Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development.
The netrins are laminin-like axon guidance molecules that are conserved among Caenorhabditis elegans, Drosophila, and vertebrates and that have chemoattractive and chemorepellant properties. To study the possible actions of this gene family in the developing and adult mammalian nervous systems, we have cloned a partial cDNA which corresponds to a region conserved among chick netrin-1, netrin-2, and unc-6 and studied its expression and that of a netrin receptor, dcc, the deleted in colorectal cancer gene, in the developing and adult rat CNS. The localization of cells expressing netrin or dcc suggests that these genes, in addition to their actions in defining the ventral midline, may act in controlling retinal ganglion cell axon guidance in the optic nerve, cell migration in the developing cerebellum and olfactory epithelium, and development and maintenance of connections to the substantia nigra and corpus striatum.


Neurodevelopmental changes across adolescence in viewing and labeling dynamic peer emotions.
Adolescence is a sensitive period of social-affective development, characterized by biological, neurological, and social changes. The field currently conceptualizes these changes in terms of an imbalance between systems supporting reactivity and regulation, specifically nonlinear changes in reactivity networks and linear changes in regulatory networks. Previous research suggests that the labeling or reappraisal of emotion increases activity in lateral prefrontal cortex (LPFC), and decreases activity in amygdala relative to passive viewing of affective stimuli. However, past work in this area has relied heavily on paradigms using static, adult faces, as well as explicit regulation. In the current study, we assessed cross-sectional trends in neural responses to viewing and labeling dynamic peer emotional expressions in adolescent girls 10-23 years old. Our dynamic adolescent stimuli set reliably and robustly recruited key brain regions involved in emotion reactivity (medial orbital frontal cortex/ventral medial prefrontal cortex; MOFC/vMPFC, bilateral amygdala) and regulation (bilateral dorsal and ventral LPFC). However, contrary to the age-trends predicted by the dominant models in studies of risk/reward, the LPFC showed a nonlinear age trend across adolescence to labeling dynamic peer faces, whereas the MOFC/vMPFC showed a linear decrease with age to viewing dynamic peer faces. There were no significant age trends observed in the amygdala.


Whole-cell recording from honeybee olfactory receptor neurons: ionic currents, membrane excitability and odourant response in developing workerbee and drone.
Whole-cell recording techniques were used to characterize ionic membrane currents and odourant responses in honeybee olfactory receptor neurons (ORNs) in primary cell culture. ORNs of workerbee (female) and drone (male) were isolated at an early stage of development before sensory axons connect to their target in the antennal lobe. The results collectively indicate that honeybee ORNs have electrical properties similar, but not necessarily identical to, those currently envisaged for ORNs of other species. Under voltage clamp at least four ionic currents could be distinguished. Inward currents were made of a fast transient, tetrodotoxin-sensitive sodium current. In some ORNs a cadmium-sensitive calcium current was detected. ORNs showed heterogeneity in their outward currents: either outward currents were made of a delayed rectifier type potassium current, which was partially blocked by tetraethyl ammonium or quinidine, or were composed of a delayed rectifier type and a transient calcium-dependent potassium current, which was cadmium-sensitive and abolished by removal of external calcium. The proportion of each of the two outward currents, however, was different within the ORNs of the two sexes suggesting a gender-specific functional heterogeneity. ORNs showed heterogeneity in action potential firing properties: depolarizing current steps elicited either one action potential or, as in most of the cells, it led to repetitive spiking. Action potentials were tetrodotoxin-sensitive suggesting they are carried by sodium. Odourant stimulation with different mixtures and pure substances evoked depolarizing receptor potentials with superimposed action potentials when spike threshold was reached. In summary, honeybee ORNs are remarkably mature at early stages in their development.


A Case of Prefemoral Fat Pad Impingement Syndrome Caused by Hyperplastic Fat Pad.
We report a rare case of prefemoral fat pad impingement syndrome that was caused by a hyperplasia of the normal suprapatellar fat pad. Pain and catching were observed in the proximal-lateral patellofemoral joint, and MRI imaging confirmed a hyperplasic mass in the same area. Although conservative treatment showed no signs of improvement, symptoms improved after an arthroscopic excision of the mass. Prefemoral fat pad impingement syndrome is related to patellar motion and should be considered as one of the underlying causes of anterior knee pain (AKP). Surgeons should recognize that a small hyperplasia composed of normal adipose tissue can cause AKP.


[Successful chronic daily administration of oral etoposide for a case of adult T cell leukemia].
A 54-year-old woman with leucocytosis and skin lesion was hospitalized and diagnosed as chronic type adult T cell leukemia (ATL) in August 1989. Since her ATL cell count and LDH level increased after hospitalization, oral administration of etoposide was started at a dose of 100 mg/day for seven days. The oral administration of etoposide induced another chronic state of ATL. After 10 months without medication, she was readmitted because of an acute ATL crisis. After daily administration of etoposide at a dose of 50 mg/day, the white blood cell count and serum LDH level decreased to the normal range, and abnormal lymphocytes of peripheral blood disappeared. The low-dose daily administration of etoposide at a dose of 25 approximately 50 mg/day could be maintained over six months. No severe side effects except for alopecia and mild myelosuppression were noted during the treatment. Chronic daily administration of oral etoposide is one candidate for the treatment of ATL in an outpatient clinic.


Applying community-based participatory research to better understand and improve kinship care practices: insights from the Democratic Republic of Congo, Nigeria, and Sierra Leone.
While the principles behind community-based participatory research are firmly established, the process of taking community-based participatory research with children and youth to scale and integrating it into the programming of non-governmental organizations has been scarcely documented. This article reflects on the experiences of Save the Children in implementing a multicountry community-based participatory research program to increase understanding of kinship care in the Democratic Republic of Congo, Nigeria, and Sierra Leone. The article discusses challenges faced and lessons learned and highlights how the research process enabled action and advocacy initiatives at different levels-leading to an increase in support and policy attention for children living in kinship care.


Basics of breastfeeding. Part VI. Some breastfeeding problems and solutions.
Management of several potential physical problems is presented: sore breasts, engorgement, leaking, breast infections, nipple damage, and thrush. Then problem-solving for the separated mother and breastfeeding infant, genetic abnormalities, and slow weight gain are discussed. The final sections deal with maternal medication and environmental contaminants in breast milk.


The management of gas-filled eyes in the emergency department.
Background. Intraocular gas bubbles are commonly used in retinal surgery. There are specific management guidelines that need to be followed to ensure surgical success, and there are also unique ophthalmic and systemic complications that can occur in such patients. Objective. To educate emergency department personnel about important issues in the management of patients who have a gas-filled eye following retinal surgery. Case Report. A patient with a gas-filled eye developed several complications including pain, severe vision loss, high-grade atrioventricular (AV) block, and pneumocephalus. Conclusion. Awareness of potential problems that may arise in patients with gas-filled eyes who present to the emergency department may help minimize morbidity for such patients.


SEASTAR: systematic evaluation of alternative transcription start sites in RNA.
Alternative first exons diversify the transcriptomes of eukaryotes by producing variants of the 5' Untranslated Regions (5'UTRs) and N-terminal coding sequences. Accurate transcriptome-wide detection of alternative first exons typically requires specialized experimental approaches that are designed to identify the 5' ends of transcripts. We developed a computational pipeline SEASTAR that identifies first exons from RNA-seq data alone then quantifies and compares alternative first exon usage across multiple biological conditions. The exons inferred by SEASTAR coincide with transcription start sites identified directly by CAGE experiments and bear epigenetic hallmarks of active promoters. To determine if differential usage of alternative first exons can yield insights into the mechanism controlling gene expression, we applied SEASTAR to an RNA-seq dataset that tracked the reprogramming of mouse fibroblasts into induced pluripotent stem cells. We observed dynamic temporal changes in the usage of alternative first exons, along with correlated changes in transcription factor expression. Using a combined sequence motif and gene set enrichment analysis we identified N-Myc as a regulator of alternative first exon usage in the pluripotent state. Our results demonstrate that SEASTAR can leverage the available RNA-seq data to gain insights into the control of gene expression and alternative transcript variation in eukaryotic transcriptomes.


Population genetic structure of Aedes (Stegomyia) aegypti (L.) at a micro-spatial scale in Thailand: implications for a dengue suppression strategy.
The genetic population structure of Aedes (Stegomyia) aegypti (L.), the main vector of dengue virus, is being investigated in areas where a novel dengue suppression program is to be implemented. The aim of the program is to release and establish mosquito populations with impaired virus transmission capabilities. To model effects of the release and devise protocols for its implementation, information about the genetic structure of populations at a range of spatial scales is required. This study investigates a potential release site in the Hua Sam Rong Subdistrict of Plaeng Yao District, Chachoengsao Province, in eastern Thailand which comprises a complex of five villages within a 10 km radius. Aedes aegypti resting indoors was sampled at four different times of year from houses within the five villages. Genetic markers were used to screen the mosquitoes: two Exon Primed Intron Crossing (EPIC) markers and five microsatellite markers. The raw allele size was determined using several statistical software packages to analyze the population structure of the mosquito. Estimates of effective population size for each village were low, but there was no evidence of genetic isolation by geographic distance. The presence of temporary genetic structure is possibly caused by genetic drift due to large contributions of adults from a few breeding containers. This suggests that the introduction of mosquitoes into an area needs to proceed through multiple releases and targeting of sites where mosquitoes are emerging in large numbers.


Understanding secondary injury.
Secondary injury is a term applied to the destructive and self-propagating biological changes in cells and tissues that lead to their dysfunction or death over hours to weeks after the initial insult (the "primary injury"). In most contexts, the initial injury is usually mechanical. The more destructive phase of secondary injury is, however, more responsible for cell death and functional deficits. This subject is described and reviewed differently in the literature. To biomedical researchers, systemic and tissue-level changes such as hemorrhage, edema, and ischemia usually define this subject. To cell and molecular biologists, "secondary injury" refers to a series of predominately molecular events and an increasingly restricted set of aberrant biochemical pathways and products. These biochemical and ionic changes are seen to lead to death of the initially compromised cells and "healthy" cells nearby through necrosis or apoptosis. This latter process is called "bystander damage." These viewpoints have largely dominated the recent literature, especially in studies of the central nervous system (CNS), often without attempts to place the molecular events in the context of progressive systemic and tissue-level changes. Here we provide a more comprehensive and inclusive discussion of this topic.


Stroke patients, what to do and what to avoid.
In Italy (130,000 new strokes in the general population per year) ischemic stroke is the third cause of death, after cardiovascular disease and neoplastic disease with a prevalence of 6.5%. Different physicians are involved in the emergent evaluation and treatment of the acute ischemic stroke. As other acute events, the initial evaluation must be addressed to assess the patient's airway and breath-ing and cardiocirculatory conditions. The neurological examination must not be exhaustive and it should be completed in 5-10 minutes and a particular attention should be given to clinical findings leading to the suspect of an intracranial hemorrhages. A plain CT scan of the brain is the most important initial diagnostic study. Emergency therapy must be mainly directed to the correction of hypovolemia, hypoxia and the treatment of severe hypertension, hypoglycemia, intracranial hypertension and seizures. The goal is to achieve and to maintain an adequate cerebral perfusion by lowering the intracranial pressure (treating the cerebral oedema) and by increasing the mean arterial pressure, with an appropriate volemic expansion and/or with inotropic or vasopressor drugs. The thrombolytic therapy with intravenous recombinant tessutal plasminogen activator (r-TPA) when not specifically contraindicated, is recommended within 3 hours of onset of ischemic stroke. The benefit of intravenous r-TPA for acute ischemic stroke beyond 3 hours from the onset has never been proved.


Synthesis and characterization of a catechol metabolite of glutethimide (Doriden) in human urine.
A metabolite of glutethimide, 2-ethyl-2-(3,4-dihydroxyphenyl)-glutarimide, previously identified in enzymatically hydrolyzed human urine of overdosed victims was prepared synthetically and its chemical and spectral data compared to the proposed material. Results of these comparisons confirm the presence of a catechol metabolite of glutethimide in the urine of patients severely intoxicated by the parent drug.


Effects of Climate and Climate Change on Vectors and Vector-Borne Diseases: Ticks Are Different.
There has been considerable debate as to whether global risk from vector-borne diseases will be impacted by climate change. This has focussed on important mosquito-borne diseases that are transmitted by the vectors from infected to uninfected humans. However, this debate has mostly ignored the biological diversity of vectors and vector-borne diseases. Here, we review how climate and climate change may impact those most divergent of arthropod disease vector groups: multivoltine insects and hard-bodied (ixodid) ticks. We contrast features of the life cycles and behaviour of these arthropods, and how weather, climate, and climate change may have very different impacts on the spatiotemporal occurrence and abundance of vectors, and the pathogens they transmit.


Full-wave electromagnetic modes and hybridization in nanoparticle dimers.
The plasmon hybridization theory is based on a quasi-electrostatic approximation of the Maxwell's equations. It does not take into account magnetic interactions, retardation effects, and radiation losses. Magnetic interactions play a dominant role in the scattering from dielectric nanoparticles. The retardation effects play a fundamental role in the coupling of the modes with the incident radiation and in determining their radiative strength; their exclusion may lead to erroneous predictions of the excited modes and of the scattered power spectra. Radiation losses may lead to a significant broadening of the scattering resonances. We propose a hybridization theory for non-Hermitian composite systems based on the full-Maxwell equations that, overcoming all the limitations of the plasmon hybridization theory, unlocks the description of dielectric dimers. As an example, we decompose the scattered field from silicon and silver dimers, under different excitation conditions and gap-sizes, in terms of dimer modes, pinpointing the hybridizing isolated-sphere modes behind them.


Application of (1)H DOSY for Facile Measurement of Polymer Molecular Weights.
To address the practical issues of polymer molecular weight determination, the first accurate polymer weight-average molecular weight determination method in diverse living/controlled polymerization via DOSY (diffusion-ordered NMR spectroscopy) is reported. Based on the linear correlation between the logarithm of diffusion coefficient (log D) and the molecular weights (log Mw), external calibration curves were created to give predictions of molecular weights of narrowly-dispersed polymers. This method was successfully applied to atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT), and ring-opening metathesis polymerization (ROMP), with weight-average molecular weights given by this method closely correlated to those obtained from GPC measurement.


SATB1 Mediates Long-Range Chromatin Interactions: A Dual Regulator of Anti-Apoptotic BCL2 and Pro-Apoptotic NOXA Genes.
Aberrant expression of special AT-rich binding protein 1 (SATB1), a global genomic organizer, has been associated with various cancers, which raises the question of how higher-order chromatin structure contributes to carcinogenesis. Disruption of apoptosis is one of the hallmarks of cancer. We previously demonstrated that SATB1 mediated specific long-range chromosomal interactions between the mbr enhancer located within 3'-UTR of the BCL2 gene and the promoter to regulate BCL2 expression during early apoptosis. In the present study, we used chromosome conformation capture (3C) assays and molecular analyses to further investigate the function of the SATB1-mediated higher-order chromatin structure in co-regulation of the anti-apoptotic BCL2 gene and the pro-apoptotic NOXA gene located 3.4Mb downstream on Chromosome 18. We demonstrated that the mbr enhancer spatially juxtaposed the promoters of BCL2 and NOXA genes through SATB1-mediated chromatin-loop in Jurkat cells. Decreased SATB1 levels switched the mbr-BCL2 loop to mbr-NOXA loop, and thus changed expression of these two genes. The SATB1-mediated dynamic switch of the chromatin loop structures was essential for the cooperative expression of the BCL2 and NOXA genes in apoptosis. Notably, the role of SATB1 was specific, since inhibition of SATB1 degradation by caspase-6 inhibitor or caspase-6-resistant SATB1 mutant reversed expression of BCL-2 and NOXA in response to apoptotic stimulation. This study reveals the critical role of SATB1-organized higher-order chromatin structure in regulating the dynamic equilibrium of apoptosis-controlling genes with antagonistic functions and suggests that aberrant SATB1 expression might contribute to cancer development by disrupting the co-regulated genes in apoptosis pathways.


Towards Personalized Antithrombotic Treatments: Focus on P2Y12 Inhibitors and Direct Oral Anticoagulants.
Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y12 inhibitors and direct oral anticoagulants. The review will additionally focus on the existing PBPK and POPPK models for these two categories of drugs. Lastly, we address potential scenarios for their implementation in clinics, along with the main limitations and challenges.


Ultrasmall microlens array based on vertically aligned carbon nanofibers.
An ultrasmall tunable microlens with a diameter of 1.5 μm is fabricated using nematic liquid crystals (electrically tunable medium) and vertically aligned carbon nanofibers (CNFs, electrodes). Individual CNFs are grown at the center of circular dielectric regions. This allows the CNFs to produce a more Gaussian electric field profile and hence more uniformity in lens array switching.


SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy.
Heart failure (HF) is a major global cause of morbidity and mortality. This study aimed to elucidate the role of secreted protein acidic and rich in cysteine-related modular calcium-binding protein 2 (SMOC2) in HF development and its underlying mechanism. Using a rat HF model, SMOC2 expression was examined and then knocked down via transfection to assess its impact on cardiac function and damage. The study also evaluated the effects of SMOC2 knockdown on autophagy-related molecules and the transforming growth factor beta 1 (TGF-β1)/SMAD family member 3 (Smad3) signaling pathway. Intraperitoneal injection of the TGF-β agonist (SRI-011381) into the HF rat model was performed to explore the SMOC2-TGF-β1/Smad3 pathway relationship. SMOC2 expression was elevated in HF rats, while its downregulation improved cardiac function and damage. SMOC2 knockdown reversed alterations in the LC3-II/I ratio, Beclin-1, and p62 levels in HF rats. Through transmission electron microscope, we observed that SMOC2 knockdown restored autophagosome levels. Furthermore, SMOC2 downregulation inhibited the TGF-β1/Smad3 signaling pathway, which was counteracted by SRI-011381. In conclusion, SMOC2 knockdown inhibits HF development by modulating TGF-β1/Smad3 signaling-mediated autophagy, suggesting its potential as a therapeutic target for HF.


Genetics internet resources for allied health professionals.
As the field of genetics continues to grow at a rapid rate, so does the application to patient care delivered by allied health professionals. At the same time, it has been shown that allied health professionals often lack confidence in their knowledge of genetics as a result of limited education about genetics. The current study was an interdisciplinary effort devised to explore Internet resources for learning about human genetics as they apply to the allied health professions. A rating scale was developed to assess the format and the content of the websites and to assess other websites that may be identified in the future. Four of the seven websites that received the highest mean ratings are discussed in more detail. Two of the websites address basic concepts in genetics, and the other two provide resources for current topics and research in genetics as it pertains to patient care.


Applying systems-level spectral imaging and analysis to reveal the organelle interactome.
The organization of the eukaryotic cell into discrete membrane-bound organelles allows for the separation of incompatible biochemical processes, but the activities of these organelles must be coordinated. For example, lipid metabolism is distributed between the endoplasmic reticulum for lipid synthesis, lipid droplets for storage and transport, mitochondria and peroxisomes for β-oxidation, and lysosomes for lipid hydrolysis and recycling. It is increasingly recognized that organelle contacts have a vital role in diverse cellular functions. However, the spatial and temporal organization of organelles within the cell remains poorly characterized, as fluorescence imaging approaches are limited in the number of different labels that can be distinguished in a single image. Here we present a systems-level analysis of the organelle interactome using a multispectral image acquisition method that overcomes the challenge of spectral overlap in the fluorescent protein palette. We used confocal and lattice light sheet instrumentation and an imaging informatics pipeline of five steps to achieve mapping of organelle numbers, volumes, speeds, positions and dynamic inter-organelle contacts in live cells from a monkey fibroblast cell line. We describe the frequency and locality of two-, three-, four- and five-way interactions among six different membrane-bound organelles (endoplasmic reticulum, Golgi, lysosome, peroxisome, mitochondria and lipid droplet) and show how these relationships change over time. We demonstrate that each organelle has a characteristic distribution and dispersion pattern in three-dimensional space and that there is a reproducible pattern of contacts among the six organelles, that is affected by microtubule and cell nutrient status. These live-cell confocal and lattice light sheet spectral imaging approaches are applicable to any cell system expressing multiple fluorescent probes, whether in normal conditions or when cells are exposed to disturbances such as drugs, pathogens or stress. This methodology thus offers a powerful descriptive tool and can be used to develop hypotheses about cellular organization and dynamics.


Effect of selenite treatment on ultrastructural changes in experimental diabetic rat bones.
It is known that streptozotocin (STZ)-induced diabetes causes functional and structural alterations in some types of tissue and organ. A number of methods have been used to characterize the properties of diabetic tissues and their diagnosis. Selenium compounds, playing an antioxidant role, can restore some altered metabolic parameters and diminished functions in experimental diabetes. The first aim of the present study was to investigate the effects of STZ-induced diabetes on structural properties of rat long bones. Electron and light microscopic observations showed deleterious alterations in the structure of the diabetic rat long bones, the most prominent effect being in osteocytic cells. Fine cytoplasmic processes of the osteocytes seemed to be shortened, and diabetes affected the normal cytoplasmic processes in a negative manner. The second aim of the present study was to evaluate the effects of sodium selenite treatment for 4 wk on the long bones of the diabetic rats. Electron and light microscopic observations demonstrated that sodium selenite treatment prevented the STZ-induced structural as well as ultrastructural changes in the long bones of the rats. In conclusion, this study first showed that a period of 5-wk diabetes was enough to cause some important and degenerative changes in the structure of the bone tissues, and, second, it demonstrated that sodium selenite treatment of the diabetic rats could normalize these alterations.


[The clinicomethodological aspects of the etiology of coronary artery disease].
Having analyzed more than 150 original papers dedicated to the study of cardial pathology risk factors from clinical (specific) and methodological (philosophic) points of view, the authors put forward a hypothesis of the etiology of diseases (by the example of coronary artery disease) as a "critical mass" of these risk factors. Reasoning from it, the authors suggest the ways of using this statement by large quantitative evaluation of clinical data, and application of mathematic modeling to the diagnostics and prognostics of cardial pathology in each particular case.


MicroRNA-33-3p Regulates Vein Endothelial Cell Apoptosis in Selenium-Deficient Broilers by Targeting E4F1.
Selenium (Se) is a type of nutrient element. The tissues of organisms can have pathological damage, including apoptosis, due to Se deficiency. Apoptosis is an important cell process and plays a key role in vascular disease and Se-deficient symptoms. In this study, the Se-deficient broiler model was duplicated, miR-33-3p in the vein was overexpressed in response to Se-deficiency, and miR-33-3p target gene E4F transcription factor 1 (E4F1) expression was also confirmed. We utilized ectopic miR-33-3p expression to validate its function for apoptosis. The results showed that miR-33-3p-targeted E4F1 are involved in the glucose-regulated protein 78- (GRP78-) induced endoplasmic reticulum stress (ERS) apoptosis pathway. We presumed that Se deficiency might trigger apoptosis via downregulating miR-33-3p. Interestingly, the miR-33-3p inhibitor and VER-155008 (GRP78 inhibitor) partly hindered the apoptosis caused by Se deficiency. Thus, the above information provides a new avenue toward understanding the mechanism of Se deficiency and reveals a novel apoptotic injury regulation model in vascular disease.


Carboranylporphyrins for boron neutron capture therapy of cancer.
A major challenge for cancer treatment is the preferential and irreversible killing of tumor cells and minimal damage of normal tissues, both in the site of the malignancy and in the body. The agents used in boron neutron capture therapy (BNCT) are supposed to have the following advantages over many conventional chemotherapeutics: 1) when irradiated with thermal neutrons, an unstable isotope (11)B is formed whose rapid decay yields local and a thermal effect; 2) because the free path of the released particles is close to the cell diameter, the tissues outside the tumor should gain less damage; 3) local radioactivity and heat should be harmful for cells that, in the course of their natural history, acquired the determinants of altered response to many toxic stimuli. However, a higher specificity of damage would be achieved if the drugs accumulate mostly in cancer cells rather than in non-malignant counterparts. Therefore, optimization of agents for BNCT presumes the design of chemicals with improved accumulation/ retention in cancer cells. In particular, carboranyl-substituted porphyrins, the stable conjugates of macrocyclic porphyrins with complex boron-containing polyhedra, are considered good candidates for BNCT due to their uptake by cancer cells and high boron content. Importantly, the proposed mechanisms of pharmacological effects of carboranylporphyrins make these compounds potentially appropriate for elimination of pleiotropically resistant tumor cells.


Idiopathic polypoidal choroidal vasculopathy (IPCV) presenting with simultaneous choroidal neovascular membrane (CNM).
Idiopathic polypoidal choroidal vasculopathy (IPCV), a rare retinal condition initially described in 1982, is characterized by retinal pigment epithelial (RPE) detachments associated with choroidal polypoidals. Although it is recognized as a unique entity, many consider it a peculiar representation of choroidal neovascular membrane (CNM), commonly associated with age-related macular degeneration (ARMD). We report a case of IPCV with simultaneous presentation of CNM. Dilated examination and fluorescein angiography (FA) revealed RPE detachments associated with choroidal polypoidals. FA also revealed a lacy hyperfluorescent vascular lesion. Ocular manifestations, differential diagnoses, and treatment options are discussed, with emphasis on similarities and differences between IPCV and CNM. It is imperative to consider IPCV in the differential diagnosis of RPE detachments, including those associated with CNM. Careful funduscopic evaluation, FA, and/or indocyanine green videoangiography analysis helps confirm the diagnosis.


Robotic valvuloplastic esophagogastrostomy using double flap technique following proximal gastrectomy: technical aspects and short-term outcomes.
Valvuloplastic esophagogastrostomy by double flap technique (VEG-DFT) is a promising procedure to prevent reflux after proximal gastrectomy (PG), and is achieved by the burial of the abdominal esophagus into the gastric submucosa; however, laparoscopic VEG-DFT is technically demanding due to complicated suturing and ligation maneuvers. The present study was designed to determine the feasibility and safety of robotic VEG-DFT. After robotic PG, seromuscular flaps were extracorporeally created at the anterior wall of the remnant stomach through a small umbilical incision. Then, using a robot, the posterior wall of the esophagus was fixed to the cranial end of the mucosal window, and layer-to-layer sutures were placed between the anterior aspects of esophagus and the remnant stomach. Finally, the anastomosis was covered by seromuscular flaps. Short-term outcomes of 12 consecutive patients who underwent VEG-DFT between January 2014 and December 2015 were assessed. Operations were successfully completed using robotic assistance in all patients. Median operative, surgeon console, and anastomosis times were 406 (324-613 min), 267 (214-483), and 104 (76-186) min, respectively, and median estimated blood loss was 31 (5-130) ml. The first six cases were required to reach a learning plateau. Both mortality and morbidity rates within 30 days after surgery were 0%. Postoperative hospital stay was 10 (9-30) days. No postoperative reflux esophagitis was observed, whereas anastomotic stenosis, which required endoscopic balloon dilation, developed in three patients (25%) in postoperative month 2. There was a significant association between the total number of stitches used for VEG-DFT and anastomotic stenosis (p < 0.001). Robotic assistance may be useful for VEG-DFT with a short learning curve. Attention is required to prevent postoperative anastomotic stenosis possibly caused by an excessive number of stitches for esophagogastrostomy.


Study on the Phenotypic Diversity of 33 Ornamental Xanthoceras sorbifolium Cultivars.
Xanthoceras sorbifolium, belonging to the family Sapindaceae, has a beautiful tree shape, elegant leaves, large and many brightly colored flowers, and a long flowering duration. This plant is widely applied in gardens. In this study, 33 cultivars of Xanthoceras sorbifolium were selected from the perspective of ornamental properties, and their phenotypic traits, such as leaves, flowers, and branches, were measured and analyzed, and their phenotypic diversity was comprehensively evaluated using principal component analysis, in order to investigate the phenotypic diversity characteristics of Xanthoceras sorbifolium. The results showed that the genetic diversity index of the qualitative traits varied from 0.14 to 1.50, and that of quantitative traits varied from 1.76 to 2.05. The quantitative traits were more diverse than the qualitative traits. The coefficient of variation of the qualitative traits ranged from 16.90% to 57.96%, and that of quantitative traits ranged from 12.92% to 32.87%. The phenotypic traits of the tested cultivars had relatively rich variation. Furthermore, the level of the phenotypic diversity index of Xanthoceras sorbifolium was not consistent with the level of coefficient of variation, indicating large variation and uneven distribution of variation. Through principal component analysis, 17 quantitative characters were extracted into five principal components, with a cumulative contribution rate of 79.82%, representing the primary information on the quantitative characters of ornamental Xanthoceras sorbifolium cultivars. The F value of the 33 samples ranged from -2.79 to 1.93, and the comprehensive scores of seven cultivars were greater than 1, indicating that these cultivars had rich phenotypic diversity. Therefore, the screening, development, and utilization of fine germplasm resources of Xanthoceras sorbifolium should focus on these cultivars. The 33 cultivars were subsequently clustered into five categories through systematic clustering. The cluster analysis provided references for breeding ornamental Xanthoceras sorbifolium cultivars with different utilization values, such as large white flowers, small red flowers, large red flowers, large orange flowers, and double-petaled flowers.


Real-time polymerase chain reaction monitoring of epithelial cell adhesion molecule-induced T-cell stimulation in patients with lung cancer and healthy individuals using LightCycler technology.
The epithelial cell adhesion molecule is strongly expressed in carcinomas of diverse histologic origin and has attracted attention as a target for immunotherapy. We have previously demonstrated that the epithelial cell adhesion molecule-derived human leukocyte antigen-A*0201-restricted nonamer peptide ILYENNVIT(184-192) can be efficiently recognized by peptide-specific cytotoxic T lymphocytes (CTL). Using this peptide (Ep-2) we could readily expand precursor CTL and demonstrate their cytotoxicity by standard chromium-release assay. We now sought to evaluate the immune reactivity of Ep-2-specific CTL expanded from the peripheral blood mononuclear cells by real-time quantitative polymerase chain reaction assay (LightCycler system) measuring the change in interferon-gamma mRNA levels upon stimulation. Cytotoxic T lymphocyte response against the Ep-2 peptide in two patients with epithelial cell adhesion molecule-expressing lung cancer and three healthy donors was compared with the chromium-release assay. In vitro expanded epithelial cell adhesion molecule-specific CTL precursors that exhibited significantly elevated interferon-gamma mRNA levels also lysed Ep-2 peptide-pulsed target cells. Our study indicates that quantitative polymerase chain reaction may be a supplement to chromium-release assay for monitoring in vitro expanded CTL precursor reactivity.


Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial.
Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.


Identification and characterization of a cyclosporin binding cyclophilin from Staphylococcus aureus Newman.
Cyclophilins, a class of peptidyl-prolyl cis-trans isomerase (PPIase) enzymes, are inhibited by cyclosporin A (CsA), an immunosuppressive drug. Staphylococcus aureus Newman, a pathogenic bacterium, carries a gene for encoding a putative cyclophilin (SaCyp). SaCyp shows significant homology with other cyclophilins at the sequence level. A three-dimensional model structure of SaCyp harbors a binding site for CsA. To verify whether SaCyp possesses both the PPIase activity and the CsA binding ability, we have purified and investigated a recombinant SaCyp (rCyp) using various in vitro tools. Our RNase T1 refolding assay indicates that rCyp has a substantial extent of PPIase activity. rCyp that exists as a monomer in the aqueous solution is truly a cyclophilin as its catalytic activity specifically shows sensitivity to CsA. rCyp appears to bind CsA with a reasonably high affinity. Additional investigations reveal that binding of CsA to rCyp alters its structure and shape to some extent. Both rCyp and rCyp-CsA are unfolded via the formation of at least one intermediate in the presence of guanidine hydrochloride. Unfolding study also indicates that there is substantial extent of thermodynamic stabilization of rCyp in the presence of CsA as well. The data suggest that rCyp may be exploited to screen the new antimicrobial agents in the future.


Development of the chondrocranium in the suckermouth armored catfish Ancistrus cf. triradiatus (Loricariidae, Siluriformes).
The chondrocranium of the suckermouth armored catfish Ancistrus cf. triradiatus was studied. Its development is described based on specimens ranging from small prehatching stages with no cartilage visible, to larger posthatching stages where the chondrocranium is reducing. Cleared and stained specimens, as well as serial sections, revealed a cartilaginous skeleton with many features common for Siluriformes, yet several aspects of A. cf. triradiatus are not seen as such in other catfishes, or to a lesser extent. The skull is platybasic, but the acrochordal cartilage is very small and variably present, leaving the notochord protruding into the hypophyseal fenestra in the earlier stages. The ethmoid region is slender, with a rudimentary solum nasi. A lateral commissure and myodomes are present. The larger posterior myodome is roofed by a prootic bridge. The maxillary barbel is supported by a conspicuous cartilaginous rod from early prehatching stages. The ceratohyal has four prominent lateral processes. Infrapharyngobranchials I-II do not develop. During ontogeny, the skull lengthens, with an elongated ethmoid, pointing ventrally, and a long and bar-shaped hyosymplectic-pterygoquadrate plate. Meckel's cartilages point medially instead of rostrally.


Glucose and pyruvate metabolism in preimplantation blastocysts from normal and diabetic rats.
Glucose metabolism was analysed in day-5 rat blastocysts incubated in the presence of [5-3H]-, [6-14C]- or [U-14C]glucose. Glycolysis, quantified by 3H2O recovery rate, was the main pathway of glucose utilization by fresh (11.5 +/- 0.36 pmol per embryo h-1) or cultured (24 h) blastocysts (20.4 +/- 0.6 pmol per embryo h-1). Glucose consumption rate was almost saturated at a medium glucose concentration of 0.28 mmol l-1 (Km: 0.17 mmol l-1; Vmax: 23 pmol per embryo h-1). A further 10% increase in glucose utilization was obtained with a tenfold higher glucose concentration (3 mmol l-1). Phloretin completely abolished the rapid component of glucose utilization kinetics, suggesting the existence of a Na(+)-independent glucose transport system. Less than 1% of [6-14C]glucose consumed by cultured blastocysts was oxidized through the Krebs cycle. [1-14C]pyruvate, however, was oxidized at a rate of 2 pmol per embryo h-1 by fresh blastocysts. The pentose-phosphate pathway accounted for about 2% of glucose utilization. One to two per cent of the total glucose metabolized in 24 h was retained in macromolecules. Insulin had no effect on glucose uptake, utilization, incorporation and turnover, or on pyruvate oxidation. Blastocysts from diabetic mothers utilized glucose at a rate similar to that of normal blastocysts. These results show that glucose is actively taken up by rat blastocysts and utilized mainly through the Embden-Meyerhof pathway, which is rapidly saturated at low glucose concentrations. Retention of glucose-derived products in macromolecules, although relatively small, may modulate the effect of high glucose concentrations on embryo growth.(ABSTRACT TRUNCATED AT 250 WORDS)


Bilateral primary ovarian non-Hodgkin's lymphoma and fertility preservation: 5-year follow-up.
Primary ovarian non-Hodgkin's lymphoma is a very rare disease. Median age at diagnosis is estimated at 42 years, something that leads to fertility preservation issues in many cases. This was a case report study, presenting a rare case of bilateral primary ovarian non-Hodgkin's lymphoma. A 38-year old nulliparous woman, underwent exploratory laparotomy because of bilateral ovarian masses. Left salpingooophorectomy, partial omentectomy and excision of an ovarian mass of the right ovary was performed. Great effort in order to preserve healthy ovarian tissue of the right ovary as well as the right fallopian tube was given, due to fertility reasons. Final histology showed bilateral diffuse large B-cell primary ovarian non-Hodgkin's lymphoma. Postoperatively, the patient underwent chemotherapy with the CHOP regimen in combination with rituximab. Five years after initial diagnosis, the patient remains well with normal menstrual cycle, without evidence of recurrence. Fertility preservation issues in some cases of rare gynecological malignancies could be managed via minimally invasive oncological approach.


Affairs of the Heart: Innovation in Cardiovascular Research and Development.
Cardiovascular disease represents the single largest contributor to morbidity and mortality, yet the flow of therapeutic innovation is lagging. Globally, academia, industry, and regulatory agencies must work together to address this gap, and ensure new disruptive therapeutic modalities to address growing needs of patients and society.


A dual-core double emulsion platform for osmolarity-controlled microreactor triggered by coalescence of encapsulated droplets.
Droplet-based microfluidics has provided a means to generate multi-core double emulsions, which are versatile platforms for microreactors in materials science, synthetic biology, and chemical engineering. To provide new opportunities for double emulsion platforms, here, we report a glass capillary microfluidic approach to first fabricate osmolarity-responsive Water-in-Oil-in-Water (W/O/W) double emulsion containing two different inner droplets/cores and to then trigger the coalescence between the encapsulated droplets precisely. To achieve this, we independently control the swelling speed and size of each droplet in the dual-core double emulsion by controlling the osmotic pressure between the inner droplets and the collection solutions. When the inner two droplets in one W/O/W double emulsion swell to the same size and reach the instability of the oil film interface between the inner droplets, core-coalescence happens and this coalescence process can be controlled precisely. This microfluidic methodology enables the generation of highly monodisperse dual-core double emulsions and the osmolarity-controlled swelling behavior provides new stimuli to trigger the coalescence between the encapsulated droplets. Such swelling-caused core-coalescence behavior in dual-core double emulsion establishes a novel microreactor for nanoliter-scale reactions, which can protect reaction materials and products from being contaminated or released.


Amplified protein sensing using deep purple fluorophores on homogeneous Au substrates.
We report here the first observation of appreciable enhancement of fluorescence induced by large Au colloids. Au monolayers with Au colloids of 40 nm, 59 nm, and 81 nm in radii, were formed on silane modified glass surfaces, respectively. The nanoparticle densities were varied by varying the deposition times and documented by scanning electron microscopy. Two types of samples were prepared, with large inter-particle distance and hence little or no inter-particle coupling and small inter-particle distance with inter-particle coupling. The fluorescence enhancement was examined by using a self assembled monolayer of the fluorophore-protein conjugate with Deep Purple as a fluorophore and Bovine Serum Albumin as protein (DP-BSA). The data show the over 15 fold enhancement under optimized conditions and reveal strong variations with both inter-particle distance and particle size. Nanostructures of appropriate size with optimized inter-particle distance thus prepared can produce promising substrates for decent fluorescence enhancement. We demonstrated that the Au colloid monolayers on glass surfaces are promising substrates for fluorescence enhancement with outstanding macroscopic homogeneity. This important feature will pave the way for the application of our substrates in biotechnology and life sciences such as imaging and sensing of biomolecules in proteomics.


Extraction of uraemic toxins with activated carbon restores the functional properties of albumin.
Previous work has demonstrated that a partial normalization of the conformation of albumin from uraemic plasma and a substantial restoration of its binding abilities can be achieved by extraction with activated charcoal. This is best achieved at pH 3, but exposure of whole plasma to this low pH leads to the loss of some essential components. The melting curves and ligand-binding abilities of uraemic albumin have been investigated after extraction with a new generation of activated carbon at three pH values (7.2, 3.0 and 5.08). Albumin isolated from uraemic plasma had a characteristically increased melting temperature because of bound ligands. Extraction of uraemic plasma at pH 7.2, 5.08 and 3.0 induced low-temperature shifts of albumin thermo-adsorption maximum T1 of 1.4, 3.8, 2.4 degrees C and T2 of 0.8, 3.9 and 1.2 degrees C, respectively. Flow microcalorimetry data demonstrated a decrease in the ability of uraemic albumin to bind octanoate, phenol red, salicylic acid, warfarin and diazepam. Purification of uraemic plasma at pH 5.08 completely restored the binding affinity of albumin for all the marker ligands. Highly efficient activated carbons, with clinically feasible acidification of plasma, can remove strongly albumin-bound uraemic toxins. Investigation of the melting curve of the isolated albumin is a new biophysical way to monitor both its molecular condition and the extent of removal of protein-bound toxins by dialysis. The melting curve provides new qualitative and quantitative information about albumin in an analogous way to an electrocardiogram and the heart.


Radiation capture and conversion efficiencies of Miscanthus sacchariflorus, M. sinensis and their naturally occurring hybrid M. × giganteus.
Miscanthus is a rhizomatous C4 grass of great interest as a biofuel crop because it has the potential to produce high yields over a wide geographical area with low agricultural inputs on marginal land less suitable for food production. At the moment, a clonal interspecific hybrid Miscanthus × giganteus is the most widely cultivated and studied in Europe and the United States, but breeding programmes are developing newer more productive varieties. Here, we quantified the physiological processes relating to whole season yield in a replicated plot trial in Wales, UK. Light capture and conversion efficiency were parameterized for four carefully selected genotypes (M. sinensis, M. sacchariflorus and Miscanthus × giganteus). Differences in the canopy architecture in mature stands as measured by the extinction coefficient (k) were small (0.55-0.65). Sensitivity analysis on a mathematical model of Miscanthus was performed to quantify the accumulative intercepted photosynthetically active radiation (iPAR) in the growing season using (i) k, (ii) variation in the thermal responses of leaf expansion rate, (iii) base temperature for degree days and (iv) date start of canopy expansion. A 10% increase in k or leaf area per degree day both had a minimal effect on iPAR (3%). Decreasing base temperature from 10 to 9 °C gave an 8% increase in iPAR. If the starting date for canopy expansion was the same as shoot emergence date, then the iPAR increases by 12.5%. In M. × giganteus, the whole season above ground and total (including below ground) radiation-use efficiency (RUE) ranged from 45% to 37% higher than the noninterspecific hybrid genotypes. The greater yields in the interspecific hybrid M. × giganteus are explained by the higher RUE and not by differences in iPAR or partitioning effects. Studying the mechanisms underlying this complex trait could have wide benefits for both fuel and food production.


Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha.
A strong correlation between the TT(-889) genotype over CC(-889) of the interleukin-1 alpha (IL-1 alpha) transcription regulatory region and age of Alzheimer's disease onset has recently been reported. To determine the functional effects of the genetic variants on plasma protein levels, we cloned the promoter region and determined its activity. The TT genotype significantly increased the transcriptional activity of the IL-1 alpha gene with respect to the CC genotype. A slight increase of the IL-1 alpha mRNA and protein levels was also observed in the plasma.


Patients Presenting with a Hot, Swollen Joint: A Single-Centre Retrospective Analysis.
A hot, swollen joint is a common clinical condition encountered in the ED and elective orthopaedic and rheumatology clinics. These patients can be difficult to manage and properly treat. The aim of this study was to report a single centre retrospective analysis of patients presenting to our institution for a hot, swollen joint over a three-month period. The study included patients presenting with a hot, swollen joint to ED or electively to clinics. The synovial fluid was aspirated and sent for microbiological and cytological investigation. P value was set to < 0.001. 36 patients (22 M, 14 F) with a mean age of 72.8 ± 17.4 years met our criteria. 20 cases (55.6 %) involved the knee joint, the wrist in 10 cases (27.8%), the elbow in 3 cases (8.3%) and the shoulder in 3 cases (8.3%). Of the 36 synovial fluid samples collected, only 7 (19.4%) reported evidence of infection. On cytological examination of the synovial fluid, 21 (58.3%) reported presence of calcium pyrophosphates crystals (Pseudogout), 4 (11.1 %) reported presence of uric acid crystals (Gout) and 11 (30.5%) reported absence of crystals. We found a significant correlation between age and the diagnosis of pseudogout and between previous antibiotic treatment and ED presentation. Our study sheds light on the high incidence of crystal-related pathologies. In order to improve our management of this common condition and enhance our understanding of the clinical diagnosis in certain patient population, further high-profile clinical studies are needed.


Epstein-Barr Virus Gene BARF1 Expression is Regulated by the Epithelial Differentiation Factor ΔNp63α in Undifferentiated Nasopharyngeal Carcinoma.
Epstein-Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral latency BARF1 is exclusively expressed in epithelial tumors such as nasopharyngeal (NPC) and gastric carcinoma (GC) but not in lymphomas, indicating that activation of the BARF1 promoter is cell type specific. Undifferentiated NPC is characterized by high expression of ΔNp63 isoforms of the epithelial differentiation marker p63, a member of the p53 family of transcription factors. Transcription factor binding site analysis indicated potential p53 family binding sites within the BARF1 promoter region. This study investigated ability of various p53 family members to transactivate the BARF1 promoter. Using BARF1 promoter luciferase reporter constructs we demonstrate that only p63 isoform ΔNp63α is capable of transactivating the BARF1 promoter, but not the TAp63 isoforms, p53 or p73. Direct promoter binding of ΔNp63α was confirmed by Chromatin Immune Precipitation (ChIP) analysis. Deletion mutants of the BARF1 promoter revealed multiple ΔNp63 response elements to be responsible for BARF1 promoter transactivation. However, ΔNp63α alone was not sufficient to induce BARF1 in tumor cells harboring full EBV genomes, indicating that additional cofactors might be required for full BARF1 regulation. In conclusion, in EBV positive NPC and GC, BARF1 expression might be induced by the epithelial differentiation marker ΔNp63α, explaining BARF1 expression in the absence of lytic reactivation.


Dental caries experience and barriers to care in young children with disabilities in Ireland.
Dental caries among preschool children remains a significant dental public health problem. In Ireland, there are no national data available regarding dental caries levels in preschool children. Furthermore, the number of young children with disabilities and their dental caries levels remains unknown. The aim of the present study was to measure the dental caries levels in a sample of preschool children with disabilities. A team of trained and calibrated dentists examined a sample of all 0- to 6-year old preschool children with disabilities in two health service administrative areas under standardized conditions. Dental caries was recorded using WHO criteria. Of a total of 422 participants, 337 datasets were included in the study. Of these 337 examined children, approximately 75.1% had a cognitive disability and 12.9% had a noncognitive disability. In 12% of the children, a diagnosis had not yet been established. Dental caries at dentin level was detected from the age of 4 years. The overall mean decayed/missing/ filled teeth (dmft) was 0.49 (SD, 1.39). The analysis of mean dmft levels in children with positive (dmft > 0) scores revealed a mean dmft of 1.14. The evidence from this study demonstrated that dental caries levels in preschool children with disabilities in Ireland are low when compared with the general population. Furthermore, children aged 3 years or younger exhibited no dental caries at dentin level and therefore were not affected by early childhood caries. An adjustment of current oral health prevention practice may lead to a further reduction in dental caries levels in this section of the child population.


Silent Partner in Blood Vessel Homeostasis? Pervasive Role of Nitric Oxide in Vascular Disease.
The endothelium generates powerful mediators that regulate blood flow, temper inflammation and maintain a homeostatic environment to prevent both the initiation and progression of vascular disease. Nitric oxide (NO) is arguably the single most influential molecule in terms of dictating blood vessel homeostasis. In addition to direct effects associated with altered NO production (e.g. vasoconstriction, excessive inflammation, endothelial dysfunction), NO is a critical modulator of vaso-relevant pathways including cyclooxygenase (COX)-derived prostaglandin production and angiotensin II generation by the renin-angiotensin system. Furthermore, NO may influence the selectivity of COX-2 inhibitors and ultimately contribute to controversies associated with the use of these drugs. Consistent with a central role for NO in vascular disease, disruptions in the production and bioavailability of NO have been linked to hypertension, diabetes, hypercholesterolemia, obesity, aging, and smoking. The ability of the vessel wall to control disease-associated oxidative stress may be the most critical determinant in maintaining homeostatic levels of NO and subsequently the prospect of stroke, myocardial infarction and other CV abnormalities. To this end, investigation of mechanisms that alter the balance of protective mediators, including pathways that are indirectly modified by NO, is critical to the development of effective therapy in the treatment of CV disease.


[The Role of Urinary Lipocalin in Prognostication of Hospital Complications in Patients With Ischemic Heart Disease After Coronary Artery Bypass Grafting].
To assess significance of urinary neutrophil gelatinase-associated lipocalin (NGAL) for predicting hospital complications in subjects with ischemic heart disease (IHD) after coronary artery bypass grafting (CABG). The study included 720 subjects who underwent CABG between 03/2011 and 04/2012. Blood serum creatinine level, glomerular filtration rate (GFR) (MDRD formula) and NGAL concentration were measured before and on day 7 after CABG. The following unfavorable outcomes of operative intervention: myocardial infarction (MI), stroke or transient ischemic attack, acute or progression of chronic renal disease, remediastinotomy were registered during in-hospital period. Additive EuroSCORE was calculated for all patients. There were no significant differences in serum creatinine level and GFR both before and on day 7 after CABG between groups of patients with different risk assessed by EuroSCORE, and with complicated and uncomplicated postoperative course. Urine NGAL level before and on day 7 after CABG was significantly higher in high and medium compared with low EuroSCORE risk groups. Preoperative NGAL urine level was significantly higher in patients with than in those without MI or stroke after CABG. NGAL urine level was also higher in patients with development of acute renal failure (ARF) compared with those without ARF. Both pre- and postoperative NGAL urine levels were higher in patients with unfavorable outcome while there were no significant differences in serum creatinine levels and CRF between patients with favorable and unfavorable outcomes. Preoperative measurement of urinary NGAL - a preclinical marker of acute kidney injury - allowed to predict more accurately the hospital risk of development of adverse cardiovascular and renal complications of CABG.


Spatial heterogeneity distribution of soil total nitrogen and total phosphorus in the Yaoxiang watershed in a hilly area of northern China based on geographic information system and geostatistics.
Soil total nitrogen (STN) and total phosphorus (STP) are important indicators of soil nutrients and the important indexes of soil fertility and soil quality evaluation. Using geographic information system (GIS) and geostatistics, the spatial heterogeneity distribution of STN and STP in the Yaoxiang watershed in a hilly area of northern China was studied. The results showed that: (1) The STN and STP contents showed a declining trend with the increase in soil depth; the variation coefficients (Cv) of STN and STP in the 0- to 10-cm soil layer (42.25% and 14.77%, respectively) were higher than in the 10- to 30-cm soil layer (28.77% and 11.60%, respectively). Moreover, the Cv of STN was higher than that of STP. (2) The maximum C0/(C0 + C1) of STN and STP in the soil layers was less than 25%, this indicated that a strong spatial distribution autocorrelation existed for STN and STP; and the STP showed higher intensity and more stable variation than the STN. (3) From the correlation analysis, we concluded that the topographic indexes such as elevation and slope direction all influenced the spatial distribution of STN and STP (correlation coefficients were 0.688 and 0.518, respectively). (4) The overall distribution of STN and STP in the Yaoxiang watershed decreased from the northwest to the southeast. This variation trend was similar to the watershed DEM trend and was significantly influenced by vegetation and topographic factors. These results revealed the spatial heterogeneity distribution of STN and STP, and addressed the influences of forest vegetation coverage, elevation, and other topographic factors on the spatial distribution of STN and STP at the watershed scale.


Sparse Representation With Spatio-Temporal Online Dictionary Learning for Promising Video Coding.
Classical dictionary learning methods for video coding suffer from high computational complexity and interfered coding efficiency by disregarding its underlying distribution. This paper proposes a spatio-temporal online dictionary learning (STOL) algorithm to speed up the convergence rate of dictionary learning with a guarantee of approximation error. The proposed algorithm incorporates stochastic gradient descents to form a dictionary of pairs of 3D low-frequency and high-frequency spatio-temporal volumes. In each iteration of the learning process, it randomly selects one sample volume and updates the atoms of dictionary by minimizing the expected cost, rather than optimizes empirical cost over the complete training data, such as batch learning methods, e.g., K-SVD. Since the selected volumes are supposed to be independent identically distributed samples from the underlying distribution, decomposition coefficients attained from the trained dictionary are desirable for sparse representation. Theoretically, it is proved that the proposed STOL could achieve better approximation for sparse representation than K-SVD and maintain both structured sparsity and hierarchical sparsity. It is shown to outperform batch gradient descent methods (K-SVD) in the sense of convergence speed and computational complexity, and its upper bound for prediction error is asymptotically equal to the training error. With lower computational complexity, extensive experiments validate that the STOL-based coding scheme achieves performance improvements than H.264/AVC or High Efficiency Video Coding as well as existing super-resolution-based methods in rate-distortion performance and visual quality.


Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway.
Pramipexole is a dopamine D2 receptor agonist indicated for treating Parkinson disorder. This study was aimed to investigate the effect of pramipexole in forced swimming test (FST) in mice and the possible involvement of activation of D2 receptors and inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) on this effect. Intraperitoneal administration of pramipexole (1-3mg/kg) reduced the immobility time in the FST similar to fluoxetine (20mg/kg, i.p.). This effect of pramipexole (1mg/kg, i.p.) was ceased when mice were pretreated with haloperidol (0.15mg/kg, i.p,) and sulpiride (5mg/kg, i.p) as D2 receptor antagonists, NMDA (75mg/kg,i.p.), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.05mg/kg, i.p., a NMDA receptor antagonist) l-NG-Nitro arginine methyl ester (l-NAME, 10mg/kg, i.p., a non-specific nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (30mg/kg, i.p., a neuronal NOS inhibitor) and methylene blue (10mg/kg, i.p.), an inhibitor of both NOS and soluble guanylyl cyclase (sGC) in combination with the sub-effective dose of pramipexole (0.3mg/kg, i.p.) reduced the immobility. Altogether, our data suggest that the antidepressant-like effect of pramipexole is dependent on the activation of D2 receptor and inhibition of either NMDA receptors and/or NO-cGMP synthesis. These results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of pramipexole and reinforce the role of D2 receptors, NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant mechanism of this agent.


Pilot study of elevated levels of insulin-like growth factor-binding protein-2 as indicators of hepatocellular carcinoma.
Insulin-like growth factor-binding protein-2 (IGFBP-2) is expressed in many malignant tissues, and elevated serum levels can be indicators of tumour activity in addition to conventional tumour markers. Our aim was to evaluate the role of IGFBP-2 levels together with insulin-like growth factor (IGF)-I, IGF-II and IGFBP-3 in the diagnostic work-up of patients with hepatocellular carcinoma (HCC). In 50 (39 males, 11 females) histologically confirmed and TNM-graded patients with HCC who had not received adjuvant chemotherapy, the basal serum levels of IGF-I, IGF-II, IGFBP-3, IGFBP-2 and alpha-fetoprotein (AFP) were measured. The median age of the patients was 66 (37-84) years, body mass index was normal (25 (35-16) kg/m2). The levels of IGF-I, IGF-II and IGFBP-3 were diminished, as is the case when nutrition, hepatic function and growth hormone (GH) secretion are decreased. The levels of AFP and IGFBP-2 were markedly high. In 37 cases, IGFBP-2 levels were above the age-related norm, and in 40 cases AFP levels were also elevated. In 3 cases, both AFP and IGFBP-3 were normal, and in 4 cases AFP was high but IGFBP-2 normal, whereas in 10 cases AFP was normal but IGFBP-2 was high. In addition to AFP, IGFBP-2 appears to be a suitable marker for the evaluation of the serological status of HCC patients. A longitudinal study during disease management is required to assess the full potential of IGFBP-2 measurements as a marker.


Presence and awareness of infectious disease among Chinese migrant workers.
This cross-sectional study set out to identify the health status and health beliefs and behaviors with regard to TB and HIV-AIDS among 407 rural male migrant workers in China. Surveyed workers' awareness level for AIDS transmission was 67.7% and for TB transmission 56.8%. These workers had high rates of acute illness in the previous month (depression 18.3%, physical injury 16.3%, dermatological ailment 9.6%, respiratory infection 9.4%). One or more of the four symptoms of TB were found in 22.3% of the workers. Prevalent TB symptoms were associated with previously having had TB (chi-square = 69.98, p = .000) and having previously lived with a TB patient (F = 13.99, p = .000). The relative risk for having had TB if the worker had lived with someone with TB was 5.69 (chi-square 7.65, p = .006). Screening for TB symptoms, a history of having lived with someone with TB, or having previously had TB, has the potential to serve as a cost-effective and easy first-line TB screening among large mobile populations.


Children's perceptions of homelessness.
The purpose of this study was to describe what it is like to be homeless from the school-age child's unique perspective. A convenience sample of 14 school-aged children currently living in a shelter was interviewed about their experiences with homelessness. The children described their experiences openly with vivid details, and five themes were identified in the data: (a) I am not homeless, (b) I like living in a shelter sometimes, (c) living in a shelter is hard, (d) stop the violence, and (e) I need approval. Data are presented to support how the themes were labeled. Understanding the perspectives of children who live in shelters can be an important aspect in providing care to them and their families when they are treated by nurses in hospitals, schools, and communities.


Persistent Exposure to Porphyromonas gingivalis Promotes Proliferative and Invasion Capabilities, and Tumorigenic Properties of Human Immortalized Oral Epithelial Cells.
Recent epidemiological studies revealed a significant association between oral squamous cell carcinoma (OSCC) and Porphyromonas gingivalis, a major pathogen of periodontal disease. As a keystone pathogen of periodontitis, P. gingivalis is known not only to damage local periodontal tissues, but also to evade the host immune system and eventually affect systemic health. However, its role in OSCC has yet to be defined. To explore the underlying effect of chronic P. gingivalis infection on OSCC and to identify relevant biomarkers as promising targets for therapy and prevention, we established a novel model by exposing human immortalized oral epithelial cells (HIOECs) to P. gingivalis at a low multiplicity of infection (MOI) for 5-23 weeks. The P. gingivalis infected HIOECs were monitored for tumor biological alteration by proliferation, wound healing, transwell invasion, and gelatin zymography assays. Microarray and proteomic analyses were performed on HIOECs infected with P. gingivalis for 15 weeks, and some selected data were validated by quantitative real-time PCR and (or) western blot on cells infected for 15 and 23 weeks. Persistent exposure to P. gingivalis caused cell morphological changes, increased proliferation ability with higher S phase fraction in the cell cycle, and promoted cell migratory and invasive properties. In combining results of bioinformatics analyses and validation assays, tumor-related genes such as NNMT, FLI1, GAS6, lncRNA CCAT1, PDCD1LG2, and CD274 may be considered as the key regulators in tumor-like transformation in response to long-time exposure of P. gingivalis. In addition, some useful clinical biomarkers and novel proteins were also presented. In conclusion, P. gingivalis could promote tumorigenic properties of HIOECs, indicating that chronic P. gingivalis infection may be considered as a potential risk factor for oral cancer. The key regulators detected from the present model might be used in monitoring the development of OSCC with chronic periodontal infection.


Corn silage from corn treated with foliar fungicide and performance of Holstein cows.
Foliar fungicide application to corn plants is used in corn aimed for corn silage in the dairy industry, but questions regarding frequency of application and its effect on corn silage quality and feed conversion when fed to dairy cows remain prevalent. The objective of this study was to evaluate the effects of various foliar fungicide applications to corn on dry matter intake (DMI), milk production, and milk composition when fed to dairy cows. Sixty-four Holstein cows with parity 2.5±1.5, 653±80kg of body weight, and 161±51d in milk were blocked and randomly assigned to 1 of 4 corn silage treatments (total mixed ration with 35% of the dry matter as corn silage). Treatments were as follows: control (CON), corn silage with no applications of foliar fungicide; treatment 1 (1X), corn silage from corn that received 1 application of pyraclostrobin (PYR) foliar fungicide (Headline; BASF Corp.) at corn vegetative stage 5; treatment 2 (2X), corn silage from corn that received the same application as 1X plus another application of a mixture of PYR and metconazole (Headline AMP; BASF Corp.) at corn reproductive stage 1 ("silking"); and treatment 3 (3X), corn silage from corn that received the same applications as 2X as well as a third application of PYR and metconazole at reproductive stage 3 ("milky kernel"). Corn was harvested at about 32% dry matter and 3/4 milk line stage of kernel development and ensiled for 200d. Treatments were fed to cows for 5wk, with the last week being used for statistical inferences. Week -1 was used as a covariate in the statistical analysis. Dry matter intake tended to be lower for cows fed corn silage treated with fungicide than CON (23.8, 23.0, 19.5, and 21.3kg for CON, 1X, 2X, and 3X, respectively). A linear treatment effect for DMI was observed, with DMI decreasing as foliar fungicide applications increased. Treatments CON, 1X, 2X, and 3X did not differ for milk yield (34.5, 34.5, 34.2, and 34.4kg/d, respectively); however, a trend for increased feed conversion represented by fat-corrected milk/DMI (1.65 vs. 1.47) and energy-corrected milk/DMI (1.60 vs. 1.43) was noted for cows fed corn silage with fungicide compared with CON. In conclusion, cows receiving corn silage treated with foliar fungicide had better conversion of feed dry matter to milk than those receiving CON silage.


[A multi-resistant bacterium before the era of antibiotics : the agent of melioidosis].
Melioidosis is an infectious, tropical and emerging disease, due to a bacterium of the hydrotelluric environment, Burkholderia pseudomallei, which is considered as a potential biological weapon because of its exceptional resistance and virulence capacities. Its worldwide spread, outside the original endemic foci of Southeast Asia and Australia, is favoured by global warming and the diabetes mellitus pandemic, which is the main predisposing factor.In humans, melioidosis is an opportunistic infection, following professional (rice farmers, soldiers) or accidental contamination, by inhalation or inoculation. B. pseudomallei is a facultative intracellular bacterium that can overcome host immune defences, induce acute, subacute, or chronic invasive infection, or remain latent for years. The acute infection is polymorphic, bacteraemic in more than 50% of cases, frequently complicated by shock, and revealed by visceral abscesses, most often pulmonary. It is fatal in 20 to 50% of cases, the prognosis depending on the delay before the establishment of effective first-line antibiotic therapy, using ceftazidime or carbapenems, and therefore on the speed of bacteriological diagnosis.B. pseudomallei is a saprophytic bacterium, resident of the rhizosphere where it has developed and accumulated capacities to overcome environmental stresses and competition with organisms living in such ecosystem. These adaptation mechanisms are also the virulence factors that make melioidosis serious, in particular the efflux pumps that are the main support for its multi-resistance to antibiotics.


Fitness consequences of infection of Arabidopsis thaliana with its natural bacterial pathogen Pseudomonas viridiflava.
Variation in plant resistance to pathogen infection is commonly observed in interactions between wild plants and their foliar pathogens. Models of host-pathogen interactions indicate that a large cost of infection is generally necessary to maintain this variation, yet there is limited evidence that foliar pathogens cause detectable fitness reductions in wild host plants. Most published work has focused on fungal pathogens. Pseudomonas viridiflava, a common bacterial pathogen of the annual weed Arabidopsis thaliana across its range, comprises two distinct genetic clades that cause disease symptoms of different severity. Here we measured the extent of infection of wild A. thaliana populations in the Midwest, USA, and examined the effect on seed production, in field and growth-chamber experiments, of experimental inoculation with isolates from the two clades. We found infection with P. viridiflava varied from 0 to 56% in Midwest A. thaliana populations, with the possibility of several leaves per plant infected later in the growing season. In the growth chambers, experimental inoculation reduced seed set by averages of 15 and 11% for clades A and B, respectively. In the field experiment, only clade A affected plant fitness significantly, reducing seed set by an average of 38%. Underlying these average effects we observed both negative and positive effects of infection, and variation in both fitness among plant genotypes and sensitivity to environmental conditions.


F-18-fluoro-2-deoxyglucose positron emission tomography/computed tomography in the follow-up of breast cancer with elevated levels of tumor markers.
The value of combined positron emission tomography (PET)/computed tomography (CT) in the follow-up of patients with breast cancer with elevated tumor markers but without proven metastases or local recurrence was assessed. Thirty-four women underwent PET/CT. The PET and CT images were first analyzed separately; fused findings were then interpreted, blinded to the results of the other modalities. The results of CT, PET, and PET/CT were compared with each other and correlated to the final diagnosis. The PET/CT identified 149 malignant foci in 24 patients (71%). The CT detected 96 of these foci in 18 patients, whereas PET identified 124 foci in 17 patients. Differences between CT and PET were not significant. Differences between PET/CT and CT (P < 0.01) and PET/CT and PET (P < 0.01) were significant. The person-based sensitivity of PET/CT, PET, and CT was 96%, 88% and 96%, respectively. Specificity of PET/CT, PET, and CT was 89%, 78%, and 78%, respectively. The PET/CT is a valuable modality for the follow-up of patients with breast cancer and elevated levels of tumor markers.


Evidence that the alpha and alpha (+)isoforms of the catalytic subunit of (Na+, K+)-ATPase reside in distinct ciliary epithelial cells of the mammalian eye.
Polyclonal antibodies against the canine kidney (Na+,K+)-ATPase were used to examine the localization and distribution of this protein in intact ciliary processes (CP) from bovine eyes by indirect immunofluorescence. The basolateral surface of non-pigmented (NPE) and pigmented (PE) ciliary epithelial cells was found to be stained specifically for the (Na+,K+)-ATPase. Immunoblot analysis of intact CP, separated PE and NPE cells by density gradients and cultured ciliary epithelial cells, revealed two forms of the catalytic subunit of the (Na+,K+)-ATPase: the alpha and alpha (+). The alpha (+) form was enriched in NPE cells while alpha was in PE cells.


Spectroscopic observation of higher vibrational levels of C2 through visible band systems.
Higher vibrational levels of the C2 molecule than those observed so far were investigated for the X(1)Σ(g)(+), A(1)Π(u), a(3)Π(u), c(3)Σ(u)(+), and d(3)Π(g) states through the Phillips, Swan, and d(3)Π(g)-c(3)Σ(u)(+) band systems under a jet-cooled condition. The term values and the molecular constants for 21 new vibronic levels were determined from rotationally resolved excitation spectra. The determined term values and rotational constants were compared to those derived from high-level ab initio potential curves. Perturbations identified in low J levels of the d(3)Π(g) (v = 8) state are most likely to be caused by the 1(5)Π(g) (v = 3) state.


Prognostic factors and treatment modalities in uterine sarcoma.
The aim of this study was to identify the impact of various prognostic factors in the management of uterine sarcoma. Fifty-nine patients with uterine sarcoma were treated at King Faisal Specialist Hospital and Research Center between 1980 and 1997. Forty-three patients (73%) were treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, 7 (12%) total abdominal hysterectomy and bilateral salpingo-oophorectomy with sampling of pelvic lymph nodes, and 9 (15%) had biopsy only. Nine patients received adjuvant treatment; five had radiation therapy (XRT), two had chemotherapy, one had combined XRT and chemotherapy, and one received hormonal treatment. Leiomyosarcoma cases accounted for 42% of all the uterine sarcomas, carcinosarcoma cases for 34%, and endometrial stromal sarcoma (ESS) for 24%. Fifty (85%) patients had pathologic grade II and III tumor, with only 9 patients grade I. Twenty-seven patients (46%) were classified surgically as stage I, 7 (12%) as stage II, 17 (29%) as stage III, and 8 (13%) had stage IV tumor. Recurrences developed in 34 patients (71%). The 5- and 10-year overall actuarial survival for all patients was 42%, and the corresponding relapse-free survivals for those who achieved complete response after primary treatment (48 patients) were 27% and 20%. On the univariate analysis, grade I tumors (p = 0.04), ESS (p = 0.02), nonmetastatic stage (p = 0.05), and negative peritoneal cytology (p = 0.04) were associated with better overall survival. Factors associated


Human fetal islet response to interferon gamma.
Investigation was made of the ability of human fetal islets to express major histocompatibility complex class I and class II gene products after in vitro exposure to 1,000 U/ml Interferon Gamma (IFN) for 48 hours as well as the effect of such exposure on insulin secretion and autologous mixed islet lymphocyte response. Flow cytometry analysis revealed that the mean fluorescence activity of both HLA-ABC (class I) and HLA-DR (class II) was significantly (p < 0.01) increased vs the control after IFN incubation. (class I: Control = 125 +/- 35 SD, IFN = 995 +/- 418 S.D.; class II: Control = 70 +/- 30 SD, IFN = 300 +/- 74 S.D.). Cells containing surface expression of DR and intracellular insulin by flow cytometry following depletion of phagocytic cells were also quantified and increased from 0 to 0.67 percent following exposure to IFN. Autologous splenocytes responded to cells previously incubated with IFN with a three fold increase in 3H-thymidine uptake. Interferon gamma exposed, DR positive insulin containing cells contained one third the insulin of DR negative insulin containing cells (2.1 +/- 1.5 vs 6.6 +/- 3.4 microU/cell) but were nevertheless capable of stimulated insulin secretion. Thus, pharmacologic events leading to increased fetal pancreatic interferon concentrations initiate both immune and nonimmune processes that may predispose susceptible individuals to diabetes.


Supplementary prescribing case study.
A principle aim of supplementary prescribing is to enable faster access to medicines for people who have a chronic condition. The example of a young person with diabetes is used to demonstrate the benefits of nurse specialists being able to prescribe. The way in which prescribing requirements, such as clinical management plans, relate to existing multi-disciplinary team management of children with chronic illness is also illustrated. Having the young person and family as partners within the team is essential; use of management plans reinforces this partnership and allows care to be delivered in a structured way.


Alchemical Calculation of Relative Free Energies for Charge-Changing Mutations at Protein-Protein Interfaces Considering Fixed and Variable Protonation States.
The calculation of relative free energies (ΔΔG) for charge-changing mutations at protein-protein interfaces through alchemical methods remains challenging due to variations in the system's net charge during charging steps, the possibility of mutated and contacting ionizable residues occurring in various protonation states, and undersampling issues. In this study, we present a set of strategies, collectively termed TIRST/TIRST-H+, to address some of these challenges. Our approaches combine thermodynamic integration (TI) with the prediction of pKa shifts to calculate ΔΔG values. Moreover, special sets of restraints are employed to keep the alchemically transformed molecules separated. The accuracy of the devised approaches was assessed on a large and diverse data set comprising 164 point mutations of charged residues (Asp, Glu, Lys, and Arg) to Ala at the protein-protein interfaces of complexes with known three-dimensional structures. Mean absolute and root-mean-square errors ranging from 1.38 to 1.66 and 1.89 to 2.44 kcal/mol, respectively, and Pearson correlation coefficients of ∼0.6 were obtained when testing the approaches on the selected data set using the GPU-TI module of Amber18 suite and the ff14SB force field. Furthermore, the inclusion of variable protonation states for the mutated acid residues improved the accuracy of the predicted ΔΔG values. Therefore, our results validate the use of TIRST/TIRST-H+ in prospective studies aimed at evaluating the impact of charge-changing mutations to Ala on the stability of protein-protein complexes.


H2O2/DMSO-Promoted Regioselective Synthesis of 3,3'-Bisimidazopyridinylmethanes via Intermolecular Oxidative C(sp(2))-H Bond Activation of Imidazoheterocycles.
In the past decade, metal-free approaches for C-C bond formation have attracted a great deal of attention due to their ease of use and low cost. This report represents a novel and metal-free synthesis of 3,3'-bisimidazopyridinylmethanes via intermolecular oxidative C(sp(2))-H bond functionalization of imidazo[1,2-a]pyridines with dimethyl sulfoxide as the carbon synthon (CH2) using H2O2 as a mild oxidant under air. A library of 3,3'-bis(2-arylimidazo[1,2-a]pyridin-3-yl)methanes has been achieved in good to excellent yields. The present methodology has been successfully applied to imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles. Furthermore, the current approach was also extended for the synthesis of unsymmetrical 3,3'-bisimidazopyridinylmethanes under optimized reaction conditions. A mechanistic pathway is proposed on the basis of experiments with radical scavengers and DMSO-d6 and ESI-MS observations.


Healing of apical periodontitis in type II diabetes mellitus patients: A prospective study.
This study aimed to compare the healing of periapical bone between type II diabetes patients and healthy patients after root canal treatment. This study included 26 diabetic patients and the control group with healthy patients matching the diabetic group in age and sex. The study included only teeth with satisfactory coronal restoration. The periapical index system was used to evaluate the periapical status of treated teeth at follow-ups after 6 and 12 months. Analysis of the results revealed a significantly higher healing rate in the control group compared to the diabetic group only at the 6-month follow-up (66.6 vs. 33.3%; Χ2 = 4.857; p = 0.0275). Analysis of the full-scale PAI index disclosed significantly higher PAI values in the diabetic subjects at 6- and 12-month follow-up. The regression analysis showed that the risk of apical periodontitis persistence increased significantly with female gender (OR = 3.92; 95% CI = 1.04-14.79; p = 0.043), diabetes mellitus (OR = 4.27; 95% CI: 1.18-15.50; p = 0.027) and higher household income (OR = 5.39; 95% CI = 1.33-21.89; p = 0.018). Root canal treatment remains an effective means of conservative treatment in diabetic patients. While the healing is not compromised, regular follow-ups are necessary to monitor the healing process.


Ketamine, midazolam and vecuronium infusion. Anaesthesia for Down's syndrome and congenital heart disease.
A ketamine, midazolam and vecuronium infusion was used for total intravenous anesthesia in a patient with Down's syndrome, a ventricular septal defect and pulmonary hypertension. A mixture of ketamine 200 mg, midazolam 5 mg and vecuronium 12 mg in 50 ml of normal saline was infused at 0.5 ml/kg/hour. This simple technique and ventilation with 100% oxygen maintained tissue oxygenation and cardiovascular stability.


Thoracic epidural analgesia -- a double blind study between etidocaine and bupivacaine.
In a double-blind study on 40 patients for elective upper abdominal surgery, measurements was made of onset time, duration and segmental spread of analgesia, systolic blood pressure, heart rate and peak expiratory flow during thoracic epidural analgesia with etidocaine 1% and bupivacaine 0.5%, both containing adrenaline 5 mug/ml. No major differences were found between the two agents. The results differ in many aspects from those obtained with these agents in lumbar epidural analgesia.


Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses.
Mechanical stretch, an important growth stimulus, results not only from pulsatile blood flow and diastolic stretch of the ventricles [cyclic stretch (CS)] but also from tissue expansion during growth [constant static stretch (SS)]. We compared growth factor receptor expression and vasculogenic/angiogenic responses of rat coronary microvascular endothelial cells (ECs) by exposing cells to CS (10% elongation at 30 cycles/min) and SS (constant 10% elongation). Both CS and SS increased VEGF receptor (VEGF-R)2 protein levels and the extent of tube formation and branching. Moreover, both CS and SS enhanced VEGF-induced cell proliferation and tube formation, indicating that both types of stretch increase the sensitivity of ECs to VEGF. Blockade of VEGF-R2 prevented the increases in EC proliferation and aggregate tube length. However, CS but not SS enhanced EC Tie-2 protein and migration. CS affected a greater increase in tube length and branch formation than did SS. A unique finding was that SS but not CS increased VEGFR-1 in ECs. Our study is the first to distinguish between the effects of CS and SS on growth factor receptor expression and rat coronary microvascular EC proliferation, migration, and tube formation. In conclusion, EC angiogenic responses to these two types of stretch display both differences and similarities, but both CS and SS are dependent on VEGF-R2 signaling for their vasculogenic/angiogenic effects.


Prevalence of fra(X) in the county of Funen in Denmark is lower than expected.
Population based cytogenetic fra(X) surveys have not previously been reported from Denmark. In the present study we present an estimate of fra(X) based on 1) information from the Danish Central Cytogenetic Registry of diagnosed fra(X) males of all age groups in all Denmark in the period 1980-1992 and 2) a systematic cytogenetic fra(X) survey of 175 of 8-10-year-old children with special educational needs resident in a defined, demographically representative area of Denmark (the county of Funen). The study was performed in 1988-90 before the cloning of the FMR-1 gene. In the county of Funen there were 7,837 male children in the age group of 8-10 years. In the cytogenetic survey of learning disabled children, no fra(X) positive was diagnosed. There were 99 registered males with fra(X) in all Denmark, equivalent to a prevalence of 0.04 per 1,000 males (confidence interval 0.032:1,000-0.048:1,000). Molecular fra(X) surveys of different, large populations are needed in order to estimate the frequency of fra(X) and clarify whether significant differences in prevalence exist in different populations.


Acceptance and Willingness to Pay for Vaccine Against Human Papilloma Virus (HPV) Among Parents of Boys in Central Vietnam.
Human papilloma virus (HPV) vaccine for adolescents was recommended as an effective prevention strategy of HPV-related cancers. In Vietnam, HPV vaccination has not been introduced to male adolescent. This study was conducted to examine the acceptance of having boys vaccinated against HPV and its underlying reasoning, and to identify their parent's willingness to pay (WTP) for HPV vaccination in central Vietnam. 785 parents of boys were directly interviewed based on a structured questionnaire. Parent's acceptability of HPV vaccine for their sons was identified by one question with response on 3-point scale (agree, don't know, and disagree). Multivariate logistic regression model was used to determine contributing factors to participant's acceptance. Bidding game method was applied to elicit WTP values for HPV vaccination with initial bid of 161.2 USD. The results showed that 49.2% of parents agreed to have their sons vaccinated against HPV. Factors that influenced parent's acceptance including son's age older than 12 years (OR = 1.5; 95% CI: 1.08-1.98); being eldest son (OR = 1.6; 95% CI: 1.13-2.19), being mother (OR = 1.4; 95% CI: 1.01-1.91), parents with high educational level (OR = 1.7; 95% CI: 1.11-2.47) and their knowledge of HPV and HPV vaccine (OR = 1.8; 95% CI: 1.23-2.65). Average WTP value for full doses of HPV vaccine was 137.5 USD, ranging between 9 USD and 188.3 USD. Parents' knowledge of HPV and HPV vaccine was the only factor affecting WTP value (Rho: 0.11; p-value: 0.030). The findings suggest a strategy be introduced for HPV vaccination to male adolescents in Vietnam.


Hyponatraemia in the first week of life in preterm infants. Part I. Arginine vasopressin secretion.
Continuous sequential urinary arginine vasopressin measurements in 14 preterm, ventilated infants suggest that both osmoreceptor and volume receptor systems are able to stimulate the prolonged secretion of arginine vasopressin from 26 weeks' gestation. The kidney is able to respond to arginine vasopressin stimulation from the first day of life and from 26 weeks' gestation. A maximum urine osmolality not exceeding 550 mOsm/kg was reached which varied with hydration of the infant. Excretion of arginine vasopressin and urine osmolality increased during deterioration of respiratory illness, mask ventilation, bilateral pneumothoraces, and severe intraventricular haemorrhage. The data show that inappropriate arginine vasopressin secretion is common during illness in the first week of life in preterm infants and that strict attention must be paid to water balance during this time.