bone and implant. An optimized design of the neck region of an implant, in combination with a carefully controlled implant insertion depth that sets the threads of the implant neck well below the upper edge of the cortical bone, should be especially effective in improving the biomechanical environment for the maintenance of bone in implant/bone systems.


Theory of volumetric capacitance of an electric double-layer supercapacitor.
Electric double-layer supercapacitors are a fast-rising class of high-power energy storage devices based on porous electrodes immersed in a concentrated electrolyte or ionic liquid. As yet there is no microscopic theory to describe their surprisingly large capacitance per unit volume (volumetric capacitance) of ~100 F/cm(3), nor is there a good understanding of the fundamental limits on volumetric capacitance. In this paper we present a non-mean-field theory of the volumetric capacitance of a supercapacitor that captures the discrete nature of the ions and the exponential screening of their repulsive interaction by the electrode. We consider analytically and via Monte Carlo simulations the case of an electrode made from a good metal and show that in this case the volumetric capacitance can reach the record values. We also study how the capacitance is reduced when the electrode is an imperfect metal characterized by some finite screening radius. Finally, we argue that a carbon electrode, despite its relatively large linear screening radius, can be approximated as a perfect metal because of its strong nonlinear screening. In this way the experimentally measured capacitance values of ~100 F/cm(3) may be understood.


Interactions, functions, and independence of plasma membrane STIM1 and TRPC1 in vascular smooth muscle cells.
Stromal interaction molecule 1 (STIM1) is a predicted single membrane-spanning protein involved in store-operated calcium entry and interacting with ion channels including TRPC1. Here, we focus on endogenous STIM1 of modulated vascular smooth muscle cells, which exhibited a nonselective cationic current in response to store depletion despite strong buffering of intracellular calcium at the physiological concentration. STIM1 mRNA and protein were detected and suppressed by specific short interfering RNA. Calcium entry evoked by store depletion was partially inhibited by STIM1 short interfering RNA, whereas calcium release was unaffected. STIM1 short interfering RNA suppressed cell migration but not proliferation. Antibody that specifically bound STIM1 revealed constitutive extracellular N terminus of STIM1 and extracellular application of the antibody caused fast inhibition of the current evoked by store depletion. The antibody also inhibited calcium entry and cell migration but not proliferation. STIM1 interacted with TRPC1, and TRPC1 contributed partially to calcium entry and cationic current. However, the underlying processes could not be explained only by a STIM1-TRPC1 partnership because extracellular TRPC1 antibody suppressed cationic current only in a fraction of cells, TRPC1-containing channels were important for cell proliferation as well as migration, and cell surface localization studies revealed TRPC1 alone, as well as with STIM1. The data suggest a complex situation in which there is not only plasma membrane-spanning STIM1 that is important for cell migration and TRPC1-independent store-operated cationic current but also TRPC1-STIM1 interaction, a TRPC1-dependent component of store-operated current, and STIM1-independent TRPC1 linked to cell proliferation.


Signal and depth enhancement for in vivo flow cytometer measurement of ear skin by optical clearing agents.
The in vivo flow cytometry (IVFC) has shown a great potential for detecting circulating tumor cells quantitatively in the bloodstream. However, the detection depth suffers from the strong light scattering of tissue. In this study, an innovative ear skin optical clearing agent (ESOCA) is employed to improve the signal quality of the IVFC. Our results show that compared with commonly used glycerol, topical application of ESOCA can enhance the transmittance of rat ear significantly in vivo. The labeled red blood cells can be detected by the IVFC with higher signal quality and greater detection depth. This study is very helpful for potential tumor metastasis studies by the IVFC in deep tissues.


Refinement of analgesia following thoracotomy and experimental myocardial infarction using the Mouse Grimace Scale.
What is the central question of this study? There is an ethical imperative to optimize analgesia protocols for laboratory animals, but this is impeded by our inability to recognize pain reliably. We examined whether the Mouse Grimace Scale (MGS) provides benefits over a standard welfare scoring system for identifying a low level of pain in the frequently used murine surgical model of myocardial infarction. What is the main finding and its importance? Low-level pain, responsive to analgesia, was detected by MGS but not standard methods. In this model, most of the pain is attributable to the thoracotomy, excepted in mice with very large infarcts. This approach represents a model for assessing postsurgical analgesia in rodents. The Mouse Grimace Scale (MGS) was developed for assessing pain severity, but the general applicability to complex postsurgical pain has not been established. We sought to determine whether the MGS provides benefits over and above a standard welfare scoring system for identifying pain in mice following experimental myocardial infarction. Female C57BL/6J mice (n = 60), anaesthetized with isoflurane, were subjected to thoracotomy with ligation of a coronary artery or sham procedure. A single s.c. dose of buprenorphine (1.1 mg kg(-1) ) was given at the time of surgery and pain assessed at 24 h by MGS and a procedure-specific welfare scoring system. In some animals, a second dose of 0.6 mg kg(-1) buprenorphine was given and pain assessment repeated after 30 min. The MGS was scored from multiple photographs by two independent blinded observers with good correlation (r = 0.98). Using the average MGS score of both observers, we identified a subset of mice with low scores that were not considered to be in pain by the welfare scoring system or by single observer MGS. These mice showed a significant improvement with additional analgesia, suggesting that this low-level pain is real. Pain attributable to the myocardial injury, as opposed to thoracotomy, persisted at 24 h only in mice with large infarcts >40%. In conclusion, the use of a multi-observer, post hoc version of the MGS is a sensitive tool to assess the efficacy of postsurgical analgesic protocols. Following surgical induction of myocardial infarction, we identified a significant proportion of mice that were in low-level pain at 24 h that were not identified by other assessment methods.


Whole-brain death reconsidered.
The author, a philosopher, suggests that the concept of death should be left as it is 'in its present indeterminate state', and that we ought to reject attempts to define death in terms of whole-brain death or any other type of brain death, including cerebral death and 'irreversible coma'. Instead of 'fiddling with the definition of death' clear rules should be established specifying 'what can be appropriately done to whom when'.


Microsurgical breast reconstruction for nipple-sparing mastectomy.
Nipple-sparing mastectomy warrants thorough preoperative evaluation to effectively achieve risk reduction, high patient satisfaction, and improved aesthetic outcome. To the authors' knowledge, this review represents the largest series of microsurgical breast reconstructions following nipple-sparing mastectomies. All patients undergoing nipple-sparing mastectomy with microsurgical immediate breast reconstruction treated at New York University Medical Center (2007-2011) were identified. Patient demographics, breast cancer history, intraoperative details, complications, and revision operations were examined. Descriptive statistical analysis, including t test or regression analysis, was performed. In 51 patients, 85 free flap breast reconstructions (n = 85) were performed. The majority of flaps were performed for prophylactic indications [n = 55 (64.7 percent)], mostly through vertical incisions [n = 40 (47.0 percent)]. Donor sites included abdominally based [n = 66 (77.6 percent)], profunda artery perforator [n = 12 (14.1 percent)], transverse upper gracilis [n = 6 (7.0 percent)], and superior gluteal artery perforator [n = 1 (1.2 percent)] flaps. The most common complications were mastectomy skin flap necrosis [n = 11 (12.7 percent)] and nipple necrosis [n = 11 (12.7 percent)]. There was no correlation between mastectomy skin flap or nipple necrosis and choice of incision, mastectomy specimen weight, body mass index, or age (p > 0.05). However, smoking history was associated with nipple necrosis (p < 0.01). This series represents a high-volume experience with nipple-sparing mastectomy followed by immediate microsurgical reconstruction. When appropriately executed, it can deliver low complication rates. Therapeutic, IV.


Prevalence of cerebral palsy in north-east Italy from 1965 to 1989.
This study examines the prevalence of cerebral palsy (CP) in two north-east Italian provinces, Padua and Rovigo (overall population 1030 000). Six-hundred and ten children with a diagnosis of CP (330 male, 280 female), born between 1965 and 1989, were studied. The prevalence of CP progressively increased from the 1960s to the mid-1980s, and then decreased in the 5-year period, 1985 to 1989. These quantitative changes were associated with qualitative ones. For example, the number of low-birthweight (LBW) infants progressively increased, similar to results of epidemiological studies from other European countries. The clinical features of the types of CP in this study (hemiplegia, diplegia, ataxic diplegia, quadriplegia, pure ataxia, dyskinesia) generally correspond with those described in other studies. However, the prevalence of quadriplegia in this study is higher. The prevalence of types of CP related to preterm birth, such as diplegia, increased over the years, while those associated with term babies, such as dyskinesia, decreased. This study suggests that prenatal factors are associated with some types of CP, while in others, such as diplegia, quadriplegia, and dyskinesia, the perinatal factors are notable. Perinatal factors were associated with LBW children, while prenatal factors were greater for normal-birthweight infants. The variation in the prevalence of CP over the years, with two peaks corresponding with the introduction of neonatal intensive care units in Padua and Rovigo, suggests that changes in neonatal care could influence the levels of CP, independent of the original presence of predisposing prenatal factors.


Molecular mechanisms of antibiotic resistance.
Over the past decade, resistance to antibiotics has emerged as a crisis of global proportion. Microbes resistant to many and even all clinically approved antibiotics are increasingly common and easily spread across continents. At the same time there are fewer new antibiotic drugs coming to market. We are reaching a point where we are no longer able to confidently treat a growing number of bacterial infections. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge.


[Enteroparasitoses in food handlers of the public schools in Uberlândia (Minas Gerais), Brazil].
A prospective study based on a parasitologic survey was carried out with a view toward controlling enteroparasitoses in food handlers who work in public primary schools in Uberlândia, Minas Gerais, Brazil. The study subjects were 264 individuals from 57 schools, from whom three fecal samples (C) were collected: C1 in September 1989, C2 in April 1990, and C3 in September 1990. The participants were predominantly female (259 women and 5 men) and ranged in age from 20 to 66 years. A total of 792 samples were preserved in 10% formalin and analyzed using the method of Hoffman, Pons, and Janer. Intestinal parasites were found in 17%, 10%, and 10% of the C1, C2, and C3 samples, respectively. The following organisms were found in C1: Giardia lamblia (8%), ancylostomids (6%), Ascaris lumbricoides (3%), Entamoeba histolytica (2%), Strongyloides stercoralis, Hymenolepis nana, Taenia sp., and Trichuris trichiura (less than 1% each). Parasites found in C2 were: ancylostomids (5%), G. lamblia (2%), A. lumbricoides (1%), S. stercoralis, H. nana, Taenia sp., and Enterobius vermicularis (less than 1% each). In C3, the parasites observed were: ancylostomids (5%), G. lamblia (3%), A. lumbricoides (2%), S. stercoralis, and E. vermicularis (less than 1% each). After each collection, the individuals found to be infected received specific treatment. The authors recommend the establishment of epidemiologic surveillance through periodic parasitologic exams, specific treatment, and training on hygienic food handling and personal hygiene for all food handlers.


Ophthalmic drug abuse: An observational study from community pharmacies.
There has been a trend in the past five years in Jordan for ophthalmic anticholinergic preparations to be misused or abused. This is done mainly to experience mental altering effects such as mood changes, euphoria or hallucinations. Such products are mostly obtained from community pharmacies without a prescription. This study aimed to observe the requests of ophthalmic preparations in community pharmacies in Amman, Jordan, and evaluating the most popular and frequently requested ophthalmic drops suspected of abuse. Also, it aimed to describe the current methods that Jordanian community pharmacists use to manage such requests. A prospective cross-sectional observational study was conducted between November 2016 and January 2017 at sixteen different community pharmacies in Amman. All ophthalmic products requested were observed during this period. A total of 140 ophthalmic product requests for 130 customers were observed. Dry eye was the most common complaint for which the customer requested the medication (n = 30, 23.1%) and direct self-medication (ie-requesting the product by name), was the most frequent method of purchase (n = 63, 48.5%). In 19 cases (14.6%), product requests were suspected to be for non-medical (ie-abuse) purposes. Most of the suspected cases were for Pentolate® (n = 11, 57.9%), whereas 7 were for Prisoline® (36.8%) and 1 for Naphcon-A® (5.3%). The majority of observed cases were for products requested without a prescription (n = 16, 84.2%), and in 12 cases out of which, sale was refused (63.2%). More effort and enforcement of pharmacy regulation for safe dispensing is needed to reduce the abuse of ophthalmic products. Educating pharmacists and ophthalmologists would help raise awareness and control the type of drug abuse.


Avogadro: an advanced semantic chemical editor, visualization, and analysis platform.
The Avogadro project has developed an advanced molecule editor and visualizer designed for cross-platform use in computational chemistry, molecular modeling, bioinformatics, materials science, and related areas. It offers flexible, high quality rendering, and a powerful plugin architecture. Typical uses include building molecular structures, formatting input files, and analyzing output of a wide variety of computational chemistry packages. By using the CML file format as its native document type, Avogadro seeks to enhance the semantic accessibility of chemical data types. The work presented here details the Avogadro library, which is a framework providing a code library and application programming interface (API) with three-dimensional visualization capabilities; and has direct applications to research and education in the fields of chemistry, physics, materials science, and biology. The Avogadro application provides a rich graphical interface using dynamically loaded plugins through the library itself. The application and library can each be extended by implementing a plugin module in C++ or Python to explore different visualization techniques, build/manipulate molecular structures, and interact with other programs. We describe some example extensions, one which uses a genetic algorithm to find stable crystal structures, and one which interfaces with the PackMol program to create packed, solvated structures for molecular dynamics simulations. The 1.0 release series of Avogadro is the main focus of the results discussed here. Avogadro offers a semantic chemical builder and platform for visualization and analysis. For users, it offers an easy-to-use builder, integrated support for downloading from common databases such as PubChem and the Protein Data Bank, extracting chemical data from a wide variety of formats, including computational chemistry output, and native, semantic support for the CML file format. For developers, it can be easily extended via a powerful plugin mechanism to support new features in organic chemistry, inorganic complexes, drug design, materials, biomolecules, and simulations. Avogadro is freely available under an open-source license from http://avogadro.openmolecules.net.


The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: A systematic review and meta-analysis.
One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. However, published evidence of the protective effect of these antibodies is conflicting. We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-1(42) and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-1(19) (responders versus nonresponders, 54%, 95% confidence interval [CI] [33%-68%] and 18% [4%-30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2(FC27) 0.82, 95% CI 0.62-1.08, p = 0.16 and MSP-2(3D7) 0.92, 95% CI 0.75-1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens. These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors' Summary.


Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles.
Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is still the standard medication for this purpose. The effectiveness of triggering with a GnRH agonist compared to HCG measured as pregnancy and ovarian hyperstimulation(OHSS) rates are unknown. To compare the effectiveness of a GnRH agonist with HCG for triggering final oocyte maturation in IVF and ICSI patients undergoing controlled ovarian hyperstimulation in a GnRH antagonist protocol followed by embryo transfer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE , EMBASE, the National Research Register, the Medical Research Council's Clinical Trials Register, and the NHS Centre for Reviews and Dissemination database. We also examined the reference lists of all known primary studies and review articles, citation lists of relevant publications and abstracts of major scientific meetings. All randomised controlled studies (RCTs) reporting data comparing clinical outcomes for women undergoing IVF and ICSI cycles and using a GnRH agonist in comparison with HCG for final oocyte maturation triggering. Two review authors independently assessed trial quality and extracted data. We identified 11 RCTs (n = 1055). Eight studies assessed fresh autologous cycles and three studies assessed donor-recipient cycles. In fresh-autologous cycles, GnRH agonist was less effective than HCG in terms of the live birth rate per randomised woman (OR 0.44, 95% CI 0.29 to 0.68; 4 RCTs) and ongoing pregnancy rate per randomised woman (OR 0.45, 95% CI 0.31 to 0.65; 8 RCTs). For a group with a 30% live birth or ongoing pregnancy rate using HCG, the rate would be between 12% and 22% using an GnRH agonist. Moderate to severe ovarian hyperstimulation syndrome (OHSS) incidence per randomised woman was significantly lower in the GnRH agonist group compared to the HCG group (OR 0.10, 95% CI 0.01 to 0.82; 5 RCTs). For a group with a 3% OHSS rate using HCG the rate would be between 0% and 2.6% using GnRH agonist. In donor recipient cycles, there was no evidence of a statistical difference in the live birth rate per randomised woman (OR 0.92, 95% CI 0.53 to 1.61; 1 RCT). We do not recommend that GnRH agonists be routinely used as a final oocyte maturation trigger in fresh autologous cycles because of lowered live birth rates and ongoing pregnancy rates. An exception could be made for women with high risk of OHSS, after appropriate counselling.


Mesenchymal stromal cells: facilitators of successful transplantation?
Mesenchymal stromal/stem cells (MSCs) possess immunomodulatory and reparative properties. Through specific interactions with immune cells that participate in both innate and adaptive responses, MSCs exposed to an inflammatory microenvironment can downregulate many immune effector functions. Clinical trials focusing on MSCs to treat graft-versus-host disease (GvHD) and autoimmune diseases are underway. Current analyses suggest that MSCs will improve cell and solid organ transplantation by ameliorating rejection and possibly eliminating the requirement for prolonged regimens of conventional immunosuppressive drugs. This review examines the in vitro and in vivo evidence for the clinical use of bone marrow derived MSCs.


Perioperative management of patients for osteo-odonto-kreatoprosthesis under general anaesthesia: A retrospective study.
An osteo-odonto-keratoprosthesis (OOKP) procedure is indicated in patients with failed corneal transplant but having intact retina for visual improvement. We studied perioperative concerns of patients who underwent the staged OOKP procedure. This was a retrospective analysis of patients who underwent OOKP. The information regarding symptoms, associated comorbidities, perioperative events including anaesthetic management were collected. Eight patients (five females and three males) underwent the staged OOKP procedure. The median age was 18 years. The median weight was 45 kg. The median duration of loss of vision was 4 years. The aetiology of blindness included Stevens-Johnson's syndrome (SJS) (7) and chemical burn (1). Four patients had generalized skin problem due to SJS. All cases were managed under general anaesthesia, and airway management included nasotracheal intubation for stage I and orotracheal intubation for stage II. The median mallampati classification was I prior to OOKP stage I procedure while it changed to II at stage II procedure. Two patients required fibreoptic nasotracheal intubation. One patient had excessive oozing from the mucosal harvest site and was managed conservatively. In one patient, tooth harvesting was done twice as the first tooth was damaged during creating a hole in it. We conclude that OOKP requires multidisciplinary care. Anaesthesiologist should evaluate the airway carefully and disease-associated systemic involvements. The use of various drugs requires caution and steroid supplementation should be done. Airway difficulty should be anticipated, mandating thorough evaluation. Re-evaluation of airway is prudent as it may become difficult during the staged OOKP procedure.


Catecholamines mediate multiple fetal adaptations during placental insufficiency that contribute to intrauterine growth restriction: lessons from hyperthermic sheep.
Placental insufficiency (PI) prevents adequate delivery of nutrients to the developing fetus and creates a chronic state of hypoxemia and hypoglycemia. In response, the malnourished fetus develops a series of stress hormone-mediated metabolic adaptations to preserve glucose for vital tissues at the expense of somatic growth. Catecholamines suppress insulin secretion to promote glucose sparing for insulin-independent tissues (brain, nerves) over insulin-dependent tissues (skeletal muscle, liver, and adipose). Likewise, premature induction of hepatic gluconeogenesis helps maintain fetal glucose and appears to be stimulated by both norepinephrine and glucagon. Reduced glucose oxidation rate in PI fetuses creates a surplus of glycolysis-derived lactate that serves as substrate for hepatic gluconeogenesis. These adrenergically influenced adaptive responses promote in utero survival but also cause asymmetric intrauterine growth restriction and small-for-gestational-age infants that are at greater risk for serious metabolic disorders throughout postnatal life, including obesity and type II diabetes.


HIV-1-triggered release of type I IFN by plasmacytoid dendritic cells induces BAFF production in monocytes.
HIV-1 infection leads to numerous B cell abnormalities, including hypergammaglobulinemia, nonspecific B cell activation, nonspecific class switching, increased cell turnover, breakage of tolerance, increased immature/transitional B cells, B cell malignancies, as well as a loss of capacity to generate and maintain memory, all of which contribute to a global impairment of the immune humoral compartment. Several cytokines and soluble factors, which are increased in sera of HIV-1-infected individuals, have been suggested to directly or indirectly contribute to these B cell dysfunctions, and one of these is the B cell-activating factor (BAFF). We report in this study that HIV-1 (X4- and R5-tropic) upregulates BAFF expression and secretion by human monocytes. Moreover, we show that the virus-mediated production of BAFF by monocytes relies on a type I IFN response by a small percentage of plasmacytoid dendritic cells (pDCs) present in the monocyte cultures. HIV-1-induced type I IFN by pDCs triggers BAFF production in both classical and intermediate monocytes, but not in nonclassical monocytes, which nonetheless display a very strong basal BAFF production. We report also that basal BAFF secretion was higher in monocytes obtained from females compared with those from male donors. This study provides a novel mechanistic explanation for the increased BAFF levels observed during HIV-1 infection and highlights the importance of pDC/monocyte crosstalk to drive BAFF secretion.


A uniform framework for estimating illumination chromaticity, correspondence, and specular reflection.
Based upon a new correspondence matching invariant called illumination chromaticity constancy, we present a new solution for illumination chromaticity estimation, correspondence searching, and specularity removal. Using as few as two images, the core of our method is the computation of a vote distribution for a number of illumination chromaticity hypotheses via correspondence matching. The hypothesis with the highest vote is accepted as correct. The estimated illumination chromaticity is then used together with the new matching invariant to match highlights, which inherently provides solutions for correspondence searching and specularity removal. Our method differs from the previous approaches: those treat these vision problems separately and generally require that specular highlights be detected in a preprocessing step. Also, our method uses more images than previous illumination chromaticity estimation methods, which increases its robustness because more inputs/constraints are used. Experimental results on both synthetic and real images demonstrate the effectiveness of the proposed method.