Multi-Organ Morphological Findings in a Humanized Murine Model of Sickle Cell Trait.
Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening of vessel basal lamina, are ubiquitous in the lung, liver, kidney, and spleen of SCT carrier mice. The lung shows the most significant alterations, with a distortion of the general tissue architecture, while the heart is the least affected. Collectively, our findings contribute novel data to the histopathological modifications at microscopic and ultrastructural levels, underlying the heterozygous beta-globin gene mutation, and indicate the translational suitability of the Townes model to characterize the features of multiple organ involvement in the SCT carriers.


Modeling of inter-sample variation in flow cytometric data with the joint clustering and matching procedure.
We present an algorithm for modeling flow cytometry data in the presence of large inter-sample variation. Large-scale cytometry datasets often exhibit some within-class variation due to technical effects such as instrumental differences and variations in data acquisition, as well as subtle biological heterogeneity within the class of samples. Failure to account for such variations in the model may lead to inaccurate matching of populations across a batch of samples and poor performance in classification of unlabeled samples. In this paper, we describe the Joint Clustering and Matching (JCM) procedure for simultaneous segmentation and alignment of cell populations across multiple samples. Under the JCM framework, a multivariate mixture distribution is used to model the distribution of the expressions of a fixed set of markers for each cell in a sample such that the components in the mixture model may correspond to the various populations of cells, which have similar expressions of markers (that is, clusters), in the composition of the sample. For each class of samples, an overall class template is formed by the adoption of random-effects terms to model the inter-sample variation within a class. The construction of a parametric template for each class allows for direct quantification of the differences between the template and each sample, and also between each pair of samples, both within or between classes. The classification of a new unclassified sample is then undertaken by assigning the unclassified sample to the class that minimizes the distance between its fitted mixture density and each class density as provided by the class templates. For illustration, we use a symmetric form of the Kullback-Leibler divergence as a distance measure between two densities, but other distance measures can also be applied. We show and demonstrate on four real datasets how the JCM procedure can be used to carry out the tasks of automated clustering and alignment of cell populations, and supervised classification of samples.


The role of insulator elements in large-scale chromatin structure in interphase.
Insulator elements can be classified as enhancer-blocking or barrier insulators depending on whether they interfere with enhancer-promoter interactions or act as barriers against the spreading of heterochromatin. The former class may exert its function at least in part by attaching the chromatin fiber to a nuclear substrate such as the nuclear matrix, resulting in the formation of chromatin loops. The latter class functions by recruiting histone-modifying enzymes, although some barrier insulators have also been shown to create chromatin loops. These loops may correspond to functional nuclear domains containing clusters of co-expressed genes. Thus, insulators may determine specific patterns of nuclear organization that are important in establishing specific programs of gene expression during cell differentiation and development.


Tetraphenylphosphonium Bromide as a Cathode Buffer Layer Material for Highly Efficient Polymer Solar Cells.
Here, we introduced the role of small organic molecule tetraphenylphosphonium bromide (QPhPBr) as an electron-transporting layer (ETL) material for fabricating high-efficiency bulk heterojunction polymer solar cells (PSCs). Their significantly higher power conversion efficiency (PCE) in well-known active layer devices (PTB7-Th:PC71BM, PBDTTT-CT:PC71BM, and P3HT:PC71BM) was observed compared to that of the bare Al cathode. The use of N719 as an ETL was also demonstrated. Observed data reveal that QPhPBr-based devices exhibit high PCEs up to 9.18, 8.42, and 4.81% from PTB7-Th, PBDTTT-CT, and P3HT, respectively. For comparisons, the bare Al devices show PCEs of 5.37, 4.75, and 3.01%, respectively. Moreover, further enhancement of PSC efficiency (9.83, 8.69, and 5.35%) is achieved from mixed binary solution of N719:QPhPBr because of modulated adjustment of the work function of the Al electrode. Our results indicate the excellent function of tetraphenylphosphonium bromide and its binary blend as effective small-molecule organic materials to regulate the metal surface properties and the potential used as excellent cathode buffer layer materials for realizing high-efficiency PSCs.


Novel Insights into the Dermal Bioaccessibility and Human Exposure to Brominated Flame Retardant Additives in Microplastics.
In this study, we optimized and applied an in vitro physiologically based extraction test to investigate the dermal bioaccessibility of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), incorporated as additives in different types of microplastics (MPs), and assess human dermal exposure to these chemicals. The dermal bioaccessibility of PBDEs in polyethylene (PE) MPs was significantly higher (P < 0.05) than in polypropylene (PP) MPs. Both log Kow and water solubility influenced the dermal bioaccessibility of PBDEs. For HBCDDs in polystyrene MPs, the dermally bioaccessible fractions were 1.8, 2.0, and 1.6% of the applied dose for α-, β-, and γ-HBCDDs, respectively. MP particle size and the presence of cosmetic formulations (antiperspirant, foundation, moisturizer and sunscreen) influenced the bioaccessibility of PBDEs and HBCDDs in MP matrices at varying degrees of significance. Human exposure to ∑PBDEs and ∑HBCDDs via dermal contact with MPs ranged from 0.02 to 22.2 and 0.01 to 231 ng (kg bw)-1 d-1 and from 0.02 to 6.27 and 0.2 to 65 ng (kg bw)-1 d-1 for adults and toddlers, respectively. Dermal exposure to PBDEs and HBCDDs in MPs is substantial, highlighting for the first time the significance of the dermal pathway as a major route of human exposure to additive chemicals in microplastics.


Xcp-mediated protein secretion in Pseudomonas aeruginosa: identification of two additional genes and evidence for regulation of xcp gene expression.
In Pseudomonas aeruginosa, several exoproteins synthesized with a signal sequence (elastase, lipase, phospholipases, alkaline phosphatase and exotoxin A) are secreted by a two-step mechanism. They first cross the inner membrane in a signal sequence-dependent way, and are further translocated across the outer membrane in a second step requiring secretion functions encoded by several xcp genes. Ten xcp genes have already been characterized (Bally et al., 1992a). In this study, two additional xcp genes, xcpP and xcpQ, are described. They are located in the 40 min region of the chromosome where they probably define an operon, divergent from the xcpR-Z operon previously characterized in this region. These two genes encode two proteins, XcpP and XcpQ, similar to PulC and PulD of the pul system of Klebsiella oxytoca. Moreover, the two divergent operons share a common regulation which is growth-phase dependent.


Cultural Biases in Current Medical Practices with a Specific Attention to Orthopedic Surgery: a Review.
Due to the increasing diversity within the United States population, there is an ever-increasing need for increased education on cultural literacy and tolerance in medical schools and residency programs. The purpose of this article was to review how a person's culture can play a substantive role in effecting and influencing (1) medical diagnosis, (2) patient and health provider medical decision-making, (3) the patient's perception of disease, and (4) the doctor-patient relationships. Many of the decisions we make as orthopedic surgeons must account for the patient's cultural needs, as much of our work impacts patients' daily activities and function. When considering the patient's perception of disease, validated tools have been developed, such as the Patient-Specific Index, which can be used to assess the feelings, goals, and expectations of patients. Cultural competency should be a part of curricula at every level of medical education.


[Effect of cholesterol oxidation products, polyunsaturated fatty acids and the synthetic antioxidant ionol on experimental hypercholesterolemia in rabbits].
Oral administration to rabbits of purified commercial cholesterol entailed a substantial delay in the development of hypercholesterolemia as compared with estimates obtained in a group of animals given analogous doses of crude cholesterol. Administration of polyunsaturated fatty acids from hydrobiont lipids led to a dramatic suppression of hypercholesterolemia at the late stages of experiment (2.5 months). After administering ethyl esters of polyunsaturated fatty acids combined with the synthetic antioxidant ionol the level of blood plasma cholesterol did not differ significantly from that in intact animals. It is suggested that minor oxidation products contained by commercial cholesterol produce a hypercholesterolemic effect.


Genetic predisposition testing: clinical implications for oncology nurses.
To describe for oncology nurses the clinical implications of genetic predisposition testing for alterations in cancer susceptibility genes. Published research and educational manuscripts, books, conference proceedings, and personal experiences. Genetic predisposition testing for inherited cancer risk has profound clinical implications that eventually will affect all areas of nursing practice. The provision of genetic information raises issues about cancer risk management, psychosocial sequelae, and legal and professional liability. Most healthcare professionals, including nurses, are not adequately prepared to manage the issues resulting from genetic predisposition testing. Furthermore, little data are available to guide practice. Unique educational strategies are needed to prepare providers in this practice arena. Genetic predisposition testing is becoming more common in general oncology and primary care communities. Nurses will play a major role in the support, counseling, education, informed consent, and follow-up care of individuals who are considering undergoing or who have undergone testing. To meet the needs of patients and their families, oncology nurses must prepare themselves for this new area of practice.


Friendships and suicidality among Mexican American adolescent girls and boys.
Friendship factors have been implicated in adolescent suicidality, but this relationship has not been verified across ethnicities. This study examined suicidality and friendship problems (i.e., social isolation, poor friendship quality, friends' school disconnection, and friends' delinquency) among Mexican American adolescents, an understudied, vulnerable group in terms of suicidality. Three hundred thirty-eight community adolescents, two-thirds of whom were educationally at-risk, participated in the study. Suicidal ideation and behavior rates were high, particularly among girls. Friends' school disconnectedness increased girls' odds for suicidal ideation by 13%. This association was even greater for girls in good academic standing. Friendship problems were not associated with suicidality in boys. Ethnic identity was a minor factor in suicidal ideation, and only for girls. These findings confirm, among Mexican American adolescents, the role of gender in the relationship between friendship and suicidality.


Synchronization mechanism and Arnold tongues for dust density waves.
The nonlinear phenomenon of synchronization is characterized experimentally for dust density waves, i.e., dust acoustic waves, which are self-excited due to an ion streaming instability. The waves propagate in a dust cloud with a natural frequency of 22 Hz. We synchronize these waves to a different frequency using a driving electrode that sinusoidally modulates the ion density. We study four synchronized states, with frequencies that are multiples of 1, 2, 3, and 1/2 of the driving frequency. Comparing to phenomena that are typical of the van der Pol paradigm, we find that synchronization of our waves exhibit the signature of the suppression mechanism but not that of the phaselocking mechanism. Additionally, synchronization of our waves exhibits three characteristics that differ from the van der Pol paradigm: a threshold amplitude that can be seen in the Arnold tongue diagram, a branching of the 1:1 harmonic tongue at its lower extremity, and a nonharmonic state. The latter state appears to be a nonlinear oscillation; it is neither at the natural frequency nor a synchronized state.


Induction of secretory phospholipase A2 in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain.
Although mRNA expression of group IIA secretory phospholipase A2 (sPLA2-IIA) has been implicated in responses to injury in the CNS, information on protein expression remains unclear. In this study, we investigated temporal and spatial expression of sPLA2-IIA mRNA and immunoreactivity in transient focal cerebral ischemia induced in rats by occlusion of the middle cerebral artery. Northern blot analysis showed a biphasic increase in sPLA2-IIA mRNA expression following 60-min of ischemia-reperfusion: an early phase at 30 min and a second increase at a late phase ranging from 12 h to 14 days. In situ hybridization localized the early-phase increase in sPLA2-IIA mRNA to the affected ischemic cortex and the late-phase increase to the penumbral area. Besides sPLA2-IIA mRNA, glial fibrillary acidic protein (GFAP) and cyclo-oxygenase-2 mRNAs, but not cytosolic PLA2, also showed an increase in the penumbral area at 3 days after ischemia-reperfusion. Immunohistochemistry of sPLA2-IIA indicated positive cells in the penumbral area similar to the GFAP-positive astrocytes but different from the isolectin B4-positive microglial cells. Confocal microscopy further confirmed immunoreactivity of sPLA2-IIA in reactive astrocytes but not in microglial cells. Taken together, these results demonstrate for the first time an up-regulation of the inflammatory sPLA2-IIA in reactive astrocytes in response to cerebral ischemia-reperfusion.


Peroxisomal lipid metabolism.
Peroxisomes are present in virtually all eukaryotic cells. At present, they are known to contain more than 50 enzymes, more than half of which play a role in lipid metabolism. During the past two decades, considerable knowledge has been gained about the role of peroxisomes in lipid metabolism, the implications of induction of hepatic peroxisome proliferation and the peroxisomal fatty acid beta-oxidation enzyme system in the development of hepatocellular carcinomas in rats and mice by structurally diverse groups of chemicals designated as peroxisome proliferators, and the biochemical basis for inheritable diseases in humans caused by disturbances and/or deficiencies in peroxisomal lipid metabolism. Nevertheless, many unanswered questions remain. The ontogeny and homeostatic interrelationships between the enzymes of the peroxisomal and mitochondrial lipid metabolism have yet to be fully elucidated. The mechanism(s) by which PPARs are activated also remains unclear. Information about the interplay between PPAR, RXR alpha, HSP72, and other possible regulatory molecules is necessary to elucidate the transcriptional activation of inducible peroxisomal genes. The assumption that multiple signaling pathways may be responsible for the pleiotropic responses induced by structurally different peroxisome proliferators requires further examination. Finally, studies to identify and characterize different PPARs and PPREs from inducible peroxisomal genes from a variety of species are also required for a clear understanding of the role of peroxisomal beta-oxidation enzyme system in the pathogenesis of hepatocellular carcinogenesis induced by peroxisome proliferators.


Association of Toll-Like Receptor 4 on Human Monocyte Subsets and Vulnerability Characteristics of Coronary Plaque as Assessed by 64-Slice Multidetector Computed Tomography.
Although Toll-like receptor 4 (TLR-4) is involved in monocyte activation in patients with accelerated forms of atherosclerosis, the relationship between the expression of TLR-4 on circulating monocytes and coronary plaque vulnerability has not previously been evaluated. We investigated this relationship using 64-slice multidetector computed tomography (MDCT) in patients with stable angina pectoris (SAP).Methods and Results:We enrolled 65 patients with SAP who underwent MDCT. Three monocyte subsets (CD14++CD16-, CD14++CD16+, and CD14+CD16+) and expression of TLR-4 were measured by flow cytometry. Intracoronary plaques were assessed by 64-slice MDCT. We defined vulnerability of intracoronary plaques according to the presence of positive remodeling (remodeling index >1.05) and/or low CT attenuation (<35 HU). The circulating CD14++CD16+monocytes more frequently expressed TLR-4 than CD14++CD16-and CD14+CD16+monocytes (P<0.001). The relative proportion of the expression of TLR-4 on CD14++CD16+monocytes was significantly greater in patients with vulnerable plaque compared with those without (10.4 [4.1-14.5] % vs. 4.5 [2.8-7.8] %, P=0.012). In addition, the relative proportion of TLR-4 expression on CD14++CD16+monocytes positively correlated with the remodeling index (r=0.28, P=0.025) and negatively correlated with CT attenuation value (r=-0.31, P=0.013). Upregulation of TLR-4 on CD14++CD16+monocytes might be associated with coronary plaque vulnerability in patients with SAP.


Meta-analysis of Noninsertional Achilles Tendinopathy.
Achilles tendinopathy is a common clinical problem that can be either insertional or noninsertional. A variety of treatment methods have been described, although little consensus exists on an optimal method or methods. We sought to investigate the current evidence on different treatment methods for noninsertional Achilles tendinopathy, with a focus on functional outcomes. We performed a review of the available literature in PubMed and the Cochrane Central Register of Controlled Trials. Data from included studies were categorized according to treatment method and analyzed with respect to functional outcome and complication rate. In total, 1420 abstracts were reviewed, of which 72 articles containing 3523 patients met inclusion criteria. Within the 72 studies included, 6 operative techniques and 19 nonoperative treatments were evaluated. A wide variety of treatments are available for noninsertional Achilles tendinopathy, although newer treatments and most operative methods lack high-level evidence. Eccentric exercise is the most thoroughly studied and supported nonoperative treatment, while tenotomy and debridement is the operative procedure with the most evidence of efficacy. Platelet-rich plasma injections and extracorporeal shockwave therapy have proven to be viable second-line nonoperative treatments. Gastrocnemius recession and flexor hallucis longus transfer have shown benefit in case series. Level II, systematic review.


A weighted region-based level set method for image segmentation with intensity inhomogeneity.
Image segmentation is a fundamental task in image processing and is still a challenging problem when processing images with high noise, low resolution and intensity inhomogeneity. In this paper, a weighted region-based level set method, which is based on the techniques of local statistical theory, level set theory and curve evolution, is proposed. Specifically, a new weighted pressure force function (WPF) is first presented to flexibly drive the closed contour to shrink or expand outside and inside of the object. Second, a faster and smoother regularization term is added to ensure the stability of the curve evolution and that there is no need for initialization in curve evolution. Third, the WPF is integrated into the region-based level set framework to accelerate the speed of the curve evolution and improve the accuracy of image segmentation. Experimental results on medical and natural images demonstrate that the proposed segmentation model is more efficient and robust to noise than other state-of-the-art models.


Transatrial access for left atrial pressure (LAP) monitoring line placement in arterial switch operation (ASO) in neonates.
Left Atrial pressure monitoring is a useful and accurate method to guide Left ventricle filling in the patients who undergo Arterial switch operation for transposition of great arteries. We have used a different technique in three TGA patients for LA pressure monitoring line placement. After cleaning and draping,right internal jugular vein (rt IJV) located through 22G venous cannula, guide wire was put in followed by sliding the 22G x 8cm vygon arterial catheter over the guide wire into the right atrium that was directed transatrially into LA by the operating surgeon during atrial septum repair. The catheter was secured by silk on the neck and dressed with transparent dressing and was kept for a period of 48-72 hrs. LA pressure monitoring is helpful in anticipating LV dysfunction in ASO.


Identification of a Lead Candidate in the Search for Carbene-Stabilised Homoaromatics.
The effect of carbenes as Lewis donor groups on the homoaromaticity of mono- and bicyclic organic molecules is surveyed. The search for viable carbene-stabilised homoaromatics resulted in a large amount of rejected candidates as well as nine promising candidates that are further analysed for their homoaromaticity by using a number of metrics. Of these, five appeared to show modest homoaromaticity, whereas another compound showed a level of homoaromaticity comparable with the homotropylium cation benchmark compound. Isoelectronic analogues and constitutional isomers of the lead compound were investigated, however, none of these showed comparable homoaromaticity. The implications of these calculations on the design of donor-stabilised homoaromatics are discussed.


Exploring correlates of burnout dimensions in a sample of psychiatric rehabilitation practitioners: a cross-sectional study.
The primary purpose of this article is to investigate demographic and work-related correlates of three burnout dimensions, that is, emotional exhaustion, depersonalization, and diminished personal accomplishment, using a national sample of psychiatric rehabilitation practitioners (PRPs). An online survey was filled out by 1,639 PRPs who provided demographic, work-related, and burnout data. Complete data for hypotheses testing using stepwise regression analyses was available for 813 PRPs. Lower than expected levels of burnout dimensions were found among PRPs. All 3 study hypotheses were at least partially supported. Looking at individual correlates of burnout dimensions, education level was positively related to emotional exhaustion, age was negatively related to depersonalization, and age and length of service were both negatively related to diminished personal accomplishment. Personal involvement was positively related to emotional exhaustion and depersonalization. Regression results were also supportive of the mental health burnout process model, that is, emotional exhaustion explaining depersonalization, which then combined with emotional exhaustion to help further explain diminished personal accomplishment. Study limitations are acknowledged. This study updates the results of a prior 1996 PRP survey (Blankertz & Robinson, 1996) using a demographically comparable (i.e., gender, race, education level, primary area of study) sample. Reducing one's personal involvement with clients seems important to reducing PRP emotional exhaustion and depersonalization. Emotional exhaustion is generally acknowledged to be the key component to burnout and reducing it via peer support group sessions is recommended.


Towards an understanding of the bonding in polyoxometalates through bond order and bond energy analysis.
The molecular and electronic structures of transition metal complexes, [MOCl5]n- (n = 2 for M = V,Nb,Ta and n = 1 for Mo,W) and mixed-metal polyoxometalates, [M'M5O19]3-V,Nb,Ta, M = Mo,W) containing a single terminal oxo group on each metal, and of complexes of the uranyl ion [UO2]2+, [UO2(H2O)5]2+ and [UO2Cl4]2-, have been calculated using density functional methods. The calculated structures of the complexes are in good agreement with available experimental parameters. For the mixed-metal hexametalates, for which no crystallographic data is available, the calculations predict a small tetragonal compression of the clusters with only minor structural changes compared to the parent molybdate and tungstate. The metal oxygen bonding in these anions has been probed using Mayer-Mulliken, bond energy and atoms in molecule analyses (AIM). These methods provide a consistent description of the bonding in polyoxometalates. The terminal bonds between transition metal or uranium and oxygen atoms have large sigma and pi components with the pi contributions exceeding the sigma bonding. The transition metals utilize their d orbitals almost exclusively to bond to oxygen whilst uranium uses both its 5f and 6d orbitals. Oxygen atom charges increase and covalency indexes decrease with coordination number, with a marked separation of these terms according to the oxygen atom type. The total valency and AIM energies of the oxygen atoms are predicted to be almost constant for all types of oxygen site. The constancy of the bonding power of the oxygen atoms appears to be an important factor in determining the gross structures and details of the bonding in polyoxometalates. The Mayer Mulliken approach provides direct characterization of the bonding power of atoms and the extent of the interaction between pairs of atoms that is consistent with the results of the considerably more computationally demanding bond energy and AIM approaches.


Isolation of Leclercia adecarboxylata from a patient with a subungual splinter.
Leclercia adecarboxylata is a rarely described motile, aerobic, gram-negative bacillus reported to cause clinically significant solitary infections in immunocompromised patients and polymicrobial wound infections in immunocompetent patients [1-5]. We present a case of a polymicrobial infection including L. adecarboxylata in a healthy female patient with a subungual splinter, to increase awareness and aid in the diagnosis and treatment of cutaneous L. adecarboxylata infections. To our knowledge, this is the first reported case of trauma-related subungual L. adecarboxylata infection reported in the dermatology literature.


Phenotypic and metabolic plasticity shapes life-history strategies under combinations of abiotic stresses.
Plants developed various reversible and non-reversible acclimation mechanisms to cope with the multifaceted nature of abiotic-stress combinations. We hypothesized that in order to endure these stress combinations, plants elicit distinctive acclimation strategies through specific trade-offs between reproduction and defense. To investigate Brachypodium distachyon acclimation strategies to combinations of salinity, drought and heat, we applied a system biology approach, integrating physiological, metabolic, and transcriptional analyses. We analyzed the trade-offs among functional and performance traits, and their effects on plant fitness. A combination of drought and heat resulted in escape strategy, while under a combination of salinity and heat, plants exhibited an avoidance strategy. On the other hand, under combinations of salinity and drought, with or without heat stress, plant fitness (i.e., germination rate of subsequent generation) was severely impaired. These results indicate that under combined stresses, plants' life-history strategies were shaped by the limits of phenotypic and metabolic plasticity and the trade-offs between traits, thereby giving raise to distinct acclimations. Our findings provide a mechanistic understanding of plant acclimations to combinations of abiotic stresses and shed light on the different life-history strategies that can contribute to grass fitness and possibly to their dispersion under changing environments.


The health-economic studies of HPV vaccination in Southeast Asian countries: a systematic review.
The cervical cancer-related burden is an important problem in Southeast Asian (SEA) countries. However, only 3 out of 11 countries implement the comprehensive prevention program. Areas covered: This is a retrospective review from all relevant studies until 2015 from two main databases, MEDLINE/Pubmed and Embase in order to provide an evidence on the health economics of HPV vaccination in the region. Expert commentary: The implementation of HPV vaccination will generate substantial health and economic benefit in SEA countries since the number of cervical cancer cases in this region are generally high. Therefore, a clear recommendation on how HPV vaccination should be implemented in a country, for example on how many doses will be used, how much cost is required or is it a school based- or clinical based-delivery, is critically required.


Comparative microelectrode array data of the functional development of hPSC-derived and rat neuronal networks.
We present a dataset of microelectrode array (MEA) recordings from human pluripotent stem cell (hPSC)-derived and rat embryonic cortical neurons during their in vitro maturation. The data were prepared to assess extracellularly recorded spontaneous activity and to compare the functional development of these neuronal networks. In addition to recordings of spontaneous activity, we provide pharmacological responses of hPSC-derived and rat cortical cultures at their mature stage. Together with the recorded electrode raw data, we share the analysis code to form a comprehensive dataset including spike times, spike waveforms, burst activity and network synchronization metrics calculated with two different connectivity estimators. Moreover, we provide the analysis code that produced the key scientific findings published previously with this dataset. This large dataset enables investigation of the functional aspects of maturing cortical neuronal networks and provides substantial parameters to assess the differences and similarities between hPSC-derived and rat cortical networks in vitro. This publicly available dataset will be beneficial, especially for experimental and computational neuroscientists.


Chromosome evolution of near-haploid clones in an established human acute lymphoblastic leukemia cell line (NALM-16).
A cell line has been established from blood lymphoblasts of a female patient with acute lymphoblastic leukemia (ALL) shown to have near-haploid (27 chromosomes) cells in the bone marrow. The findings about the cell line were: 1) The frequency of near-haploid cells in culture decreased with time from 98.2% when the culture was started to 5.4% 15 months later. 2) Most of the other cells except the near-haploid ones were hyperdiploid, i.e., duplicates of the cells with near-haploid chromosome constitutions. 3) Chromosome evolution was seen in the near-haploid clones. The possible ancestor clone (clone A) had 27 chromosomes, one of each pair except no.10, 14, 18, and 21, which were disomic. A suggested evolution process is: clone A yields clone B (26 chromosomes: clone A, -no.10) yields clone C (27 chromosomes: clone B, +X) yields clone D (26 chromosomes: clone C, -no.21), clone E (28 chromosomes: clone C, +NO.20). Clone B and D, each with 26 chromosomes, appeared to contain the lowest number of chromosomes, appeared to contain the lowest number of chromosomes ever described for human somatic cell clones in vitro. 4) Changes in the constitutions of the hyperdiploid cell clones were preceded by evolution and changes in the near-haploid clones. 5) In near-haploid cells with 2 X-chromosomes, 1 exhibited late DNA replication; in hyperdiploid cells with 3-5 X-chromosomes, 2 were non-late DNA-replicating. 6) Fresh (uncultured) and cultured leukemia cells were antigenically typical non-T, non-B or common type ALL cells (positive for la-like and null-type ALL antigens and negative for surface membrane immunoglobulin).


Association of nonalcoholic fatty liver disease and growth hormone deficiency: a systematic review and meta-analysis.
An association exists between nonalcoholic fatty liver disease (NAFLD) and growth hormone (GH). Patients with growth hormone deficiency (GHD) may be more susceptible to NAFLD. The prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) in GHD patients is currently unknown. Multiple databases were searched for experiments related to NAFLD (or NASH) and GHD. Screening, quality evaluation and data extraction were carried out independently by two authors. Analyses used random or fixed effects models, including NAFLD prevalence, NASH prevalence, odds ratio (OR) and 95% confidence interval (CI). We included 10 studies with a total of 782 participants. The results showed that the prevalence of NAFLD in GHD patients was 51% (95% CI: 39-63). The risk of NAFLD in GHD patients was significantly higher than that in controls (age-, sex- or body mass index-matched, without GHD) (pooled OR = 4.27, 95% CI: 1.33-13.68%, p = 0.015). The prevalence of NASH in GHD patients was 18% (95% CI: 5-31). The prevalence of NAFLD in GHD patients is significantly higher than that in the general population, especially NASH. There is a need to develop targeted strategies for the early identification, prevention, or control of NAFLD/NASH in patients with GHD.


A CREB1 Gene Polymorphism (rs2253206) Is Associated with Prospective Memory in a Healthy Cohort.
Prospective memory (PM) is generally defined as remembering to perform intended actions in the future and is important for functioning in daily life. Cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB1) plays an important role in cognitive functions. In this study, we hypothesized that genetic variation in the CREB1 gene is associated with PM. We genotyped a CREB1 promoter polymorphism rs2253206 and tested it for association with PM in 619 healthy subjects. PM performance was measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), the Comprehensive Assessment of Prospective Memory (CAPM), and the Memory for Intentions Screening Test (MIST). Generalized linear model analysis was conducted for each PM test independently using different inheritance models to identify any associations (p < 0.05). After multiple testing adjustments, a significant association was found between the rs2253206 genotype and PM performance for CAPM instrumental activities of daily living measure (p = 0.016). These results suggest that the rs2253206 polymorphism in the CREB1 gene locus is associated with PM in healthy individuals and contributes to knowledge on the genetics of this particular type of memory.


Plasma renin activity (PRA) in type I diabetes mellitus: PRA and metabolic control in diabetes.
Plasma renin activity (PRA) and aldosterone were evaluated in 39 diabetic children and adolescents and in 39 healthy subjects. The mean values of PRA in the diabetics were higher than in controls not only basal (means +/- SD: 2.7 +/- 1.1 vs. 1.3 +/- 0.6 ng/ml/h) but also after physical exercise (5.2 +/- 3.84 vs. 2.8 +/- 0.7 ng/ml/h). Aldosterone was similar in diabetics and controls (basal: 18.1 +/- 6.6 vs. 16.9 +/- 5.1 pmol/l; after physical exercise: 5.3 +/- 14.1 vs. 39.9 +/- 7.1 pmol/l). There was a significant correlation between HbA1c and PRA after exercise (p less than 0.01). The diabetic children were subdivided into 3 groups according to their stable HbA1c values (group A: less than 8.5%; group B: 8.5-10.9%; group C: greater than 11.0%). A group of diabetics (group C) were re-evaluated after a long period of a good metabolic control. The values of PRA were decreased and similar to the controls (PRA basal values: 1.7 +/- 1.9 ng/ml/h; after exercise: 3.2 +/- 2.9 ng/ml/h). Our study suggests that PRA abnormalities present in diabetic patients can be reversible if a good metabolic control is achieved.


Extracellular accumulation of bioactive substances; interleukin-1beta (IL-1beta) and plasminogen activator inhibitor-1 (PAI-1) in stored blood units and relation to bacterial contamination.
Bacterial contamination of blood and its cellular components remains an unresolved problem in transfusion medicine and is considered to be the most common microbiological cause of transfusion associated morbidity and mortality. The present work was designed to explore the levels of two bioactive compounds interleukin-1 beta (IL-1beta) and plasminogen activator inhibitor-1 (PAI-1) in stored blood units and their relation to bacterial contamination of these units. This study was conducted on 112 blood units obtained from blood bank of Mansoura University Children Hospital. Sequential blood samples were obtained both immediately at donation and after 10 days for measurement of IL-1beta and PAI-1 and for bacterial culture by BACTEC 9050 system. There was statistically significant increase in both IL-1 beta and PAI-1 (P = 0.0001) after 10 days of blood units storage. Bacteriological culture revealed no growth in 68% and positive growth in 32% of blood units. The commonest isolated organism was Staphylococcus aureus (15%) followed by Staphylococcus epidermedis (13%) then Yersinia sp. and Enterobacter sp. (2%) for each. From the present study we could conclude that stored blood units contain platelets and WBCs derived bioactive substances PAI-1 and IL-1beta which increase with the duration of blood storage. Furthermore, the extended duration of storage carries the danger of blood contamination by bacteria. Automated blood culture system seems to be helpful in identification of bacterial contamination of blood units. We recommend fresh blood transfusion as early as possible and the practice of Leucofiltration to avoid blood transfusion complications.


Axonal projections from the rostral expiratory neurones of the Bötzinger complex to medulla and spinal cord in the cat.
Axonal projections of eighty-four rostral medullary expiratory neurones of the Bötzinger complex were tested using antidromic mapping techniques in anaesthetized cats. A projection to the ventral respiratory neurones of the medulla (n.r.a.) was shown in eleven out of twelve tested neurones. Also a spinal projection to the C5-C6 cervical segments was evident in more than 72% of tested neurones; probably near 100% project to cervical cord. These axonal projections were found bilaterally in both brain stem and spinal cord. The majority of Bötzinger complex expiratory neurones were seen to have two to four axonal collaterals to the ventro-lateral (v.l.) nucleus of the solitary tract (n.t.s.) and/or the n.r.a. and/or the spinal cord. In eight out of twelve of the tested neurones, electrophysiological evidence of axonal arborization in more than one of n.r.a. inspiratory, n.r.a. expiratory or v.l. n.t.s. regions was obtained. Similar evidence for the terminal arborization was found for 26% of tested neurones in the phrenic motor nucleus. The descending spinal expiratory axons of the Bötzinger complex neurones are located in the dorsal and medial parts of the lateral funiculus in C4 and C5 segments. Conduction velocity measurements indicate that these are large myelinated axons. We propose that the Bötzinger complex expiratory neurones are a source of synaptic inhibition for n.r.a. inspiratory neurones and phrenic motoneurones.


Method for Multiplexed Integration of Synergistic Alleles and Metabolic Pathways in Yeasts via CRISPR-Cas9.
CRISPR-Cas has proven to be a powerful tool for precision genetic engineering in a variety of difficult genetic systems. In the highly tractable yeast S. cerevisiae, CRISPR-Cas can be used to conduct multiple engineering steps in parallel, allowing for engineering of complex metabolic pathways at multiple genomic loci in as little as 1 week. In addition, CRISPR-Cas can be used to consolidate multiple causal alleles into a single strain, bypassing the laborious traditional methods using marked constructs, or mating. These tools compress the engineering timeline sixfold or more, greatly increasing the productivity of the strain engineer.


The dysfunction of CD4(+)CD25(+) regulatory T cells contributes to the abortion of mice caused by Toxoplasma gondii excreted-secreted antigens in early pregnancy.
Toxoplasma gondii is an opportunistic intracellular parasite that is highly prevalent in human and warm-blooded animals throughout the world, leading to potentially severe congenital infections. Although the abortion caused by T. gondii is believed to be dependent on the timing of maternal infection during pregnancy, the mechanism remains unclear. This study was focused on the effects of T. gondii excreted-secreted antigens on pregnant outcomes and CD4(+)CD25(+) Foxp3(+) regulatory T cells at different stages of pregnancy. The results showed that in mice the frequency and suppressive function of CD4(+)CD25(+) regulatory cells were diminished after injection of T. gondii excreted-secreted antigens at early and intermediate stages of pregnancy. The abortion caused by T. gondii excreted-secreted antigens at early pregnancy could be partly prevented by adoptively transferring of CD4(+)CD25(+) cells from the mice injected with T. gondii excreted-secreted antigens at late pregnancy, but not from the mice with the same treatment at early pregnancy. Furthermore, T. gondii excreted-secreted antigens induced apoptosis of CD4(+)CD25(+) regulatory cells of mice in early and intermediate stages of pregnancy by down-regulating their Bcl-2 expressions and Bcl-2/Bax ratio. This study provides new insights into the mechanism that T. gondii infection is the high risk factor for abortion in early pregnancy.


Whole-body retention and distribution of orally administered radiolabelled zerovalent iron nanoparticles in mice.
Zerovalent iron nanoparticles (nZVI) are used for in situ remediation of contaminated ground water, raising the possibility that nZVI particles or their altered residues could contaminate the ground water. Therefore, it is important to study their effects on humans and other organisms in vivo. The objective of this study was to assess the whole-body retention and terminal disposition of neutron-activated radioactive nZVI administered by oral gavage in mice. Radioactivity was primarily eliminated in the faeces within 1 day of administration. However, a small amount of iron-derived radioactivity appeared in the liver after three repeated daily doses. This prototypic study further suggests that neutron activation applied judiciously may be broadly applicable to studies of nanoparticles derived from other biologically abundant metals.


Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis.
To quantify the influence of common cytochrome P450 2C9 (CYP2C9) polymorphisms on warfarin dose requirements. A systematic review and a meta-analysis, calculating the warfarin dose reduction associated with the five most common variant CYP2C9 genotypes. Thirty-nine studies (7,907 patients) were included in the meta-analysis. Compared to the CYP2C9*1/*1 genotype, the CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 required warfarin doses that were 19.6 (95% confidence interval 17.4, 21.9), 33.7 (29.4, 38.1), 36.0 (29.9, 42.0), 56.7 (49.1, 64.3), and 78.1% (72.0, 84.3) lower, respectively. The impact of CYP2C9 genotype tended to be larger in patients without interacting drugs. Previous studies have rarely been powered to determine the quantitative influence of specific CYP2C9 genotypes on warfarin dose requirements. The results from our pooled analysis are likely to be the most accurate to date and the methodology could serve as a model for future pharmacogenetic meta-analyses.


Increased trunk fat along with decreased peripheral fat as an important predictor of hypertriglyceridaemia & hypercholesterolaemia in Indians with HIV infection.
Dyslipidaemia is a major contributor to cardiovascular morbidity, which is increased in HIV. Data on dyslipidaemia in Indians with HIV are scant. This study was undertaken to determine the predictors of dyslipidaemia and lipoatrophy in Indians with HIV infection and their relation with body composition parameters. A total of 382 consecutive patients with HIV infection were screened, of whom 257 clinically stable patients, without any acute comorbidity, having at least one year follow up underwent biochemical and DEXA analysis. The most common dyslipidaemia was hypertriglyceridaemia (47.08%), followed by hypercholesterolaemia [total cholesterol (TC)] (38.91%) and low high-density lipoprotein (HDL) cholesterol (38.52%), in patients having median age 37 (32-42) yr and HIV duration 57 (33-101) months. Patients with at least one dyslipidaemia (78.99%) had significantly higher insulin resistance (IR), per cent body fat, per cent trunk fat (PTF) and trunk limb fat ratio (TLFR). Baseline CD4 count and delta CD4 count (change in CD4 count 6-12 months following ART) had significant inverse correlation with triglycerides and TC. Patients with highest triglycerides and cholesterol quartiles had significantly higher immune reconstitution, metabolic syndrome, IR, trunk fat mass (FM), PTF and TLFR, with comparable total FM. Logistic regression revealed that body mass index, HIV duration and PTF were independent predictors of hypertriglyceridaemia, with only PTF being significant predictor of hypercholesterolaemia. Every unit increase in PTF was associated with 13 and 4.1 per cent increased hypertriglyceridaemia and hypercholesterolaemia. Lipoatrophy was present in 8.57 per cent patients and was a poor predictor of dyslipidaemia. : High occurrence of dyslipidaemia was observed in patients with HIV on anti retroviral therapy. Central adiposity (TFM) was the most important predictor of dyslipidaemia in these patients.


Biological evaluation of non-steroidal anti-inflammatory drugs-cobalt(II) complexes.
Cobalt(II) complexes with the non-steroidal anti-inflammatory drug mefenamic acid in the presence or absence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine) have been synthesized and characterized with physicochemical and spectroscopic techniques. The experimental data suggest that mefenamic acid acts as deprotonated monodentate ligand coordinated to Co(II) ion through a carboxylato oxygen. The crystal structures of tetrakis(methanol)bis-(mefenamato)cobalt(II), 1 and (2,2'-bipyridine)bis(methanol)bis(mefenamato)cobalt(II), 2 have been determined by X-ray crystallography. The EPR spectra of complexes 1 and 2 in frozen solution reveal that they retain their structures. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and bis(methanol)bis(pyridine)bis-(mefenamato)cobalt(II) exhibits the highest binding constant. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The cyclic voltammograms of the complexes recorded in dmso solution and in the presence of CT DNA in 1 : 2 dmso : buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode. Mefenamic acid and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The antioxidant activity of the compounds has been evaluated indicating their high scavenging activity against hydroxyl free radicals and superoxide radicals.


Cardiotoxicity Following Cancer Treatment.
More than half of those born after 1960 will develop cancer during their lifetime. Fortunately, owing to improved diagnosis and treatment, cure rates have risen steadily over the last three decades. With an increased survivorship, more will experience adverse effects of cancer therapeutics on the heart. As the oncologist's focus begins to encompass the issues of cancer survivorship, awareness of the management of cardiac toxicity would be prudent for all physicians looking after patients with cancer.


Identification of Pathologic and Prognostic Genes in Prostate Cancer Based on Database Mining.
Background: Prostate cancer (PCa) is an epithelial malignant tumor that occurs in the urinary system with high incidence and is the second most common cancer among men in the world. Thus, it is important to screen out potential key biomarkers for the pathogenesis and prognosis of PCa. The present study aimed to identify potential biomarkers to reveal the underlying molecular mechanisms. Methods: Differentially expressed genes (DEGs) between PCa tissues and matched normal tissues from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset were screened out by R software. Weighted gene co-expression network analysis was performed primarily to identify statistically significant genes for clinical manifestations. Protein-protein interaction (PPI) network analysis and network screening were performed based on the STRING database in conjunction with Cytoscape software. Hub genes were then screened out by Cytoscape in conjunction with stepwise algorithm and multivariate Cox regression analysis to construct a risk model. Gene expression in different clinical manifestations and survival analysis correlated with the expression of hub genes were performed. Moreover, the protein expression of hub genes was validated by the Human Protein Atlas database. Results: A total of 1,621 DEGs (870 downregulated genes and 751 upregulated genes) were identified from the TCGA-PRAD dataset. Eight prognostic genes [BUB1, KIF2C, CCNA2, CDC20, CCNB2, PBK, RRM2, and CDC45] and four hub genes (BUB1, KIF2C, CDC20, and PBK) potentially correlated with the pathogenesis of PCa were identified. A prognostic model with good predictive power for survival was constructed and was validated by the dataset in GSE21032. The survival analysis demonstrated that the expression of RRM2 was statistically significant to the prognosis of PCa, indicating that RRM2 may potentially play an important role in the PCa progression. Conclusion: The present study implied that RRM2 was associated with prognosis and could be used as a potential therapeutic target for PCa clinical treatment.


UPLC-QqQ/MS-Based Lipidomics Approach To Characterize Lipid Alterations in Inflammatory Macrophages.
In this study, UPLC-QqQ/MS-based lipidomics was applied to profile various lipids from RAW264.7 macrophages treated with different concentrations of lipopolysaccharide (LPS). The degree of inflammation increased with the LPS concentration. To elucidate the altered lipid metabolism of inflammatory macrophages, we targeted to analyze 25 lipid classes from LPS-treated RAW264.7 cells. As a result, 523 lipid species were successfully profiled by using the optimal UPLC and MRM. Statistical data analyses such as PCA, PLS-DA, and HCA differentiated five RAW264.7 cells treated with different concentrations of LPS. VIP plot, heat map, and bar plot also provided lists of up- or down-regulated lipids according to the LPS concentration. From the results, 11 classes of lipids, TG, DG, ChE, PE, PS, PI, PA, LyPC, LyPE, Cer, and dCer, were increased, and three classes, cholesterol, PC, and LyPA, were decreased in an LPS concentration-dependent manner. Furthermore, the treatment of an anti-inflammatory compound recovered the levels of PC, PE, PI, PA, LyPE, LyPA, and Cer from the activated macrophages. Finally, these results demonstrate the correlation between inflammation and lipid metabolism in macrophages. The differentially regulated lipids also have the potential to be used as biomarkers for inflammation.


[Formation and differentiation of the famous coptis regions].
From the Tang Dynasty, Xuanzhou has been considered as the famous area of genuine regional coptis as its production of high-quality. Till the Ming Dynasty, coptis resource in Xuanzhou was exhausted, and weilian, yalian (coptis produced in two districts in Sichuan) and yunlian (coptis produced in Yunnan) became famous-region coptis, three varieties of coptis coming from three districts. During the formation of new famous regions, species variation, geographical environment, historical background, cultivation technique and social economy played a role. For example, xuanlian became famous for doctors in Xinan area loved to use it to a large extent. And cultivation technique was the key point for weilian to become the famous-region herb. Now with the shrinking of planting area, yalian could be hardly considered as famous-region copitis and yunlian has withdrawn from commodity for its high cost and low production.


Long-term exposure to di(2-ethylhexyl) phthalate, diisononyl phthalate, and a mixture of phthalates alters estrous cyclicity and/or impairs gestational index and birth rate in mice.
Phthalates are found in plastic food containers, medical plastics, and personal care products. However, the effects of long-term phthalate exposure on female reproduction are unknown. Thus, this study investigated the effects of long-term, dietary phthalate exposure on estrous cyclicity and fertility in female mice. Adult female CD-1 mice were fed chow containing vehicle control (corn oil) or 0.15-1500 ppm of di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), or a mixture of phthalates (Mix) containing DEHP, DiNP, benzyl butyl phthalate, di-n-butyl phthalate, diisobutyl phthalate, and diethyl phthalate. Measurements of urinary phthalate metabolites confirmed effective delivery of phthalates. Phthalate consumption for 11 months did not affect body weight compared to control. DEHP exposure at 0.15 ppm for 3 and 5 months increased the time that the mice spent in estrus and decreased the time the mice spent in metestrus/diestrus compared to control. DiNP exposure (0.15-1500 ppm) did not significantly affect time in estrus or metestrus/diestrus compared to control. Mix exposure at 0.15 and 1500 ppm for 3 months decreased the time the mice spent in metestrus/diestrus and increased the time the mice spent in estrus compared to control. DEHP (0.15-1500 ppm) or Mix (0.15-1500 ppm) exposure did not affect fertility-related indices compared to control. However, long-term DiNP exposure at 1500 ppm significantly reduced gestational index and birth rate compared to control. These data indicate that chronic dietary exposure to phthalates alters estrous cyclicity, and long-term exposure to DiNP reduces gestational index and birth rate in mice.


Synthesis of green and blue fluorescent ladder-type conjugated imidazolium compounds.
The synthetic route to ladder-type conjugated imidazolium compounds consisting of Suzuki coupling, chlorination, and intramolecular cyclization reactions was developed. The optical properties of materials and theoretical calculations were investigated to demonstrate that methylene- and ethylene-bridged imidazolium compounds show green and blue fluorescence, respectively. The coordination ability of the counter anion had an influence on the solubility and fluorescence quantum yield of the compounds.


Point spread function analysis with saturable and reverse saturable scattering.
Nonlinear plasmonics has attracted a lot of interests due to its wide applications. Recently, we demonstrated saturation and reverse saturation of scattering from a single plasmonic nanoparticle, which exhibits extremely narrow side lobes and central peaks in scattering images [ACS Photonics 1(1), 32 (2014)]. It is desirable to extract the reversed saturated part to further enhance optical resolution. However, such separation is not possible with conventional confocal microscope. Here we combine reverse saturable scattering and saturated excitation (SAX) microscopy. With quantitative analyses of amplitude and phase of SAX signals, unexpectedly high-order nonlinearities are revealed. Our result provides greatly reduced width in point spread function of scattering-based optical microscopy. It will find applications in not only nonlinear material analysis, but also high-resolution biomedical microscopy.


Heat shock protein produced by Helicobacter pylori.
The cells of Helicobacter pylori were suspended in the medium containing 35S-methionine. After a heat shock of the cells at 42 C for 5, 10, and 30 min, the production of proteins was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Out of many proteins produced by the cells, only 66 kDa protein production was dramatically increased by heat treatment. The N-terminal amino acid sequence of 66 kDa protein was quite similar to that of 62 kDa and 54 kDa proteins previously suggested as heat shock protein (HSP) of H. pylori based on the reaction with polyclonal and monoclonal antibodies against HSP 60 family proteins produced by other bacteria. Therefore, it was concluded that H. pylori produces the 66 kDa protein as its major heat shock protein which belongs to HSP 60 family.


[Risk sharing agreements: with orphan drugs?].
To summarize available information on share risk agreements (RSA) with orphan drugs (OD). A bibliographic search was carried out in MEDLINE, EMBASE and INAHTA using 19 keywords and combinations thereof. Papers published as original, narrative and systematic reviews, editorials, commentaries, letters to the Editor, and special articles were included and reviewed. Public or private institutional reports or documents found in Google that contained relevant information were also reviewed. experience gained so far with RSA is scant. No published rigorous evaluations of outcomes of these agreements were found. It seems, however, that OD are suitable for introduction in clinical practice by means of RSA. There are two main types of RSA: financially based, and performance-outcome based. A number of theoretical advantages of SRA are described, as well as hurdles that hinder their design, implementation, and followup, and thus endangering their success. Very few RSA have clearly succeed so far. If thoroughly managed, RSA may reasonably contribute to value-based pricing of OD, improve their pharmacovigilance, knowledge about their comparative effectiveness, and to reducing uncertainty and its consequences on patients, industry, payers and clinicians. There are technical groups that can bring the essential knowledge to manage RSA in Spain. The challenge now is to be able to harmonize their assessments and appraisals, to put in motion the mechanisms needed to overcome those hurdles, and to provide them adequate political and institutional support.


The membrane-active tri-block copolymer pluronic F-68 profoundly rescues rat hippocampal neurons from oxygen-glucose deprivation-induced death through early inhibition of apoptosis.
Pluronic F-68, an 80% hydrophilic member of the Pluronic family of polyethylene-polypropylene-polyethylene tri-block copolymers, protects non-neuronal cells from traumatic injuries and rescues hippocampal neurons from excitotoxic and oxidative insults. F-68 interacts directly with lipid membranes and restores membrane function after direct membrane damage. Here, we demonstrate the efficacy of Pluronic F-68 in rescuing rat hippocampal neurons from apoptosis after oxygen-glucose deprivation (OGD). OGD progressively decreased neuronal survival over 48 h in a severity-dependent manner, the majority of cell death occurring after 12 h after OGD. Administration of F-68 for 48 h after OGD rescued neurons from death in a dose-dependent manner. At its optimal concentration (30 μm), F-68 rescued all neurons that would have died after the first hour after OGD. This level of rescue persisted when F-68 administration was delayed 12 h after OGD. F-68 did not alter electrophysiological parameters controlling excitability, NMDA receptor-activated currents, or NMDA-induced increases in cytosolic calcium concentrations. However, F-68 treatment prevented phosphatidylserine externalization, caspase activation, loss of mitochondrial membrane potential, and BAX translocation to mitochondria, indicating that F-68 alters apoptotic mechanisms early in the intrinsic pathway of apoptosis. The profound neuronal rescue provided by F-68 after OGD and the high level of efficacy with delayed administration indicate that Pluronic copolymers may provide a novel, membrane-targeted approach to rescuing neurons after brain ischemia. The ability of membrane-active agents to block apoptosis suggests that membranes or their lipid components play prominent roles in injury-induced apoptosis.


Psychopathology of first-episode psychosis in HIV-positive persons in comparison to first-episode schizophrenia: a neglected issue.
This study aims to detect different psychopathological dimensions in first-episode psychoses with different underlying causes. We evaluated 22 subjects with first-episode psychosis, who differed in biological variables (HIV-positive versus HIV-negative) and who were compared by using the Structured Clinical Interview for DSM-III-Reviewer, the 18-item Brief Psychiatric Rating Scale (BPRS), the 17-item Hamilton Depression Rating Scale, the 14-item Hamilton Anxiety Rating Scale and the Mini-Mental State Examination. HIV-positive subjects had higher mean scores on the global BPRS and on the paranoid Positive and Negative Syndrome Scale subscale compared with HIV-negative subjects. Conversely, higher prevalence of affective and anxious symptoms was found in the HIV-negative patients in comparison to HIV-positives. HIV-positives had significantly greater attention/concentration impairment than HIV-negative persons. In conclusion, taking into account psychopathological dimensions may help psychiatrists in clinical decision-making regarding the differential diagnosis of psychotic symptoms. The psychopathological pattern of first-episode psychosis in HIV-positive patients may represent an 'elementary model' of acute psychosis characterized by paranoid delusions in the absence of the usual affective symptoms.


Optical control of MAP kinase kinase 6 (MKK6) reveals that it has divergent roles in pro-apoptotic and anti-proliferative signaling.
The selective pressure imposed by extrinsic death signals and stressors adds to the challenge of isolating and interpreting the roles of proteins in stress-activated signaling networks. By expressing a kinase with activating mutations and a caged lysine blocking the active site, we can rapidly switch on catalytic activity with light and monitor the ensuing dynamics. Applying this approach to MAP kinase 6 (MKK6), which activates the p38 subfamily of MAPKs, we found that decaging active MKK6 in fibroblasts is sufficient to trigger apoptosis in a p38-dependent manner. Both in fibroblasts and in a murine melanoma cell line expressing mutant B-Raf, MKK6 activation rapidly and potently inhibited the pro-proliferative extracellular signal-regulated kinase (ERK) pathway; to our surprise, this negative cross-regulation was equally robust when all p38 isoforms were inhibited. These results position MKK6 as a new pleiotropic signal transducer that promotes both pro-apoptotic and anti-proliferative signaling, and they highlight the utility of caged, light-activated kinases for dissecting stress-activated signaling networks.


A double role for a strictly conserved serine: further insights into the dUTPase catalytic mechanism.
Ser72 at the active site of the Escherichia coli dUTPase has been mutated to an alanine, and the properties of the mutant have been investigated. The serine is absolutely conserved among the monomeric and trimeric dUTPases (including the bifunctional dCTP deaminase:dUTPases), and it has been proposed to promote catalysis by balancing negative charge at the oxygen that bridges the alpha- and beta-phosphorus of the substrate. In all reported complexes of dUTPases with the substrate analogue alpha,beta-imido-dUTP.Mg, the serine beta-OH is indeed hydrogen bonded to the alpha,beta-bridging nitrogen of the analogue. However, in the complex of the Asp90 --> Asn mutant dUTPase with the true substrate dUTP.Mg, the serine beta-OH points in the opposite direction and may form a hydrogen bond to Asn84 at the bottom of the pyrimidine pocket. Here we show that the replacement of the beta-OH by hydrogen reduces k cat from 5.8 to 0.008 s (-1) but also k -1 , the rate of substrate dissociation, from 6.2 to 0.1 s (-1) ( K M = 6 x 10 (-9) M). We conclude that the serine beta-OH exercises both ground state (GS) destabilization and transition state (TS) stabilization, effects not usually linked to a single residue. With experimental support, we argue that the beta-OH destabilizes the GS by imposing conformational constraints on the enzyme and that formation of the TS depends on a rotation of the serine side chain that not only relieves the constraints but brings the beta-OH into a position where it can electrostatically stabilize the TS. This rotation would also allow the beta-OH to promote both deamination and hydrolysis in the bifunctional deaminases. We find that the E. coli dUTPase does not catalyze the hydrolysis of the alpha,beta-imido-dUTP.Mg, suggesting that the analogue provides the hydrogen in the bond to the serine beta-OH.


Quantification the effect of ageing on characteristics of the photoplethysmogram using an optimized windkessel model.
With increasing age, some changes appeared in specifications of vessels which including dimensions and elasticity in theirs. The changes in parameters such as resistance, inertance and compliance vessels appear and eventually changes in the environmental pulse releases are in circulation. These changes clearly appear in specification of photoplethysmogram particularly in the size and position signals second peak is observed. The aim of study was to Circulatory system modeling using windkessel electrical model for evalution blood flow and Its matching with the photoplethysmogram's signal for investigate the reasons for changes of Characteristics of the Photoplethysmogram. The first purpose of this paper is to examine the age-related parameters in the Photoplethysmogram's signal and finally the diagnosis of cardiovascular disease using the model and photoplethysmogram's signal. In this study we followed some of these effects to the circulatory system by using the windkessel electrical model. The algorithm in this project appeared by optimization with the matrix coefficients of state space windkessel electrical model. Optimize of the coefficients matching with the output of the model and the photoplethysmogram's signal. Photoplethysmogram's signals from 50 healthy subjects with the age range of 20 to 50 years, shows that outputs the model and photoplethysmogram's signal in terms of error rate and cross-correlation algorithm in a fully automate, was consistent. Wavelength of the Photoplethysmogram's signals were 950 nm and The sampling rate was set at 50 Hz. Simulation results show that aging reduces the signal amplitude and delay of the second peak occurs. These changes were seen as reduce the rate of compliance and increase the rate of resistance and inertance windkessel electrical model of circulation. The high accuracy of the results led to being able to identify the age range and some cardiac arrhythmias in individuals. All the simulations were done in matlab software environment.


Synthesis of new C-6 alkyliden penicillin derivatives as beta-lactamase inhibitors.
New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C beta-lactamases are reported. Compounds 3a-c, 7a-c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli) or P-99 (a Class C enzyme, from E. cloacae), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A beta-lactamase) was observed for compound 3a when used in combination with amoxicillin.


Partial antagonism of tiletamine-zolazepam anesthesia in cheetah.
This study evaluated partial antagonism of tiletamine-zolazepam (TZ) anesthesia in cheetahs (Acinonyx jubatus) and differences between two benzodiazepine antagonists, flumazenil and sarmazenil, in this species. Four cheetahs were anesthetized three times at an interval of 14 days with an average intramuscular dose of 4.2 mg/kg TZ. In trials 2 and 3 flumazenil at 0.031 mg/kg and sarmazenil at 0.1 mg/kg, respectively, were applied intramuscularly 30 min after initial TZ injection. There was a highly significant difference between the duration of TZ anesthesia with and without antagonist. Use of the antagonists significantly shortened duration and recovery and eliminated excitatory behavior during the recovery phase. No significant differences could be determined between the two antagonists. We recommend the use of sarmazenil and flumazenil to antagonize TZ anesthesia in cheetahs.


Detection and distribution of aromatase in hypothalamus of the male rat.
Conversion of androgen to estrogen in the rat brain is catalyzed by aromatase. An in vitro assay for aromatase activity, which quantitates the production of 3H2O during the conversion of 1 beta-3H-androstenedione to estrone, was developed and validated in the present study. The distribution of aromatase activity in discrete hypothalamic nuclei was also explored. Individual hypothalamic nuclei were microdissected from 200-micron frozen sections. Tissues from 3 animals were pooled and assayed for aromatase activity. It was found that the rate of aromatase activity was linear with time up to 1 hour, and with protein concentrations up to 900 micrograms/ml tissue homogenate. A maximal rate was obtained with a substrate concentration of 0.3 microM. The aromatase activity was heterogeneously distributed within the rat brain. The greatest amount of aromatase activity was found in the preoptic area. The suprachiasmatic nucleus also contained a high level of aromatase activity. The aromatase activities in the anterior hypothalamus, ventromedial nucleus, arcuate nucleus and dorsomedial nucleus were less than half that found in the preoptic area.


Mutations in Ig V(D)J genes are distributed asymmetrically and independently of the position of V(D)J.
To study the distribution of somatic mutations in the DNA flanking the 5' side of rearranged Ig V genes, the 5' region of 14 to 21 mutant forms of three different V(D)J were sequenced. These were compared with a fourth V(D)J for which the flanking sequences of 10 mutant forms are known. The leader intron of these four V genes varied from 82 to 365 nucleotides in length. Analysis of the data showed that: 1) The mutation frequency is distributed asymmetrically with respect to the V(D)J exon with skewing in the 3' direction. 2) The distribution of mutations 5' of V(D)J seems to be related to the size of the leader intron. The significance of these findings for models of hypermutation is discussed.


Randomized trial of general hospital and residential alternative care for patients with severe and persistent mental illness.
Severe and persistent mental illnesses are often lifelong and characterized by intermittent exacerbations requiring hospitalization. Providing needed care within budgetary constraints to this largely publicly subsidized population requires technologies that reduce costly inpatient episodes. The authors report a prospective randomized trial to test the clinical effectiveness of a model of acute residential alternative treatment for patients with persistent mental illness requiring hospital-level care. Patients enrolled in the Montgomery County, Md., public mental health system who experienced an illness exacerbation and were willing to accept voluntary treatment were randomly assigned to the acute psychiatric ward of a general hospital or a community residential alternative. There were no psychopathology-based exclusion criteria. Treatment episode symptom improvement, satisfaction, discharge status, and 6-month pre- and postepisode acute care utilization, psychosocial functioning, and patient satisfaction were assessed. Of 185 patients, 119 (64%) were successfully placed at their assigned treatment site. Case mix data indicated that patients treated in the hospital (N = 50) and the alternative (N = 69) were comparably ill. Treatment episode symptom reduction and patient satisfaction were comparable for the two settings. Nine (13%) of 69 patients randomly assigned to the alternative required transfer to a hospital unit; two (4%) of 50 patients randomly assigned to the hospital could not be stabilized and required transfer to another facility. Psychosocial functioning, satisfaction, and acute care use in the 6 months following admission were comparable for patients treated in the two settings and did not differ significantly from functioning before the acute episode. Hospitalization is a frequent and high-cost consequence of severe mental illness. For patients who do not require intensive general medical intervention and are willing to accept voluntary treatment, the alternative program model studied provides outcomes comparable to those of hospital care.


Keeping up with the clinical advances: depression.
Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.


Ischemic Monomelic Neuropathy: The Case for Reintroducing a Little-Known Term.
Ischemic monomelic neuropathy (IMN) is a little-known, painful axonal neuropathy, secondary to vascular occlusion or steal phenomenon. It typically occurs after vascular bypass, hemodialysis fistulization, or diabetic microvascular disease in the absence of significant clinical features of ischemia. There is limited literature to assist in the characterization and diagnosis of this condition. We describe three patients with IMN with no surgical or peripheral vascular disease history who exhibited spontaneous, persistent foot pain, edema numbness, and weakness with denervation on needle electromyogram in a distal lower leg peripheral nerve distribution. Occlusive disease was found in all patients on angiogram, requiring vascular bypass surgery.


Use of on-farm milk progesterone information to predict fertility outcomes in dairy cows subjected to timed artificial insemination.
The objectives of this study were to evaluate the use of a qualitative on-farm milk progesterone test to predict non-pregnancy in dairy cows. Lactating Jersey cows (n = 752) were subjected to the 5-d Cosynch-72 protocol for timed artificial insemination (AI; d -8 GnRH, d -3 and -2 PGF2α, d 0 GnRH and timed AI). Milk was sampled on d -3, 0, 7, and 28 relative to timed AI, and progesterone concentrations were assessed using a lateral flow immunochromatographic test. Samples were classified into 3 groups indicative of high (hP4; test line not visible or lighter than reference), intermediate (iP4; test line similar to reference), and low (lP4; test line darker than reference) progesterone concentrations. Blood was sampled from a subset of cows (n = 50) on d -3, 0, 7, and 28 relative to timed AI, and plasma progesterone concentrations were determined by RIA. Cows were observed daily for signs of estrus based on removal of tail paint. Pregnancy was diagnosed by ultrasonography on d 34 and 62 after AI. Plasma progesterone concentrations across all time points were greater for hP4 (3.13 ± 0.20 ng/mL) followed by iP4 (1.12 ± 0.27 ng/mL) and lP4 (0.38 ± 0.23 ng/mL). Cows in lP4 on d -3 had lesser pregnancy per AI (P/AI) compared with iP4 and hP4 (17.4, 38.3, and 37.2%, respectively). For measurements performed on the day of AI (d 0), lP4 cows had greater P/AI compared with hP4 and iP4 (34.8, 0.0, and 15.6%, respectively), and the risk of pregnancy loss tended to be greater for iP4 compared with lP4. Cows in lP4 on d 7 after AI had lesser P/AI than those in iP4 and hP4 (12.0, 34.0, and 37.7%, respectively). Cows classified as lP4 on d 28 had the least P/AI on d 62 followed by iP4 and then hP4 (0.8, 9.2, and 59.4%, respectively) and were at the greatest risk for pregnancy loss (lP4 = 74.6%, iP4 = 8.4%, hP4 = 7.1%). Sensitivity and specificity to predict non-pregnancy on d 62 were 0.86 and 0.32 (d -3), 0.95 and 0.15 (d 0), 0.93 and 0.23 (d 7), and 0.99 and 0.53 (d 28), respectively. On-farm milk progesterone profiling using a lateral flow immunochromatographic test was able to identify cows without functional corpus luteum and to predict fertility outcomes following timed AI.


Diet-derived and topically applied tocotrienols accumulate in skin and protect the tissue against ultraviolet light-induced oxidative stress.
To evaluate the tissue-specific distribution of lipophilic antioxidants including various vitamin E forms (tocotrienols and tocopherols) and oxidised and reduced coenzyme Q (ubiquinone and ubiquinol), a sensitive procedure was developed using gradient HPLC with both electrochemical- and UV-detection. A unique distribution of these antioxidants in hairless mouse tissues was found, suggesting that their distribution may be dependent upon selective mechanisms for maintaining antioxidant defences. Ubiquinol-9 was highest in kidney (81 ± 29 nmol/g) and in liver (42 ± 16 nmol/g), while the highest ubiquinone-9 concentrations were found in kidney (301 ± 123 nmol/g) and heart (244 ± 22 nmol/g). Liver contained nearly identical amounts of each ubiquinol-9 (41 ± 16 nmol/g) and ubiquinone-9 (46 ± 18 nmol/g). These mice were fed a commercial chow diet containing α-tocopherol (30 ± 6 mg/kg diet), γ-tocopherol (10 ± 1), a-tocotrienol (3.1 ± 0.7) and γ-tocotrienol (7.4 ± 1.7). Of the vitamin E forms, brain contained only α-tocopherol (5.4 ± 0.1 nmol/g; 99.8%) and no detectable tocotrienols. In other tissues, the α-tocopherol content was higher (20 nmol/g), while each of the other forms represented about 1 % of the total ( γ-tocopherol 0.2 to 0.4 nmol/g, a-tocotrienol 0.1, γ-tocotrienol 0.2). Remarkably, skin contained nearly 15% tocotrienols and 1% γ-tocopherol. The unique distribution of tocotrienols in skin suggested that they might have superior protection against environment stressors. Therefore, the penetration of topically applied vitamin E (tocotrienol enriched fraction of palm oil, TRF) and vitamin E homologue concentrations before and after exposure of skin to UV-light was assessed. 20 μL of 5% TRF in polyethylene glycol-400 (PEG) was applied to 2 skin sites and 20 μL PEG to 2 other sites. After 2 h, the skin was washed and half of the sites exposed to UV-irradiation using a solar simulator (2.8 mW/cm2 for 29 min). The vitamin E content of hairless mouse skin was: α-tocopherol 9.0 ± 1.0 nmol/g skin, γ-tocopherol 0.44 ± 0.03, a-tocotrienol 0.48 ± 0.07, γ-tocotrienol 0.92 ± 0.03. Topical TRF enriched skin vitamin E: α-tocopherol 201 ± 70 nmol/g skin, γ-tocopherol 37 ± 15, a-tocotrienol 53 ± 25, and γ-tocotrienol 50 ± 24. After UV-irradiation, concentrations of all vitamin E homologues from both treatment areas decreased significantly (p<0.01), but the TRF-treated skin contained vitamin E at concentrations 7- to 30-fold higher than control values. These findings provide provocative clues on the uptake and regulation of tissue lipophilic antioxidants. The unique distribution of these antioxidant substances suggests their distribution may be dependent upon tissue-specific selective mechanisms.


Vestibular sympathetic nervous system in guinea pig.
The vestibular sympathetic fibers were examined in 20 guinea pigs by immunohistochemical demonstration of tyrosine hydroxylase and dopamine beta-hydroxylase. The vestibular sympathetics originated in the ipsilateral superior cervical ganglion and entered the internal auditory meatus along the labyrinthine artery. At the Schwann-glial border, some of the sympathetic fibers left the artery and went into both the superior and inferior divisions of the vestibular nerves and made a loose mesh-work among the Scarpa's ganglion cells while other fibers followed the labyrinthine artery. Both types of fibers entered the crista ampularis and otoconial macula after several bifurcations in the cribrosa and terminated either near the capillaries beneath the sensory epithelial or among the vestibular nerve fibers. These fibers traveled freely in the vestibular labyrinth and were not restricted to following blood vessels or vestibular nerve fibers. Some sympathetic fibers made direct contact with the vestibular efferent fibers or the vestibular afferent fibers at the node of Ranvier. Sympathetic fibers were not observed in the sensory epithelia and semicircular canals and were rarely found in the vicinity of the dark cells: however, they were found to be distributed in the endolymphatic sac.


Inhibitory Effects of Silver Nanoparticles on Removal of Organic Pollutants and Sulfate in an Anaerobic Biological Wastewater Treatment Process.
The increasing use of silver nanoparticles (AgNPs) in commercial products and industrial processes raises issues regarding the toxicity of sludge biomass in biological wastewater treatment plants, due to potential antimicrobial properties. This study investigated the effects of AgNPs on removal of organic pollutants and sulfate in an anaerobic biological sulfate reduction process. At AgNPs concentrations of up to 10 mg/L, no significant inhibition of sulfate and COD removal was observed. However, at higher concentrations (50-200 mg/L) sulfate and COD removal efficiencies were significantly decreased to 51.8% and 33.6%, respectively. Sulfate and COD reduction followed first-order kinetics at AgNPs concentrations of up to 10 mg/L and second-order kinetics at AgNPs concentrations of 50-200 mg/L. Lactate dehydrogenase release profiles showed increases in cytotoxicity at AgNPs concentrations greater than 50 mg/L suggesting cell membrane disruption. Analysis of extracellular polymeric substances (EPS) from sulfidogenic sludge biomass and of Fourier transform infrared (FT-IR) spectra showed a decrease in concentrations of carbohydrates, proteins, humic substances, and lipids in the presence of AgNPs. Moreover, the interaction of AgNPs with sludge biomass and the damage caused to cell walls were confirmed through scanning electron microscopy with energy dispersive X-ray spectroscopy.


Polypoid nodule scar after gastric endoscopic submucosal dissection: results from a multicenter study.
Background and study aims A post-endoscopic submucosal dissection (ESD) scar is expected to look homogeneous, however, some patients develop benign polypoid nodule scar (PNS). Incidence of PNS is unknown, yet these scars have direct clinical implications because they may render evaluation of post-ESD neoplastic recurrence difficult. Therefore, we reviewed the clinical experience of 5 ESD referral centers and evaluated their PNS incidence and clinical management. Patients and methods This was a retrospective multicenter case series enrolling patients that underwent R0, curative gastric ESD from 2003 to 2015 in 5 academic centers. PNS was defined as ESD site nodularity with hyperplastic or regenerative tissue histology. Results A total of 2275 patients underwent gastric ESD with endoscopy control and 28 patients (18 men/10 women) developed PNS for overall incidence of 1.2 %. Incidence of PNS ranged from 0.15 % to 11.4 % between centers. All patients that developed PNS had primary neoplastic lesions located in the distal stomach. Considering only lesions situated in the antrum (n = 912), incidence of PNS was 3.1 %. After mean follow-up of 43 months (range 6 - 192), no malignant recurrence in the PNS has been identified. In five patients (17.8 %) PNS disappeared after a mean of 18 months. Conclusion PNS occurs exclusively after ESD in the distal stomach in approximately 3.1 % of patients. Although PNS appearance can be concerning, no malignant recurrence was observed after curative R0 resection. Therefore, PNS should be viewed as a benign alteration that does not require any type of intervention, other than endoscopic surveillance.


External hernia of the supravesical fossa: Rare or simply misidentified?
External hernias of the supravesical fossa are considered rare, perhaps wrongly. Highlighting clinical and anatomical features could be useful for correct, preoperative diagnosis, thus avoiding the risk of complications such as incarceration. The study aims to demonstrate that the incidence of external protrusions of the supravesical fossa is higher that supposed. Probably, being mistaken for direct hernias, these hernia types are misidentified and not included in current classifications. This issue deserves attention due to the elevated risk of incarceration related to its distinctive structure. 249 consecutive open anterior inguinal hernia procedures were analyzed. Hernias were categorized according to the Nyhus classification. A subgroup of direct hernias involved true hernias of the supravesical fossa. Multiple ipsilateral, as well as combined hernias having a multi-component structure, were also considered. 13 true hernias of the supravesical fossa and 19 multiple ipsilateral or combined hernias composed of direct and/or indirect hernia, together with one hernia of the supravesical fossa were identified. 4 true hernias of the supravesical fossa presented signs of incarceration. In three other combined protrusions, the herniated component of the supravesical fossa also showed incarceration of the visceral content. Hernias of the supravesical fossa would appear to be more frequent than imagined. These protrusions show a diverticular shape and the base is often tightened by the stiffer medial umbilical fold. This explains the apparently higher tendency to incarceration that distinguishes this hernia type. Preoperative signs of inguinal pain and irreducibility are pathognomonic for correct diagnosis. In these cases, surgical treatment in the short term is recommended.


[Oedipus tragedy].
Taking into account Paul Ricoeur's theories, two possible hermeneutical positions in front of Oedipus' drama are considered. One is to view it as a fatalistic destiny, bred into the darkest incestuous trends any infant is fighting against, and leading to unavoidable stigmata of everlasting nature. The other is to conceive it as the response to present naked truth, resulting from deep reflexion in order to attain real consciousness of oneself. The former is the "backwards conception", having its own limitations, in its very being buried into the past. The latter, having its projections forward, centers on anguish and anxiety aroused by consciousness of oneself, seeked by the alert responsible mind, able to afford reality and truth with all their thorough implications. The author's existential position embraces the secon conception which had been already exposed by Sophocles in Oedipus in Colonna. The dialectics are set between seeing and knowing. Tiresias is blind, but he can see, because he can afford truth, and its consequence, guilt. Oedipus must fight to attain the possibility of knowing, and must go into the ordeal of losing his eyes, as the only way to reach true self realization, through facing truth and bearing anguish.


Synthesis of Aza-acyclic Nucleoside Libraries of Purine, Pyrimidine, and 1,2,4-Triazole.
Under the aegis of the Pilot Scale Library Program of the NIH Roadmap Initiative, a new library of propan-1-amine containing aza acyclic nucleosides was designed and prepared, and we now report a diverse set of 157 purine, pyrimidine, and 1,2,4-triazole- N-acetamide analogues. These new nucleoside analogues were prepared in a parallel high throughput solution-phase format. A set of diverse amines was reacted with several nucleobase N-propaldehydes utilizing reductive amination with sodium triacetoxyborohydride coupling to produce a small and diverse aza acyclic nucleoside library. All reactions were performed using 24-well reaction blocks and an automatic reagent-dispensing platform under an inert atmosphere. Final targets were purified on an automated system using solid sample loading prepacked cartridges and prepacked silica gel columns. All compounds were characterized by NMR and HRMS and were analyzed for purity by HPLC prior to submission to the Molecular Libraries Small Molecule Repository (MLSMR). Initial screening through the Molecular Libraries Probe Production Centers Network (MLPCN) demonstrated diverse and interesting biological activities.


Effective adsorption and enhanced removal of organophosphorus pesticides from aqueous solution by Zr-based MOFs of UiO-67.
Though many efforts have been devoted to the adsorptive removal of hazardous materials of organophosphorus pesticides (OPs), it is still highly desirable to develop novel adsorbents with high adsorption capacities. In the current work, the removal of two representative OPs, glyphosate (GP) and glufosinate (GF), was investigated by the exceptionally stable Zr-based MOFs of UiO-67. The abundant Zr-OH groups, resulting from the missing-linker induced terminal hydroxyl groups and the inherent bridging ones in Zr-O clusters of UiO-67 particles, served as natural anchorages for efficient GP and GF capture in relation with their high affinity toward phosphoric groups in OPs. The correlation between the most significant parameters such as contact time, OPs concentration, adsorbent dose, pH, as well as ionic strength with the adsorption capacities was optimized, and the effects of these parameters on the removal efficiency of GP and GF from the polluted aqueous solution were investigated. The adsorption of GP on UiO-67 was faster than that of GF, and a pseudo-second-order rate equation effectively described the uptake kinetics. The Langmuir model exhibited a better fit to adsorption isotherm than the Freundlich model. Thanks to the strong affinity and adequate pore size, the adsorption capacities in UiO-67 approached as high as 3.18 mmol (537 mg) g(-1) for GP and 1.98 mmol (360 mg) g(-1) for GF, which were much higher than those of many other reported adsorbents. The excellent adsorption characteristics of the current adsorbents toward OPs were preserved in a wide pH window and high concentration of the background electrolytes. These prefigured the promising potentials of UiO-67 as novel adsorbent for the efficient removal of OPs from aqueous solution.


[MS registry in Germany--design and first results of the pilot phase].
In the summer of 2001, a nationwide epidemiological multiple sclerosis (MS) register was initiated under the auspices of the German MS Society (DMSG). This project aimed at collecting epidemiological data on the number of patients with MS, course of the disease, and their social situation in Germany. During the 2-year pilot phase, five MS centers with various regional differences and treatment methods participated, leading to a representative selection of patients. In December 2003, standardised data sets of 3,458 MS patients were available for evaluation. After examining the quality of the data, 3,223 sets remained for further analysis. The demographics were similar to those obtained from other epidemiological studies: 72% of the patients were female, mean age was 42.9+/-11.2 years, mean disease duration 12.6+/-8.7 years, and 64% suffered from the relapsing-remitting form of the disease. The median EDSS was 3.0, and 69% of patients had an EDSS </=4.0. The great effect of this disorder was underscored by the fact that one third of the patients had prematurely retired due to MS. After successful completion of the pilot phase, the MS register will provide reliable data and thus serve as an important tool to improve the overall situation of MS patients in Germany.


Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes.
The authors previously demonstrated that newborn llama (NBLL) express high levels of α1 adrenergic receptors, which provide a potent vasoconstriction response when compared with newborn sheep (NBSH) gestated at sea level. However, data regarding the impact of chronic gestational hypobaric hypoxia on α-adrenergic vasoconstriction in the neonatal life has not been studied. We evaluated if gestation under chronic hypobaric hypoxia modifies α1-adrenergic vasoconstrictor function in NBLL and NBSH. We compared the vasoconstrictor response induced by potassium and α-adrenergic stimuli in isolated small femoral arteries of NBLL and NBSH gestated at high altitude (HA; 3,600 m) or low altitude (LA; 580 m). The maximal contraction (R MAX) and potency (EC50) to potassium, noradrenaline (NA), and phenylephrine (PHE) were larger in HA-NBLL than LA-NBLL. R MAX to potassium, NA, and PHE were lower in HA-NBSH when compared with LA-NBSH and potency results were similar. Competitive blockade with prazosin showed that RNLL LA/HA have a similar pA2. In contrast, NBSH had increased pA2 values in HA when compared with LA. Finally, small femoral arteries denudated or treated with LNAME in LA and HA lacked NO or endothelium participation in response to PHE stimulation. In contrast, NBSH displayed that denudation or blockade with LNAME support NO or endothelium participation in response to PHE activation. In conclusion, HA chronic hypoxia enhances α1 adrenergic receptor activity in small femoral arteries in NBLL to a higher degree than NBSH, implying a higher vasoconstriction function.


Identification of an essential pseudoknot in the putative downstream internal ribosome entry site in giardiavirus transcript.
Enhanced translation of giardiavirus-luciferase chimeric mRNA in Giardia lamblia requires the initial 264-nt viral capsid coding region as a putative internal ribosomal entry site (IRES). Essential structural elements in this site include (1) a downstream box (DB) complementary to the anti-DB at the 3' end of 16S-like rRNA, (2) stem-loops I, II, III, and IVA, and (3) a pentanucleotide 5'-UCUCC-3' immediately downstream from stem loop IVA. A search for the structural role of the pentanucleotide suggested that it may form a pseudoknot with another pentanucleotide 5'-GGAGA-3' in loop II. Alteration of the two pentanucleotides by site-directed mutagenesis resulted in a drastic reduction in translation of the transcript. But the loss was recovered by compensatory changes in the two sequences, suggesting Watson-Crick base pairings between them. Results from in vitro enzymatic and chemical structural probing supported the presence of such a pseudoknot 143 nt downstream from the initiation codon. Minor repositioning of this codon led invariably to a complete loss of translation, suggesting that the initiation site is confined within a rigid position defined by all the structural elements in the IRES including the pseudoknot. This is the first pseudoknot of its kind shown to play an important role in a downstream IRES of a viral transcript. The finding is particularly interesting because it could reflect a unique feature of translation initiation in Giardia, which is known to have exceedingly short (1-6 nt) 5' untranslated regions in its mRNAs.