Cancer mortality among workers in the German rubber industry: 1981-91.
To determine the cancer specific mortality of active and retired workers of the German rubber industry with emphasis on cancer sites which have been associated with the rubber industry in previous studies. A cohort of 11,663 German men was followed up for mortality from 1 January 1981 to 31 December 1991. Cohort members were active (n = 7536) or retired (n = 4127) at the beginning of the study, and had been employed for at least one year in one of five study plants producing types or general rubber goods. Vital status was ascertained for 99.7% of the cohort members, and cause of death found for 96.8% of the 2719 decedents. Age and calendar year adjusted standardised mortality ratios (SMR) and 95% confidence intervals (95% CI) were calculated overall from national reference rates and stratified by year of hire and by years since hire. Mortalities from all causes (SMR 108; 95% CI 104-112) and all cancers (SMR 111; 95% CI 103-119) were significantly increased in the study cohort. Significant excesses in the mortalities from lung cancer (SMR 130; 95% CI 115-147) and pleural cancer (SMR 401; 95% CI 234-642) were identified. SMRs higher than 100 were found for cancers of the pharynx (SMR 144; 95% CI 76-246), oesophagus (SMR 120; 95% CI 74-183), stomach (SMR 110; 95% CI 86-139), rectum (SMR 123; 95% CI 86-170), larynx (SMR 129; 95% CI 69-221), prostate (SMR 108; 95% CI 84-136), and bladder (SMR 124; 95% CI 86-172), as well as for leukaemia (SMR 148; 95% CI 99-213). Mortalities from liver cancer, brain cancer, and lymphoma were lower than expected. Mortalities from cancer of several sites previously associated with the rubber industry were also increased among workers of the German rubber industry. Results of the stratified analyses are consistent with a role of occupational exposure in the aetiology of some of these cancers.


Dieting reduces plasma tryptophan and alters brain 5-HT function in women.
A three week low calorie diet significantly reduced both total plasma tryptophan and the ratio of tryptophan to competing amino acids in a group of 15 healthy volunteers. Despite a similar percentage weight loss the reduction in plasma tryptophan was greater in women than men. In addition, only in women was dieting associated with increased prolactin secretion following intravenous tryptophan, a measure of brain 5-hydroxytryptamine (5-HT) function. These results suggest that dieting reduces the availability of circulating tryptophan for brain 5-HT synthesis. Women appear more vulnerable than men both to this effect and to its consequences for brain 5-HT function. Altered brain 5-HT function may play a part in some of the psychological consequences of dieting, including the development of clinical eating disorders.


Ischemic bowel secondary to ventriculoperitoneal shunt knotting: a surprisingly rare complication of ventriculoperitoneal shunting. Case report.
Small-bowel obstruction (SBO) and volvulus as a result of ventriculoperitoneal shunting are a rare phenomenon, especially when resulting in bowel necrosis. The authors report the rare event of SBO, bowel strangulation, and necrosis in a pediatric patient after the abdominal catheter became knotted around his small bowel, and they provide a comprehensive review of the literature. The authors argue that shunt configuration is an important consideration for a patient presenting with SBO, and that symptomatic shunt knotting is a reason for surgical correction.


Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in 2 European countries: a cross-sectional patient survey.
Sexual dysfunction is a common side effect of antidepressant treatment, but recognition of the problem is variable. The aim of this study was to estimate the prevalence and impact of sexual dysfunction during antidepressant treatment in 2 European countries. A cross-sectional survey of 502 adults in France and the United Kingdom. All participants were diagnosed with depression and taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), starting within the previous 3 months. Information was gathered about other medications and conditions known to impair sexual functioning, recent changes in sexual functioning, and the impact of any changes. The Medical Outcomes Study 12-Item Short-Form Health Survey and the Arizona Sexual Experience Scale were administered to measure health status and sexual functioning. Data were collected from June to July of 2002. Applying a prevalence estimate algorithm, 26.6% of the French sample and 39.2% of the U.K. sample were classified as having antidepressant-induced sexual dysfunction; 34.2% of men and 32.5% of women were classified with antidepressant-induced sexual dysfunction. There was no clear pattern of antidepressant-induced sexual dysfunction related to specific antidepressants. Patients with antidepressant-induced sexual dysfunction reported that changes in sexual functioning negatively affected their self-esteem, mood, and relationships with sexual partners. 23.8% of the French sample and 25.2% of the U.K. sample reported that they perceived that their partner was dissatisfied with their sex life. The prevalence of antidepressant-induced sexual dysfunction in this study is similar to previous estimates reported in the literature. The impact of antidepressant-induced sexual dysfunction is substantial and negatively affects quality of life, self-esteem, mood, and relationships with sexual partners.


Whey protein and essential amino acids promote the reduction of adipose tissue and increased muscle protein synthesis during caloric restriction-induced weight loss in elderly, obese individuals.
Excess adipose tissue and sarcopenia presents a multifaceted clinical challenge that promotes morbidity and mortality in the obese, elderly population. Unfortunately, the mortality risks of muscle loss may outweigh the potential benefits of weight loss in the elderly. We have previously demonstrated the effectiveness of whey protein and essential amino acids towards the preservation of lean tissue, even under the conditions of strict bedrest in the elderly. In the context of caloric restriction-based weight loss, we hypothesized that a similar formulation given as a meal replacement (EAAMR) would foster the retention of lean tissue through an increase in the skeletal muscle fractional synthesis rate (FSR). We also proposed that EAAMR would promote the preferential loss of adipose tissue through the increased energy cost of skeletal muscle FSR. We recruited and randomized 12 elderly individuals to an 8 week, caloric restriction diet utilizing equivalent caloric meal replacements (800 kcal/day): 1) EAAMR or a 2) competitive meal replacement (CMR) in conjunction with 400 kcal of solid food that totaled 1200 kcal/day designed to induce 7% weight loss. Combined with weekly measurements of total body weight and body composition, we also measured the acute change in the skeletal muscle FSR to EAAMR and CMR. By design, both groups lost ~7% of total body weight. While EAAMR did not promote a significant preservation of lean tissue, the reduction in adipose tissue was greater in EAAMR compared to CMR. Interestingly, these results corresponded to an increase in the acute skeletal muscle protein FSR. The provision of EAAMR during caloric restriction-induced weight loss promotes the preferential reduction of adipose tissue and the modest loss of lean tissue in the elderly population.


Facilitators and barriers of mental health help-seeking behaviours among adolescents in Oman: a cross-sectional study.
This study aimed to explore and identify facilitators and barriers to help-seeking behaviours among adolescents in Oman, by exploring the relationship between knowledge, attitude, and behaviour towards mental health help-seeking. A cross-sectional descriptive study was used and 424 adolescents were recruited to participate in the study. Participants were asked to complete five self-reported questionnaires, including two open-ended questions about the main motivations and barriers to seeking professional help for mental problems. It was found that those with positive help-seeking attitudes towards mental health were more knowledgeable about mental health, had more positive attitudes towards mental illness, and had higher intention to help seeking. On the contrary, those with higher help-seeker stereotypes had more negative attitudes towards mental illness. Having an adequate support system, being positive and knowledgeable about mental illness, and the reputation of mental health are the main factors facilitating seeking professional help. However, fear, lack of family support, and the time-consuming procedures were the main barriers emerging from the open-ended questions. This study contributes by identifying facilitating factors as well as barriers in an Arabic context (Oman) to fill the exiting knowledge gap; both need to be considered when planning interventions targeting the younger individuals in this society.


Nitrous oxide emissions from cattle excreta applied to a Scottish grassland: effects of soil and climatic conditions and a nitrification inhibitor.
Dung and urine excreted onto grasslands are a major source of nitrous oxide (N2O). These N2O emissions stem from inefficient utilisation of nitrogen (N) ingested by ruminants, and the inability of pasture to utilise the deposited N. Predicted growth in dairy and meat consumption means that there is a requirement to quantify N2O emissions, and investigate emission reduction mechanisms. Three 12 month 'seasonal' experiments were undertaken at Crichton, SW Scotland, where N2O emissions were measured from applications of cattle urine, dung, artificial urine and urine+a nitrification inhibitor (NI), dicyandiamide (DCD). The three application timings were 'spring', 'summer' and 'autumn', representative of early-, mid- and late grazing seasons. N2O emissions were measured from static chambers for 12 months. The aim was to quantify emissions from cattle excreta, and determine their dependence on the season of application, and the respective contribution of dung and urine to total excreta emissions. Measurement from NI amended urine was made to assess DCD's potential as an emission mitigation tool. Emissions were compared to the IPCC's default emission factor (EF) of 2% for cattle excreted N. Mean annual cumulative emissions from urine were the highest when applied in summer (5034 g N2O-N ha(-1)), with lower emissions from spring (1903 g N2O-N ha(-1)) and autumn (2014 g N2O-N ha(-1)) application, most likely due to higher temperatures and soil moisture conducive to both nitrification and denitrification in the summer months. Calculated EFs were significantly greater from urine (1.1%) than dung (0.2%) when excreta was applied in summer, and EFs varied with season of application, but in all experiments were lower than the IPCC default of 2%. These results support both lowering and disaggregating this EF into individual EFs for dung and urine. Addition of DCD to urine caused no significant reduction in emissions, suggesting that more research is required into its use as a mitigation option.


Non-matured arteriovenous fistulae for haemodialysis: diagnosis, endovascular and surgical treatment.
Non-maturation is a feature of autologous vascular access. The autologous arteriovenous fistula needs time to mature and for the vein to enlarge to a size where it can be needled for dialysis. A fistula that fails early is one that either never develops adequately to support dialysis or fails within the first three months of its use. Two variables are required for fistula maturation. Firstly, the fistula should have adequate blood flow to support dialysis and secondly, it should have enough size to allow for successful repetitive cannulation. Three main reasons for maturation failure are: arterial and venous problems and the presence of accessory veins. Early diagnostics and intervention for fistula maturation minimizes catheter use and its associated complications. The identification of immature fistulae is relatively simple. Physical examination has been highlighted to be a valuable tool in assessing fistula. Any fistula that fails to mature adequately and demonstrates abnormal physical findings should be studied aggressively. Ultrasonography can successfully identify candidates who fail to meet the recently developed criteria for immature fistulae. In recent years, digital subtraction angiography and contrast-enhanced magnetic resonance angiography has been introduced for assessment of dysfunctional haemodialysis conduits, including immature fistulae. A great majority of non-matured fistulae can be successfully salvaged using percutaneous techniques. In addition to endovascular techniques, surgical intervention can also be an option. This paper reviews the process of fistula maturation and presents information regarding how to obtain a mature fistula.


Soliton switching and multi-frequency generation in a nonlinear photonic crystal fiber coupler.
Soliton switching in nonlinear directional couplers implemented in photonic crystal fibers (PCF) examined here. A vector finite element method (FEM) has been developed to precisely calculate the dispersion along with coupling length of the guided modes. The PCF coupler geometry was carefully designed so that it can support soliton pulses. Soliton switching is demonstrated numerically at 1.55 microm for 100 femto-second (fs) pulses. Our theoretical results explain some of the key spectral features previously observed in the experiment.


Simultaneous miocene extension and shortening in the himalayan orogen.
The South Tibetan detachment system separates the high-grade metamorphic core of the Himalayan orogen from its weakly metamorphosed suprastructure. It is thought to have developed in response to differences in gravitational potential energy produced by crustal thickening across the mountain front. Geochronologic data from the Rongbuk Valley, north of Qomolangma (Mount Everest) in southern Tibet, demonstrate that at least one segment of the detachment system was active between 19 and 22 million years ago, an interval characterized by large-scale crustal thickening at lower structural levels. These data suggest that decoupling between an extending upper crust and a converging lower crust was an important aspect of Himalayan tectonics in Miocene time.


Enhanced sensitivity to higher ozone in a pathogen-resistant tobacco cultivar.
Investigations of the effects of elevated ozone (O(3)) on the virus-plant system were conducted to inform virus pathogen management strategies better. One susceptible cultivar of tobacco (Nicotiana tabacum L. cv. Yongding) and a resistant cultivar (Nicotiana tabacum L. cv. Vam) to Potato virus Y petiole necrosis strain (PVY(N)) infection were grown in open-top chambers under ambient and elevated O(3) concentrations. Above-ground biomass, foliage chlorophyll, nitrogen and total non-structural carbohydrate (TNCs), soluble protein, total amino acid (TAA) and nicotine content, and peroxidase (POD) activity were measured to estimate the effects of elevated O(3) on the impact of PVY(N) in the two cultivars. Results showed that under ambient O(3), the resistant cultivar possessed greater biomass and a lower C/N ratio after infection than the susceptible cultivar; however, under elevated O(3), the resistant cultivar lost its biomass advantage but maintained a lower C/N ratio. Variation of foliar POD activity could be explained as a resistance cost which was significantly correlated with biomass and C/N ratio of the tobacco cultivar. Chlorophyll content remained steady in the resistant cultivar but decreased significantly in the susceptible cultivar when stressors were applied. Foliar soluble protein and free amino acid content, which were related to resistance cost changes, are also discussed. This study indicated that a virus-resistant tobacco cultivar showed increased sensitivity to elevated O(3) compared to a virus-sensitive cultivar.


Measuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader.
Normal reproductive functioning is critically dependent on pulsatile secretion of luteinising hormone (LH). Assessment of LH pulsatility is important for the clinical diagnosis of reproductive disorders, but current methods are hampered by frequent blood sampling coupled to expensive serial immunochemical analysis. Here, we report the development and application of a Robotic APTamer-enabled Electrochemical Reader (RAPTER) electrochemical analysis system to determine LH pulsatility. Through selective evolution of ligands by exponential enrichment (SELEX), we identify DNA aptamers that bind specifically to LH and not to related hormones. The aptamers are integrated into electrochemical aptamer-based (E-AB) sensors on a robotic platform. E-AB enables rapid, sensitive and repeatable determination of LH concentration profiles. Bayesian Spectrum Analysis is applied to determine LH pulsatility in three distinct patient cohorts. This technology has the potential to transform the clinical care of patients with reproductive disorders and could be developed to allow real-time in vivo hormone monitoring.


Chronic stress alters the dendritic morphology of callosal neurons and the acute glutamate stress response in the rat medial prefrontal cortex.
We have previously reported that interhemispheric regulation of medial prefrontal cortex (PFC)-mediated stress responses is subserved by glutamate (GLU)- containing callosal neurons. Evidence of chronic stress-induced dendritic and spine atrophy among PFC pyramidal neurons led us to examine how chronic restraint stress (CRS) might alter the apical dendritic morphology of callosal neurons and the acute GLU stress responses in the left versus right PFC. Morphometric analyses of retrogradely labeled, dye-filled PFC callosal neurons revealed hemisphere-specific CRS-induced dendritic retraction; whereas significant dendritic atrophy occurred primarily within the distal arbor of left PFC neurons, it was observed within both the proximal and distal arbor of right PFC neurons. Overall, CRS also significantly reduced spine densities in both hemispheres with the greatest loss occurring among left PFC neurons, mostly at the distal extent of the arbor. While much of the overall decrease in dendritic spine density was accounted by the loss of thin spines, the density of mushroom-shaped spines, despite being fewer in number, was halved. Using microdialysis we found that, compared to controls, basal PFC GLU levels were significantly reduced in both hemispheres of CRS animals and that their GLU response to 30 min of tail-pinch stress was significantly prolonged in the left, but not the right PFC. Together, these findings show that a history of chronic stress alters the dendritic morphology and spine density of PFC callosal neurons and suggest a mechanism by which this might disrupt the interhemispheric regulation of PFC-mediated responses to subsequent stressors.


Operation Everest II: neuromuscular performance under conditions of extreme simulated altitude.
The force output of the ankle dorsiflexors was studied during a 40-day simulated ascent of Mt. Everest in a hypobaric chamber; both electrically activated and maximal voluntary contractions (MVCs) were employed. The purpose of this study was to establish whether, under conditions of progressive chronic hypoxia, there was a decrease in muscle force output and/or increased fatigability. We also attempted to identify the main site of any failure, i.e., central nervous system, neuromuscular junction, or muscle fiber. Muscle twitch torque (Pt), tetanic torque (Po), MVC torque, and evoked muscle compound action potential (M wave) were monitored during 205-s exercise periods in five subjects at three simulated altitudes (760, 335, and 282 Torr). All three types of torque measurement were well preserved at the three altitudes. In some subjects, the responses to stimuli interpolated during repeated MVCs provided evidence of "central" fatigue at altitude. In addition, the rate of fatigue during 20-Hz electrical stimulation was greater (P less than 0.01) at altitude and there was increased fatigability of the twitch (P less than 0.025); however, the M wave amplitude was maintained. We conclude that central motor drive becomes more precarious at altitude and is associated with increased muscle fatigue at low excitation frequencies; the latter is the result, in part, of chronic hypoxia and occurs in the muscle fiber interior because no impairment in neuromuscular transmission could be demonstrated.


Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis.
We describe the genome sequence of the protist Trichomonas vaginalis, a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds of the approximately 160-megabase genome, reflecting a recent massive expansion of genetic material. This expansion, in conjunction with the shaping of metabolic pathways that likely transpired through lateral gene transfer from bacteria, and amplification of specific gene families implicated in pathogenesis and phagocytosis of host proteins may exemplify adaptations of the parasite during its transition to a urogenital environment. The genome sequence predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.


Molecular hijacking of siroheme for the synthesis of heme and d1 heme.
Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B(12), coenzyme F(430), and heme d(1) underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular framework of modified tetrapyrroles is mediated via a common, core pathway. Herein a further branch of the modified tetrapyrrole biosynthesis pathway is described in denitrifying and sulfate-reducing bacteria as well as the Archaea. This process entails the hijacking of siroheme, the prosthetic group of sulfite and nitrite reductase, and its processing into heme and d(1) heme. The initial step in these transformations involves the decarboxylation of siroheme to give didecarboxysiroheme. For d(1) heme synthesis this intermediate has to undergo the replacement of two propionate side chains with oxygen functionalities and the introduction of a double bond into a further peripheral side chain. For heme synthesis didecarboxysiroheme is converted into Fe-coproporphyrin by oxidative loss of two acetic acid side chains. Fe-coproporphyrin is then transformed into heme by the oxidative decarboxylation of two propionate side chains. The mechanisms of these reactions are discussed and the evolutionary significance of another role for siroheme is examined.


Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile.
Faecal metronidazole and hydroxymetronidazole concentrations measured by high pressure liquid chromatography are reported during 10 episodes of Clostridium difficile colitis in nine patients. Bactericidal faecal concentrations were present in all patients with acute disease receiving oral or intravenous metronidazole, and all responded to therapy. Metronidazole and hydroxymetronidazole concentrations fell as the diarrhoea improved and neither substance was detectable in the faeces of five patients after recovery. This demonstration of intracolonic therapeutic concentrations of metronidazole supports the clinical experience of oral metronidazole being effective in the treatment of antibiotic associated diarrhoea caused by C difficile and also suggests a potential role for intravenous metronidazole in this disease.


Dependence of Present and Future European Temperature Extremes on the Location of Atmospheric Blocking.
The impact of atmospheric blocking on European heat waves (HWs) and cold spells (CSs) is investigated for present and future conditions . A 50-member ensemble of the second generation Canadian Earth System Model is used to quantify the role of internal variability in the response to blocking. We find that the present blocking-extreme temperature link is well represented compared to ERA-Interim, despite a significant underestimation of blocking frequency in most ensemble members. Our results show a strong correlation of blocking with northern European HWs in summer, spring, and fall. However, we also find a strong anticorrelation between blocking and HW occurrence in southern Europe in all seasons. Blocking increases the CS frequency particularly in southern Europe in fall, winter, and spring but reduces it in summer. For the future we find that blocking will continue to play an important role in the development of both CSs and HWs in all seasons.


Low-dose irradiation of nontransformed cells stimulates the selective removal of precancerous cells via intercellular induction of apoptosis.
An important stage in tumorigenesis is the ability of a precancerous cell to escape natural anticancer signals imposed on it by neighboring cells and its microenvironment. We have previously characterized a system of intercellular induction of apoptosis whereby nontransformed cells selectively remove transformed cells from coculture via cytokine and reactive oxygen/nitrogen species (ROS/RNS) signaling. We report that irradiation of nontransformed cells with low doses of either high linear energy transfer (LET) alpha-particles or low-LET gamma-rays leads to stimulation of intercellular induction of apoptosis. The use of scavengers and inhibitors confirms the involvement of ROS/RNS signaling and of the importance of transformed cell NADPH oxidase in the selectivity of the system. Doses as low as 2-mGy gamma-rays and 0.29-mGy alpha-particles were sufficient to produce an observable increase in transformed cell apoptosis. This radiation-stimulated effect saturates at very low doses (50 mGy for gamma-rays and 25 mGy for alpha-particles). The use of transforming growth factor-beta (TGF-beta) neutralizing antibody confirms a role for the cytokine in the radiation-induced signaling. The system may represent a natural anticancer mechanism stimulated by extremely low doses of ionizing radiation.


A multivariate analysis of age-related differences in functional networks supporting conflict resolution.
Functional neuroimaging studies demonstrate age-related differences in recruitment of a large-scale attentional network during interference resolution, especially within dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). These alterations in functional responses have been frequently observed despite equivalent task performance, suggesting age-related reallocation of neural resources, although direct evidence for a facilitating effect in aging is sparse. We used the multi-source interference task and multivariate partial-least-squares to investigate age-related differences in the neuronal signature of conflict resolution, and their behavioral implications in younger and older adults. There were interference-related increases in activity, involving fronto-parietal and basal ganglia networks that generalized across age. In addition an age-by-task interaction was observed within a distributed network, including DLPFC and ACC, with greater activity during interference in the old. Next, we combined brain-behavior and functional connectivity analyses to investigate whether compensatory brain changes were present in older adults, using DLPFC and ACC as regions of interest (i.e. seed regions). This analysis revealed two networks differentially related to performance across age groups. A structural analysis revealed age-related gray-matter losses in regions facilitating performance in the young, suggesting that functional reorganization may partly reflect structural alterations in aging. Collectively, these findings suggest that age-related structural changes contribute to reductions in the efficient recruitment of a youth-like interference network, which cascades into instantiation of a different network facilitating conflict resolution in elderly people.


Relationships between platelets and inflammatory markers in rheumatoid arthritis.
To investigate platelets and different inflammatory markers in conjunction with a substantial inflammatory reaction. We used individuals with active rheumatoid arthritis (RA) as an experimental cohort. We selected 16 patients with active RA having at least one affected joint. On day 1, platelet and neutrophil counts together with C-reactive protein (CRP) were determined. We further analysed platelet volume (MPV) and plasma levels of thrombopoietin (TPO), P-selectin, myeloperoxidase and interleukin 6 (IL-6). After 2 years when all patients failed to show any swollen joints all analyses were repeated. As expected platelet count, CRP and IL-6 were elevated in active RA. The measures correlated with each other thus reflecting the same characteristic of the inflammatory response. The neutrophil count, MPV and myeloperoxidase also mirror disease activity. They failed to correlate with other activity markers thus providing unique information. MPV and myeloperoxidase on day 1 correlated with recovery values. Therefore, they could be suitable to use when following the inflammatory reaction over a long period of time.


Social Cognition for Human-Robot Symbiosis-Challenges and Building Blocks.
The next generation of robot companions or robot working partners will need to satisfy social requirements somehow similar to the famous laws of robotics envisaged by Isaac Asimov time ago (Asimov, 1942). The necessary technology has almost reached the required level, including sensors and actuators, but the cognitive organization is still in its infancy and is only partially supported by the current understanding of brain cognitive processes. The brain of symbiotic robots will certainly not be a "positronic" replica of the human brain: probably, the greatest part of it will be a set of interacting computational processes running in the cloud. In this article, we review the challenges that must be met in the design of a set of interacting computational processes as building blocks of a cognitive architecture that may give symbiotic capabilities to collaborative robots of the next decades: (1) an animated body-schema; (2) an imitation machinery; (3) a motor intentions machinery; (4) a set of physical interaction mechanisms; and (5) a shared memory system for incremental symbiotic development. We would like to stress that our approach is totally un-hierarchical: the five building blocks of the shared cognitive architecture are fully bi-directionally connected. For example, imitation and intentional processes require the "services" of the animated body schema which, on the other hand, can run its simulations if appropriately prompted by imitation and/or intention, with or without physical interaction. Successful experiences can leave a trace in the shared memory system and chunks of memory fragment may compete to participate to novel cooperative actions. And so on and so forth. At the heart of the system is lifelong training and learning but, different from the conventional learning paradigms in neural networks, where learning is somehow passively imposed by an external agent, in symbiotic robots there is an element of free choice of what is worth learning, driven by the interaction between the robot and the human partner. The proposed set of building blocks is certainly a rough approximation of what is needed by symbiotic robots but we believe it is a useful starting point for building a computational framework.


Random quasi-phase-matched second-harmonic generation in periodically poled lithium tantalate.
We observe second harmonic generation via random quasi-phase-matching in a 2.0 mum periodically poled, 1-cm-long, z-cut lithium tantalate. Away from resonance, the harmonic output profiles exhibit a characteristic pattern stemming from a stochastic domain distribution and a quadratic growth with the fundamental excitation, as well as a broadband spectral response. The results are in good agreement with a simple model and numerical simulations in the undepleted regime, assuming an anisotropic spread of the random nonlinear component.


Mass Cytometry Enabling Absolute and Fast Quantification of Silver Nanoparticle Uptake at the Single Cell Level.
In the last decades, significant efforts have been made to investigate possible cytotoxic effects of metallic nanoparticles (NPs). Methodologies enabling precise information regarding uptake and intracellular distribution of NPs at the single cell level remain to be established. Mass cytometry (MC) has been developed for high-dimensional single cell analyses and is a promising tool to quantify NP-cell interactions. Here, we aim to establish a new MC-based quantification procedure to receive absolute numbers of NPs per single cell by using a calibration that considers the specific transmission efficiency (TE) of suspended NPs. The current MC-quantification strategy accept TE values of complementary metal solutions. In this study, we demonstrate the different transmission behavior of 50 nm silver NPs (AgNP) and silver nitrate solution. We have used identical AgNPs for calibration as for in vitro-differentiated macrophages (THP-1 cell line) in a time- and dose-dependent manner. Our quantification relies on silver intensities measuring AgNPs in the same detection mode as the cells. Results were comparable with the TE quantification strategy using AgNPs but differed when using ionic silver. Furthermore, intact and digested cell aliquots were measured to investigate the impact of MC sample processing on the amount of AgNPs/cell. Taken together, we have provided a MC-specific calibration procedure to precisely calculate absolute numbers of NPs per single cell. Combined with its unique feature of multiplexing up to 50 parameters, MC provides much more information on the single cell level than single cell-inductively coupled plasma mass spectrometry (SC-ICPMS) and, therefore, offers new opportunities in nanotoxicology.


Mitochondrial evolution.
The serial endosymbiosis theory is a favored model for explaining the origin of mitochondria, a defining event in the evolution of eukaryotic cells. As usually described, this theory posits that mitochondria are the direct descendants of a bacterial endosymbiont that became established at an early stage in a nucleus-containing (but amitochondriate) host cell. Gene sequence data strongly support a monophyletic origin of the mitochondrion from a eubacterial ancestor shared with a subgroup of the alpha-Proteobacteria. However, recent studies of unicellular eukaryotes (protists), some of them little known, have provided insights that challenge the traditional serial endosymbiosis-based view of how the eukaryotic cell and its mitochondrion came to be. These data indicate that the mitochondrion arose in a common ancestor of all extant eukaryotes and raise the possibility that this organelle originated at essentially the same time as the nuclear component of the eukaryotic cell rather than in a separate, subsequent event.


Forward and reverse (retro) iron(III) or gallium(III) desferrioxamine E and ring-expanded analogues prepared using metal-templated synthesis from endo-hydroxamic acid monomers.
A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H(+)](+), m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded analogues of for-[Fe(DFOE)] and ret-[Fe(DFOE)] were prepared from endo-hydroxamic acid monomers with one additional methylene unit in the amine-containing region, 4-[(6-aminohexyl)(hydroxy)amino]-4-oxobutanoic acid (for-HBH) or 3-(7-amino-N-hydroxyheptanamido)propanoic acid (ret-HBH), to give the corresponding tris(homoferrioxamine E) macrocycles, for-[Fe(HHDFOE)] or ret-[Fe(HHDFOE)] ([M + H(+)](+), m/zcalc 696.3, m/zobs 696.4). The MTS reaction using a constitutional isomer of for-HBH that transposed the methylene unit to the carboxylic acid containing region, 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (for-PPH), gave the macrocycle for-[Fe(HPDFOE)] in a yield significantly less than that for for-[Fe(HHDFOE)], with the gallium(III) analogue for-[Ga(HPDFOE)] unable to be detected. The work demonstrates the utility and limits of MTS for the assembly of macrocyclic siderophores from endo-hydroxamic acid monomers. Indirect measures (RP-HPLC order of elution, c log P values, molecular mechanics, and density functional theory calculations) of the relative water solubility of the ligands, the iron(III) macrocycles, and the apomacrocycles were consistent in identifying for-DFOE as the most water-soluble macrocycle from for-DFOE, ret-DFOE, for-HHDFOE, ret-HHDFOE, and for-HPDFOE. From this group, only for-DFOE is known in nature, which could suggest that water solubility is an important trait in its natural selection.


Rapid Induction of Neural Differentiation in Human Umbilical Cord Matrix Mesenchymal Stem Cells by cAMP-elevating Agents.
Human umbilical cord matrix (hUCM) is considered as a promising source of mesenchymal stem cells (MSCs) due to several advantages over other tissues. The potential of neural differentiation of hUCM-MSCs is of great interest in the context of treating neurodegenerative diseases. In recent years, considerable efforts have been made to establish in vitro conditions for improving the differentiation of hUCM-MSCs toward neuronal cells. In the present study, we evaluated the neural differentiation potential of hUCM-MSCs in the presence of cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine (IBMX). hUCM-MSCs were isolated from fetal umbilical cord and characterized by flow cytometry analysis for mesenchymal specific markers. Mesodermal differentiation potential was assessed through selective media with lineage-specific induction factors. For assessment of neural differentiation, cells were cultured in the presence of cAMP-elevating agents for 8 and 24 h. The neuronal differentiated MSCs were characterized for neuronal specific markers by immunocytochemistry and western blotting. Isolated hUCM-MSCs were found positive for mesenchymal markers (CD73, CD90, and CD105) while negative for hematopoietic markers (CD34 and CD45) .Following neural induction, most cells represented neural-like cells morphology. Neural markers including β-tubulin III (Tuj-1), neuron-specific enolase (NSE), microtubule-associated protein-2 (MAP-2) and nestin were expressed in treated cells with respect to control group. The astrocyte specific marker, glial fibrillary acidic protein (GFAP) was also shown by immunofluorescence in treated cells. (These findings demonstrate that hUCM-MSCs have the ability to rapidly differentiate into neural cell types of neuron-like cells and astrocytes by cAMP-elevating agents without the presence of growth factors.


Indices of adiposity as predictors of cardiometabolic risk and inflammation in young adults.
Studies investigating obesity and cardiometabolic risk have focused on 'at-risk' populations and methodological inconsistencies have produced equivocal findings. The present cross-sectional study investigated indices of body composition as predictors of cardiometabolic risk and their relationship with inflammation in apparently healthy young adults. A fasting blood sample was taken from consenting adults (160 males, 32 females, aged 18-40 years) for assessment of cardiometabolic risk markers (blood pressure, lipid profiles and insulin resistance) and inflammatory markers (C-reactive protein, tumour necrosis factor-α, interleukin-6, interleukin-10 and adiponectin). Together with anthropometry, fat mass (FM) and fat-free mass (FFM) were determined by dual-energy X-ray absorptiometry. FM was expressed in absolute terms (kg), as well as relative to total body weight (%), height [FM index (FMI, kg m(-2) )] and FFM (FM : FFM,%). Although anthropometric indices were associated with most cardiometabolic risk markers, the strongest relationship was observed with FMI. Relative to having a low cardiometabolic risk (≤2 markers above clinically relevant cut-offs), each kg m(-2) increase in FMI, increased the likelihood of having an increased cardiometabolic risk by 29% (odds ratio = 1.29; 95% confidence interval = 1.12-1.49). Inflammatory markers were not associated with body composition or cardiometabolic risk. FMI was the strongest predictor of overall cardiometabolic risk but not inflammation per se. However, anthropometric indices, such as body mass index and waist-to-height ratio, remain valuable surrogate measures of adiposity in this group, particularly when risk markers are considered independently.


Thrombelastography versus AntiFactor Xa levels in the assessment of prophylactic-dose enoxaparin in critically ill patients.
A standard dose of enoxaparin is frequently used for deep venous thrombosis (DVT) prophylaxis. Evidence suggests inconsistent bioavailability in intensive care unit (ICU) patients. Antifactor Xa activity (anti-Xa) has been used to monitor enoxaparin dosing but its accuracy and availability are problematic. Thrombelastography (TEG) is used to evaluate coagulation in diverse settings. The purpose of this study was to analyze whether TEG could be used to predict which enoxaparin-treated patients would develop DVT. Two hundred sixty-one simultaneous enoxaparin-active (active) and enoxaparin-neutralized (neutral) TEGs were performed in 61 surgical ICU patients over four consecutive days. Patient characteristics and anti-Xa were collected. DVT screening was per ICU protocol. Mean (+/-SEM) age was 54 (+/-2.3) years and Acute Physiology and Chronic Health Evaluation II score was 17 (+/-0.7). There were 30 trauma and 31 general surgery patients (69% men). The DVT rate was 28%. Time to clot formation (R) and percent lysis at 30 minutes were different between active versus neutralized blood (p < 0.001). R time was 1.5 minutes shorter in patients with DVT versus those without (p < 0.001) indicating hypercoagulability in DVT patients. Anti-Xa levels were similar in patients with (0.135 +/- 0.012) and without (0.135 +/- 0.007) DVT (p = 0.97). There were no differences in age, body mass index, injury severity score, Acute Physiology and Chronic Health Evaluation II score, or trauma status between DVT and non-DVT groups. TEG demonstrates differences between enoxaparin-neutralized and enoxaparin-active blood in ICU patients that may be used to guide dosing. TEG differentiates enoxaparin-treated patients who subsequently develop DVT while anti-Xa levels do not. TEG demonstrates an enoxaparin-related increase in fibrinolysis.


Relationships between Maternal Obesity and Maternal and Neonatal Iron Status.
: Obesity in pregnancy may negatively influence maternal and infant iron status. The aim of this study was to examine the association of obesity with inflammatory and iron status in both mother and infant in two prospective studies in pregnancy: UPBEAT and SCOPE. Maternal blood samples from obese (n = 245, BMI ≥ 30 kg/m²) and normal weight (n = 245, BMI < 25 kg/m²) age matched pregnant women collected at approximately 15 weeks' gestation, and umbilical cord blood samples collected at delivery, were analysed for a range of inflammatory and iron status biomarkers. Concentrations of C- reactive protein and Interleukin-6 in obese women compared to normal weight women were indicative of an inflammatory response. Soluble transferrin receptor (sTfR) concentration [18.37 nmol/L (SD 5.65) vs 13.15 nmol/L (SD 2.33)] and the ratio of sTfR and serum ferritin [1.03 (SD 0.56) vs 0.69 (SD 0.23)] were significantly higher in obese women compared to normal weight women (P < 0.001). Women from ethnic minority groups (n = 64) had higher sTfR concentration compared with white women. There was no difference in maternal hepcidin between obese and normal weight women. Iron status determined by cord ferritin was not statistically different in neonates born to obese women compared with neonates born to normal weight women when adjusted for potential confounding variables. Obesity is negatively associated with markers of maternal iron status, with ethnic minority women having poorer iron statuses than white women.


Bromoperoxidase activity of amavadin dissected: a DFT investigation.
Bromoperoxidase catalytic activity exerted by oxidated amavadin [V(HIDPA)2](-) (HIDPA = 2,2'-(hydroxyimino) dipropionate) in mono- and bis-protonated forms has been investigated by DFT. Possible reaction pathways for formation of peroxido/hydroperoxido complexes and subsequent bromide oxidation have been systematically dissected. The effect of increasing [H(+)] on catalytically active species and on halogenide oxidation has been also studied. Similarly to vanadium haloperoxidase (VHPO), the results point to a hydroperoxido amavadin adduct as the most reactive species toward bromide oxidation. However, comparison of the reactivity of amavadin and VHPO reveals also crucial differences in the catalytic mechanism of such natural V complexes.


Structures of the catalytic site mutants D99A and H48Q and the calcium-loop mutant D49E of phospholipase A2.
Crystal structures of the active-site mutants D99A and H48Q and the calcium-loop mutant D49E of bovine phospholipase A2 have been determined at around 1.9 A resolution. The D99A mutant is isomorphous to the orthorhombic recombinant enzyme, space group P212121. The H48Q and the calcium-loop mutant D49E are isomorphous to the trigonal recombinant enzyme, space group P3121. The two active-site mutants show no major structural perturbations. The structural water is absent in D99A and, therefore, the hydrogen-bonding scheme is changed. In H48Q, the catalytic water is present and hydrogen bonded to Gln48 N, but the second water found in native His48 is absent. In the calcium-loop mutant D49E, the two water molecules forming the pentagonal bipyramid around calcium are absent and only one O atom of the Glu49 carboxylate group is coordinated to calcium, resulting in only four ligands.


House officer procedure documentation using a Personal Digital Assistant: a longitudinal study.
Personal Digital Assistants (PDAs) have been integrated into daily practice for many emergency physicians and house officers. Few objective data exist that quantify the effect of PDAs on documentation. The objective of this study was to determine whether use of a PDA would improve emergency medicine house officer documentation of procedures and patient resuscitations. Twelve first-year Emergency Medicine (EM) residents were provided a Palm V (Palm, Inc., Santa Clara, California, USA) PDA. A customizable patient procedure and encounter program was constructed and loaded into each PDA. Residents were instructed to enter information on patients who had any of 20 procedures performed, were deemed clinically unstable, or on whom follow-up was obtained. These data were downloaded to the residency coordinator's desktop computer on a weekly basis for 36 months. The mean number of procedures and encounters performed per resident over a three year period were then compared with those of 12 historical controls from a previous residency class that had recorded the same information using a handwritten card system for 36 months. Means of both groups were compared a two-tailed Student's t test with a Bonferroni correction for multiple comparisons. One hundred randomly selected entries from both the PDA and handwritten groups were reviewed for completeness. Another group of 11 residents who had used both handwritten and PDA procedure logs for one year each were asked to complete a questionnaire regarding their satisfaction with the PDA system. Mean documentation of three procedures significantly increased in the PDA vs handwritten groups: conscious sedation 24.0 vs 0.03 (p = 0.001); thoracentesis 3.0 vs 0.0 (p = 0.001); and ED ultrasound 24.5 vs. 0.0 (p = 0.001). In the handwritten cohort, only the number of cardioversions/defibrillations (26.5 vs 11.5) was statistically increased (p = 0.001). Of the PDA entries, 100% were entered completely, compared to only 91% of the handwritten group, including 4% that were illegible. 10 of 11 questioned residents preferred the PDA procedure log to a handwritten log (mean +/- SD Likert-scale score of 1.6 +/- 0.9). Overall use of a PDA did not significantly change EM resident procedure or patient resuscitation documentation when used over a three-year period. Statistically significant differences between the handwritten and PDA groups likely represent alterations in the standard of ED care over time. Residents overwhelmingly preferred the PDA procedure log to a handwritten log and more entries are complete using the PDA. These favorable comparisons and the numerous other uses of PDAs may make them an attractive alternative for resident documentation.


Nutritional complementation of oxidative glucose metabolism in Escherichia coli via pyrroloquinoline quinone-dependent glucose dehydrogenase and the Entner-Doudoroff pathway.
Two glucose-negative Escherichia coli mutants (ZSC113 and DF214) were unable to grow on glucose as the sole carbon source unless supplemented with pyrroloquinoline quinone (PQQ). PQQ is the cofactor for the periplasmic enzyme glucose dehydrogenase, which converts glucose to gluconate. Aerobically, E. coli ZSC113 grew on glucose plus PQQ with a generation time of 65 min, a generation time about the same as that for wild-type E. coli in a defined glucose-salts medium. Thus, for E. coli ZSC113 the Enter-Doudoroff pathway was fully able to replace the Embden-Meyerhof-Parnas pathway. In the presence of 5% sodium dodecyl sulfate, PQQ no longer acted as a growth factor. Sodium dodecyl sulfate inhibited the formation of gluconate from glucose but not gluconate metabolism. Adaptation to PQQ-dependent growth exhibited long lag periods, except under low-phosphate conditions, in which the PhoE porin would be expressed. We suggest that E. coli has maintained the apoenzyme for glucose dehydrogenase and the Entner-Doudoroff pathway as adaptations to an aerobic, low-phosphate, and low-detergent aquatic environment.


Short-term oral rapamycin prevents age-related learning impairment in mice.
Effective treatments to prevent or delay age-related learning impairment are not generally available. In a preliminary preclinical study, mice 20 months of age were fed a diet containing 14 ppm rapamycin, an inhibitor of mTOR, for three months and then tested in a spatial navigation task. Mice fed the nonmedicated control diet showed learning impairment while mice fed the rapamycin diet were not learning impaired. This observation provides support for additional preclinical studies and suggests that short-term rapamycin treatment could be a possible strategy for preventing or delaying age-related cognitive impairment in people.


Early prediction of outcome of activities of daily living after stroke: a systematic review.
Knowledge about robust and unbiased factors that predict outcome of activities of daily living (ADL) is paramount in stroke management. This review investigates the methodological quality of prognostic studies in the early poststroke phase for final ADL to identify variables that are predictive or not predictive for outcome of ADL after stroke. PubMed, Ebsco/Cinahl and Embase were systematically searched for prognostic studies in which stroke patients were included ≤2 weeks after onset and final outcome of ADL was determined ≥3 months poststroke. Risk of bias scores were used to distinguish high- and low-quality studies and a qualitative synthesis was performed. Forty-eight of 8425 identified citations were included. The median risk of bias score was 17 out of 27 (range, 6-22) points. Most studies failed to report medical treatment applied, management of missing data, rationale for candidate determinants and outcome cut-offs, results of univariable analysis, and validation and performance of the model, making the predictive value of most determinants indistinct. Six high-quality studies showed strong evidence for baseline neurological status, upper limb paresis, and age as predictors for outcome of ADL. Gender and risk factors such as atrial fibrillation were unrelated to this outcome. Because of insufficient methodological quality of most prognostic studies, the predictive value of many clinical determinants for outcome of ADL remains unclear. Future cohort studies should focus on early prediction using simple models with good clinical performance to enhance application in stroke management and research.


Managing Chronic Pain in Children and Adolescents: A Clinical Review.
Chronic pain in children and adolescents can be difficult for a single provider to manage in a busy clinical setting. Part of this difficulty is that pediatric chronic pain not only impacts the child but also the families of these children. In this review article, we discuss etiology and pathophysiology of chronic pain, along with variables that impact the severity of chronic pain and functional loss. We review diagnosis and management of selected chronic pain conditions in pediatric patients, including headache, low back pain, hypermobility, chronic fatigue, postural orthostatic tachycardia syndrome, abdominal pain, fibromyalgia, and complex regional pain syndrome. For each condition, we create a road map that contains therapy prescriptions, exercise recommendations, and variables that may influence pain severity. Potential medications for these pain conditions and associated symptoms are reviewed. A multidisciplinary approach for managing children with these conditions, including pediatric pain rehabilitation programs, is emphasized. Lastly, we discuss psychological factors and interventions for pediatric chronic pain and potential complementary and alternative natural products and interventions.


Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during depression.
The pineal hormone melatonin regulates circadian rhythms, largely by feedback on the central biological clock of the brain, the hypothalamic suprachiasmatic nucleus (SCN). This feedback is mediated by the melatonin receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). The circadian system may play a role in the pathophysiology of mood disorders, and indeed, melatonin-receptor agonists are considered a potential therapy for depression. In order to investigate melatonin receptors in the SCN during depression, and their relationship to the major neuropeptides in the SCN, vasopressin (AVP) and vasoactive intestinal peptide (VIP), we studied the SCN in 14 depressed patients (five major depression and nine bipolar disorder) and 14 matched controls by immunocytochemistry. We show here that hypothalamic MT2 receptor immunoreactivity was limited to SCN, the supraoptic nucleus and paraventricular nucleus. We found that numbers of MT1-immunoreactive (MT1-ir) cells and AVP and/or VIP-ir cells were increased in the central SCN in depression, but numbers of MT2-ir cells were not altered. Moreover, the number of MT1-ir cells, but not MT2-ir cells was negatively correlated with age at onset of depression, while positively correlated with disease duration. CONCLUSION AND LIMITATIONS: Although every post-mortem study has limitations, MT1 receptors appeared specifically increased in the SCN of depressed patients, and may increase during the course of the disease. These changes may be involved in the circadian disorders and contribute to the efficacy of MT agonists or melatonin in depression. Moreover, we suggest that melatonin receptor agonists for depression should be targeted towards the MT1 receptor selectively.


The slow resorption with replacement by bone of a hydrothermally synthesized pure calcium-deficient hydroxyapatite.
A newly developed calcium-deficient hydroxyapatite composed of rod-shaped particles synthesized by the hydrothermal method (HHA) and stoichiometric hydroxyapatite (SHA) synthesized by the sintering method was used for in vivo implantation and in vitro culture systems to compare these biological responses. In the rabbit femur, implanted HHA was slowly resorbed and about 80% of the implant remained 24 weeks after implantation; however, up to 72 weeks after implantation, most of the implanted HHA was resorbed. The implanted SHA was unresorbed throughout the experimental period, but degradation by the invasion of newly formed bone was seen at 72 weeks after implantation. Bone histomorphometry showed that the volume of newly formed bone and the number of osteoclasts in the implanted region were significantly higher in HHA than in SHA 24 weeks after implantation. In vitro culture of C2C12 cells with the induction of osteoblastic phenotypes using recombinant bone morphogenetic protein-2 showed similar cell density and the induction of alkaline phosphatase activity between the cells on HHA and SHA discs. In vitro osteoclastogenesis of HHA and SHA discs using bone marrow macrophages and recombinant receptor activator of nuclear factor-kappaB ligand showed higher TRAP activity of osteoclasts cultured on HHA discs. These results showed that slow biodegradability did not always correlate to final replaceability in bone tissue, and suggested that the activity of osteoclasts correlated to the bone-forming activity of osteoblasts.


Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole.
Cerebral palsy and death are serious consequences of perinatal hypoxia-ischemia (HI). Important concepts can now be tested using an animal model of cerebral palsy. We have previously shown that reactive oxygen and nitrogen species are produced in antenatal HI. A novel class of neuronal nitric oxide synthase (nNOS) inhibitors have been designed, and they ameliorate postnatal motor deficits when administered prior to the hypoxic-ischemic insult. This study asks how the new class of inhibitors, using JI-8 (K(i) for nNOS: 0.014 μM) as a representative, compare with the frequently used nNOS inhibitor 7-nitroindazole (7-NI; K(i): 0.09 ± 0.024 μM). A theoretical dose equivalent to 75 K(i) of JI-8 or equimolar 7-NI was administered to pregnant rabbit dams 30 min prior to and immediately after 40 min of uterine ischemia at 22 days gestation (70% term). JI-8 treatment resulted in a significant decrease in NOS activity (39%) in fetal brain homogenates acutely after HI, without affecting maternal blood pressure and heart rate. JI-8 treatment resulted in 33 normal kits, 2 moderately and 13 severely affected kits and 5 stillbirths, compared with 8 normal, 3 moderately affected and 5 severely affected kits and 10 stillbirths in the 7-NI group. In terms of neurobehavioral outcome, 7-NI was not different from saline treatment, while JI-8 was superior to saline and 7-NI in its protective effect (p < 0.05). In the surviving kits, JI-8 significantly improved the locomotion score over both saline and 7-NI scores. JI-8 was also significantly superior to saline in preserving smell, muscle tone and righting reflex function, but 7-NI did not show significant improvement. Furthermore, a 100-fold increase in the dose (15.75 μmol/kg) of 7-NI significantly decreased systolic blood pressure in the dam, while JI-8 did not. The new class of inhibitors such as JI-8 shows promise in the prevention of cerebral palsy and is superior to the previously more commonly used nNOS inhibitor.


Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers.
A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine (Meth) addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind in-patient clinical pharmacology study to assess potential interactions between intravenous (i.v.) Meth (15 mg and 30 mg) and oral aripiprazole (15 mg). In addition, the effects of aripiprazole treatment on abstinence-related craving and cue-induced craving were evaluated. Participants included non-treatment-seeking, Meth-dependent patients (n=16), aged 18-45 yr, currently using Meth. Following baseline Meth dosing (15 mg and 30 mg), participants received 2 wk treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and Meth-related cues. Meth dosing (15 mg and 30 mg) was then repeated. Aripiprazole treatment had no effect on cue-induced Meth craving, or on daily baseline craving assessed over the course of medication treatment, although aripiprazole treatment was associated with increased craving independent of Meth dosing. Aripiprazole treatment was associated with significantly higher ratings on Addiction Research Center Inventory (ARCI) subscales reflecting euphoria and amphetamine-like effects following Meth dosing. Aripiprazole treatment was also associated with significant reductions in ratings of 'bad effects' and reductions on the ARCI subscale for sedation effects following Meth dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following Meth dosing, but had no other effects on cardiovascular responses to Meth. Aripiprazole treatment did not alter the pharmacokinetics of Meth. These findings indicate that aripiprazole treatment appears to be safe in volunteers with Meth dependence, although the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute Meth suggests that 15 mg aripiprazole is unlikely to be efficacious for the treatment of Meth dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for Meth dependence.


Mechanism of the mitogenic effect of fluoride on osteoblast-like cells: evidences for a G protein-dependent tyrosine phosphorylation process.
Recent results indicate that a fluoroalumino complex (AlFx) is probably the molecule responsible for the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells. Initial analysis suggested that a tyrosine phosphorylation (tyr phos) process similar to that induced by thrombin and activation of the p42 MAP kinase (ERK 2) mediate this cellular response. In the present study, the signaling mechanism activated by AlFx was further investigated. The results indicated that AlFx dose-dependently enhanced the tyr phos of the cell adhesion proteins FAK and paxillin, as well as of the adaptor molecules p46shc, p52shc, and p66shc and their association with GRB2. Pretreatment of MC3T3-E1 cells with cytochalasin D completely prevented FAK and paxillin tyr phos without any alteration in the tyr phos of Shc proteins and activation of ERK2 induced by AlFx. This observation suggests that in confluent MC3T3-E1 cells, there is no link between the activation of FAK induced by AlFx and the stimulation of ERK2. Pretreatment of the cells with pertussis toxin inhibited Shc phosphorylation, activation of ERK2, and markedly reduced cell replication induced by AlFx. This toxin also significantly reduced the stimulation of Pi transport activity induced by AlFx in these cells. Alteration in tyr phos induced by AlFx was not associated with any detectable inhibition of tyrosine phosphatase activity in MC3T3-E1 cell homogenates, suggesting that enhanced tyr phos induced by AlFx probably resulted from activation of a tyrosine kinase. In conclusion, the results of this study suggest that the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells is mediated by the activation of a pertussis toxin-sensitive Gi/o protein and suggest an important role for these heterotrimeric G proteins in controlling the growth and differentiation of bone-forming cells.


Optimal utility and probability functions for agents with finite computational precision.
When making economic choices, such as those between goods or gambles, humans act as if their internal representation of the value and probability of a prospect is distorted away from its true value. These distortions give rise to decisions which apparently fail to maximize reward, and preferences that reverse without reason. Why would humans have evolved to encode value and probability in a distorted fashion, in the face of selective pressure for reward-maximizing choices? Here, we show that under the simple assumption that humans make decisions with finite computational precision--in other words, that decisions are irreducibly corrupted by noise--the distortions of value and probability displayed by humans are approximately optimal in that they maximize reward and minimize uncertainty. In two empirical studies, we manipulate factors that change the reward-maximizing form of distortion, and find that in each case, humans adapt optimally to the manipulation. This work suggests an answer to the longstanding question of why humans make "irrational" economic choices.


Interactions between antidepressants, sleep aids and selected breast cancer therapy.
Depression and insomnia are very significant pathologies in cancer patients as they contribute to the patient's overall cure and quality of life. Moreover, untreated depression and ongoing insomnia are associated with decreased immune responses and lower survival rates. With all disease states and especially with cancer, close attention to drug-drug interactions and the potential impact on the efficacy of therapy is paramount. One area of particular interest due to the lack of well-done clinical trials is drug-drug interaction(s) between antidepressants and cancer treatment. Pharmacokinetics of a certain drug allows for prediction of certain drug interactions based on chemical properties of the agents involved. If the agents depend on their metabolites for activity, active drug level will be decreased through this enzyme inhibition. In this paper, we looked at the cytochrome-P450 drug interactions between antidepressants and sleep aids with Selective Estrogen Receptor Modulators (SERM). Newer SERM metabolisms are less influenced by interactions with medications used to treat depression. However, tamoxifen metabolism could be severely altered by several antidepressants. This has direct consequences as patients on tamoxifen and antidepressant can have double the risk of relapse to cancer in two years. We discussed those interactions and made recommendations for clinical use.


Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study.
Although recent studies suggest that measuring coronary artery calcification (CAC) may be superior to indirect atherosclerotic markers in predicting cardiac risk, there are limited data evaluating imaging-based biomarkers that directly quantify atherosclerosis in different vascular beds performed in a single cohort. The BioImage Study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population) sought to identify imaging biomarkers that predict near-term (3-year) atherothrombotic events. The BioImage Study enrolled 5,808 asymptomatic U.S. adults (mean age: 69 years, 56.5% female) in a prospective cohort evaluating the role of vascular imaging on cardiovascular risk prediction. All patients were evaluated by CAC and novel 3-dimensional carotid ultrasound. Plaque areas from both carotid arteries were summed as the carotid plaque burden (cPB). The primary endpoint was the composite of major adverse cardiac events (MACE) (cardiovascular death, myocardial infarction, and ischemic stroke). A broader secondary MACE endpoint also included all-cause death, unstable angina, and coronary revascularization. Over a median follow-up of 2.7 years, MACE occurred in 216 patients (4.2%), of which 82 (1.5%) were primary events. After adjustment for risk factors, and compared with individuals without any cPB, hazard ratios for MACE were 0.78 (95% confidence interval [CI]: 0.31 to 1.91), 1.45 (95% CI: 0.67 to 3.14), and 2.36 (95% CI: 1.13 to 4.92) with increasing cPB tertile, with similar results for CAC. Net reclassification significantly improved with either cPB (0.23) or CAC (0.25). MACE rates increased simultaneously with higher levels of both cPB and CAC. Detection of subclinical carotid or coronary atherosclerosis improves risk predictions and reclassification compared with conventional risk factors, with comparable results for either modality. Cost-effective analyses are warranted to define the optimal roles of these complementary techniques. (BioImage Study: A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population; NCT00738725).


Demonstration of multiple antigenic determinants on Mycoplasma pneumoniae attachment protein by monoclonal antibodies.
Distinct multiple antigenic determinants of the attachment protein of Mycoplasma pneumoniae have been identified by limited proteolytic cleavage, using specific monoclonal antibodies. Western blots prepared from the gels containing the cleaved fragments were probed with antiserum against M. pneumoniae or monoclonal antibodies. Five distinct bands with intact antigenic determinants were detected by the antiserum, of which two bands were each reactable with two monoclonal antibodies. A sequential binding assay suggested that these monoclonal antibodies recognized different antigenic sites of each band. These results demonstrate the existence of multiple antigenic sites on the attachment protein and describe procedures that should prove useful for identifying those antigenic sites critical to the specific attachment of M. pneumoniae.


Do evidence-based group parenting programs for high-risk or maltreating parents include content about psychological maltreatment?: a program review.
Psychological maltreatment (PM) is a wide-spread form of child maltreatment, both in high-risk and maltreating parents, yet there are no intervention programs that target it directly. In this study, the content of parenting programs for high-risk and maltreating parents was assessed to determine whether the program manuals include content on PM. Nine evidence-based group parenting programs for high-risk or maltreating parents (e.g., included in the SAMHSA or a comparable model program registry) were identified. Program manuals were rated for whether they included content on 18 types of psychological maltreatment (PM). Only one type of PM was rated as being included in all nine programs. Not one of the remaining PM types was rated as being included in more than four programs; and many of the PM types were not rated as being included in any program manual. Therefore, existing parenting program manuals do not contain content related to many forms of psychological maltreatment.


Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy.
The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 microl) and AP7 (10 or 20 nmol/0.5 microl), or of the NMDA receptor agonist N-methyl-d-aspartate (NMDA, 20 or 30 nmol/0.5 microl). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity.


Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders.
Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND.


Improved antibacterial phototoxicity of a neutral porphyrin in natural deep eutectic solvents.
Neutral porphyrins for antibacterial photodynamic therapy (aPDT) have received little attention due to their tendency to aggregate in aqueous media and reports of low phototoxic effect. These compounds may be less toxic to cells than positively and negatively charged photosensitisers. The preparation of highly bacterial phototoxic formulations of neutral porphyrins remains an open field of research with great potential if achievable. The purpose of this study was to develop novel hydrophilic formulations of the neutral porphyrin 5,10,15,20-tetrakis(4-hydroxyphenyl)-porphyrin (THPP) by use of natural deep eutectic solvents (NADES) prepared by the solvent evaporation method. Physical and photochemical stability and in vitro photoinactivation of Enterococcus faecalis and Escherichia coli were investigated. Two of the 15 NADES investigated demonstrated superior solubilising properties of THPP. The photostability of THPP was higher in NADES than in methanol. A 100-fold dilution of the preparations with buffer to a final concentration of 0.5-5 nM THPP resulted in complete photoinactivation of E. faecalis and E. coli both in their exponential and stationary phase. THPP demonstrated significantly higher phototoxicity when formulated in NADES than in other aqueous preparations like phosphate buffered saline. NADES as a formulation concept for photosensitisers shows a great potential in aPDT.


Engineering human islet organoids from iPSCs using an organ-on-chip platform.
Human pluripotent stem cell (hPSC)-derived islet cells provide promising resources for diabetes studies, cell replacement treatment and drug screening. Recently, hPSC-derived organoids have represented a new class of in vitro organ models for disease modeling and regenerative medicine. However, rebuilding biomimetic human islet organoids from hPSCs remains challenging. Here, we present a new strategy to engineer human islet organoids derived from human induced pluripotent stem cells (hiPSCs) using an organ-on-a-chip platform combined with stem cell developmental principles. The microsystem contains a multi-layer microfluidic device that allows controllable aggregation of embryoid bodies (EBs), in situ pancreatic differentiation and generation of heterogeneous islet organoids in parallel under perfused 3D culture in a single device. The generated islet organoids contain heterogeneous islet-specific α and β-like cells that exhibit favorable growth and cell viability. They also show enhanced expression of pancreatic β-cell specific genes and proteins (PDX1 and NKX6.1) and increased β-cell hormone specific INS gene and C-peptide protein expressions under perfused 3D culture conditions compared to static cultures. In addition, the islet organoids exhibit more sensitive glucose-stimulated insulin secretion (GSIS) and higher Ca2+ flux, indicating the role of biomimetic mechanical flow in promoting endocrine cell differentiation and maturation of islet organoids. This islet-on-a-chip system is robust and amenable to real-time imaging and in situ tracking of islet organoid growth, which may provide a promising platform for organoid engineering, disease modeling, drug testing and regenerative medicine.


Influence of antigen exposure on the loss of long-term memory to childhood vaccines in HIV-infected patients.
The role of antigen exposure and of CD4 cell deficiency in the long-term persistence of immune memory to childhood vaccines remains uncertain, particularly during HIV infection. We analyzed in vaccinated ART-treated HIV+ patients with undetectable plasma HIV and CD4 cells >250/mm(3) the persistence of two memory cell pools: effector IFNgamma-producing and proliferative central memory T cells against two vaccines: (i) vaccinia against the eradicated smallpox virus, and (ii) BCG against Mtb, a persistent pathogen. None of the HIV+ patients had IFNgamma-effector cells against VV while the one patient with BCG-specific effector T cells had a recent history of tuberculosis. Proliferative responses were detectable but showed significantly lower frequency and intensity of VV-specific than tuberculin-specific responses, independently of the CD4 nadir. Thus, differential patterns of persistence or recovery of T cell memory pools against childhood vaccines are observed in treated HIV infection that are governed by antigen exposure.


Formation Dynamics of CH3NH3PbI3 Perovskite Following Two-Step Layer Deposition.
Hybrid metal-halide perovskites have emerged as a leading class of semiconductors for optoelectronic devices because of their desirable material properties and versatile fabrication methods. However, little is known about the chemical transformations that occur in the initial stages of perovskite crystal formation. Here we follow the real-time formation dynamics of MAPbI3 from a bilayer of lead iodide (PbI2) and methylammonium iodide (MAI) deposited through a two-step thermal evaporation process. By lowering the substrate temperature during deposition, we are able to initially inhibit intermixing of the two layers. We subsequently use infrared and visible light transmission, X-ray diffraction, and photoluminescence lifetime measurements to reveal the room-temperature transformations that occur in vacuum and ambient air, as MAI diffuses into the PbI2 lattice to form MAPbI3. In vacuum, the transformation to MAPbI3 is incomplete as unreacted MAI is retained in the film. However, exposure to moist air allows for conversion of the unreacted MAI to MAPbI3, demonstrating that moisture is essential in making MAI more mobile and thus aiding perovskite crystallization. These dynamic processes are reflected in the observed charge-carrier lifetimes, which strongly fluctuate during periods of large ion migration but steadily increase with improving crystallinity.


Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA.
Iron regulatory proteins (IRPs) control the synthesis of several proteins in iron metabolism by binding to iron-responsive elements (IREs), a hairpin structure in the untranslated region (UTR) of corresponding mRNAs. Binding of IRPs to IREs in the 5' UTR inhibits translation of ferritin heavy and light chain, erythroid aminolevulinic acid synthase, mitochondrial aconitase, and Drosophila succinate dehydrogenase b, whereas IRP binding to IREs in the 3' UTR of transferrin receptor mRNA prolongs mRNA half-life. To identify new targets of IRPs, we devised a method to enrich IRE-containing mRNAs by using recombinant IRP-1 as an affinity matrix. A cDNA library established from enriched mRNA was screened by an RNA-protein band shift assay. This revealed a novel IRE-like sequence in the 3' UTR of a liver-specific mouse mRNA. The newly identified cDNA codes for a protein with high homology to plant glycolate oxidase (GOX). Recombinant protein expressed in bacteria displayed enzymatic GOX activity. Therefore, this cDNA represents the first vertebrate GOX homologue. The IRE-like sequence in mouse GOX exhibited strong binding to IRPs at room temperature. However, it differs from functional IREs by a mismatch in the middle of its upper stem and did not confer iron-dependent regulation in cells.


Naturally glossy: Gloss perception, illumination statistics, and tone mapping.
Recognizing materials and understanding their properties is very useful-perhaps critical-in daily life as we encounter objects and plan our interactions with them. Visually derived estimates of material properties guide where and with what force we grasp an object. However, the estimation of material properties, such as glossiness, is a classic ill-posed problem. Image cues that we rely on to estimate gloss are also affected by shape, illumination and, in visual displays, tone-mapping. Here, we focus on the latter two. We define some commonalities present in the structure of natural illumination, and determine whether manipulation of these natural "signatures" impedes gloss constancy. We manipulate the illumination field to violate statistical regularities of natural illumination, such that light comes from below, or the luminance distribution is no longer skewed. These manipulations result in errors in perceived gloss. Similarly, tone mapping has a dramatic effect on perceived gloss. However, when objects are viewed against an informative (rather than plain gray) background that reflects these manipulations, there are some improvements to gloss constancy: in particular, observers are far less susceptible to the effects of tone mapping when judging gloss. We suggest that observers are sensitive to some very simple statistics of the environment when judging gloss.


Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study.
To evaluate the efficacy of mitoxantrone (MTX) on clinical and neuroradiological parameters of patients who had a relapse of neuromyelitis optica spectrum (NMOS) within the 12 previous months. MTX (12 mg/m(2)) combined with methylprednisolone 1 g as three monthly courses followed by three quarterly courses was administered during an observational multicentre open study including 51 consecutive patients (28 NMO, 23 limited forms of NMO) of the French Caribbean and Guyana. The main outcome measure was the reduction of the annualised relapse rate (ARR), and the secondary outcome measures were alteration of disability measured by expanded disability status scale (EDSS) score, the time to onset of the first relapse, and the progression of neuroradiological lesions at 1 year of treatment. At 1 year of treatment, the ARR dropped from 1.82 to 0.37 (p<0.0001). The mean EDSS score improved by 1.3 points, going from 5.8 at baseline to 4.5 at 1 year (p<0.0001). The number of patients showing gadolinium (Gad)+ spinal cord lesions at baseline, that is, 46.9%, dropped to 10.6% (a 77.4% reduction; p=0.02). The median time to onset of the first relapse was 18 months. IgG-NMO seropositivity was a predictive factor of relapse (p=0.006). A case of acute myeloid leukaemia was observed after a mean time span of 4.8 years. In this observational NMO study, MTX decreased dramatically the frequency of relapses, which is directly related to progression of disability or even death in this disorder.


Understanding Cervical Cancer Screening among Latinas through the Lens of Structure, Culture, Psychology and Communication.
This study explored how structural and cultural forces work together with psychological and communication factors in influencing Pap test compliance among Latinas in Los Angeles County, a group who face health disparities related to cervical cancer screening, incidence and mortality. By adopting a multilevel approach to obtain a grounded understanding of this issue, this work revealed that structural barriers, fatalism, religious service attendance, perceived susceptibility, perceived costs, and cues to action from health care providers are all associated with Pap test compliance. Financial barriers also influence compliance, with underinsurance having a stronger negative impact compared to no insurance at all. These findings provide insights into how communication efforts can be strategically designed to address both individual- and system-level barriers to promote health-seeking behaviors among Latinas, and potentially among other population groups experiencing health disparities due to similar reasons.


Antibody Responses to Helicobacter pylori and Risk of Developing Colorectal Cancer in a European Cohort.
While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00-1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99-1.82), the latter being nonstatistically significant only in the fully adjusted model. In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence.


A calcium/calmodulin-dependent protein kinase from mammalian brain that phosphorylates Synapsin I: partial purification and characterization.
A calcium/calmodulin-dependent protein kinase, which phosphorylates a synaptic vesicle-associated protein designated Synapsin I, has been shown to be present in both soluble and particulate fractions of rat brain homogenates. In the present study, the particulate activity was solubilized by washing with a low ionic strength solution, and the enzymes from the two fractions were partially purified by ion exchange chromatography and calmodulin-Sepharose affinity chromatography. By each of several criteria, the partially purified enzymes from the two sources were indistinguishable. These criteria included specificity for various substrate proteins, concentration dependence of activation by calcium and calmodulin, pH dependence, and apparent affinities for the substrates Synapsin I and ATP. The mild conditions that released the particulate enzyme indicated that it was not tightly bound to the membrane and suggested that it may exist in a dynamic equilibrium between soluble and particulate-bound states. The partially purified enzyme preparations from both the soluble and particulate fractions contained three proteins that were phosphorylated in the presence of calcium and calmodulin, a 50-kilodalton (Kd) protein and two proteins in the 60-Kd region. When compared by phosphopeptide mapping and two-dimensional gel electrophoresis, the proteins were indistinguishable from three proteins of corresponding molecular weights that were shown by Schulman and Greengard (Schulman, H., and P. Greengard (1978) Nature 271: 478-479) to be prominent substrates for calcium/calmodulin-dependent protein kinase in a crude particulate preparation from rat brain. The 50-Kd substrate was the major Coomassie blue staining protein in both partially purified enzyme preparations. The peak of this protein coincided with that of enzyme activity during DEAE-cellulose and calmodulin-Sepharose chromatography. These results suggest that the 50-Kd phosphoprotein may be an autophosphorylatable subunit of the Synapsin I Kinase or may exist in a complex with it.


TSPO expression and brain structure in the psychosis spectrum.
Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.


Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease.
Hepatic steatosis is caused by metabolic imbalances that could be explained in part by an increase in de novo lipogenesis that results from increased sterol element binding protein 1 (SREBP-1) activity. The nuclear receptor liver receptor homolog 1 (LRH-1) is an important regulator of intermediary metabolism in the liver, but its role in regulating lipogenesis is not well understood. Here, we have assessed the contribution of LRH-1 SUMOylation to the development of nonalcoholic fatty liver disease (NAFLD). Mice expressing a SUMOylation-defective mutant of LRH-1 (LRH-1 K289R mice) developed NAFLD and early signs of nonalcoholic steatohepatitis (NASH) when challenged with a lipogenic, high-fat, high-sucrose diet. Moreover, we observed that the LRH-1 K289R mutation induced the expression of oxysterol binding protein-like 3 (OSBPL3), enhanced SREBP-1 processing, and promoted de novo lipogenesis. Mechanistically, we demonstrated that ectopic expression of OSBPL3 facilitates SREBP-1 processing in WT mice, while silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice. These findings suggest that compromised SUMOylation of LRH-1 promotes the development of NAFLD under lipogenic conditions through regulation of OSBPL3.


Residues analysis of post-harvest imidazole fungicides in citrus fruit by HPLC and GLC.
The determination of imazalil and prochloraz fungicide residues has been carried out by HPLC with an UV detector at 204 nm and by GLC with an electron capture detector (ECD). In both cases fungicide residues were extracted with hexane/acetone (90:10, v/v) after pH adjustment and purified by a liquid-liquid partitioning process. When HPLC was used for prochloraz and imazalil analysis, it was necessary to eliminate the interfering substances with a further clean-up process. This was also required when samples with low residue levels were analyzed by GLC. Recovery was always higher than 70%. The detection limit was 0.04 ppm for the HPLC method and 0.02 for the GLC method. Imazalil and prochloraz residues in "Washington Navel" oranges and "Hernandina" clementine fruits, dipped in a 1000 ppm fungicide solution, are reported.


Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.
Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydrocurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.


Experience from the first UK inter-regional specialist multidisciplinary meeting in the diagnosis and management of IgG4-related disease.
Immunoglobulin G4-related disease (IgG4-RD) is a complex multisystem fibro-inflammatory disorder, requiring diagnostic differentiation from malignancy and other immune-mediated conditions, and careful management to minimise glucocorticoid-induced toxicity and prevent progressive organ dysfunction. We describe the experience of the first inter-regional specialist IgG4-RD multidisciplinary team meeting (MDM) incorporating a broad range of generalists and specialists, held 6-weekly via web-link between Oxford University Hospitals NHS Foundation Trust and University College London Hospitals NHS Foundation Trust. Over 3 years, there were 206 discussions on 156 patients. Of these, 97 (62%) were considered to have definite or possible IgG4-RD; 67% had multi-organ involvement and 23% had a normal serum IgG4. The average number of specialist opinions sought prior to MDM was four per patient. Management was changed in the majority of patients (74%) with the treatment escalation recommended in 61 cases, including 19 for rituximab. Challenges arose from delays and misdiagnosis, cross-specialty presentation and the management of sub-clinical disease. Our cross-discipline IgG4-RD MDM enabled important diagnostic and management decisions in this complex multisystem disorder, and can be used as a model for other centres in the UK.