Clinical role of 18F-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma.
18F-FDG PET/CT has rapidly become a widely used imaging modality for evaluating a variety of malignancies, including squamous cell carcinoma of the head and neck and thyroid cancer. Using both published data and the multidisciplinary experience at our institution, we provide a practical set of guidelines and algorithms for the use of 18F-FDG PET/CT in the evaluation and management of head and neck cancer and thyroid cancer.


The Thyroid Epidemiology, Audit, and Research Study (TEARS): the natural history of endogenous subclinical hyperthyroidism.
For patients with subclinical hyperthyroidism (SH), the objective of the study was to define the rates of progression to frank hyperthyroidism and normal thyroid function. Record-linkage technology was used retrospectively to identify patients with SH in the general population of Tayside, Scotland, from January 1, 1993, to December 31, 2009. All Tayside residents with at least two measurements of TSH below the reference range for at least 4 months from baseline and normal free T(4)/total T(4) and total T(3) concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from prescription, admission, and radioactive iodine treatment records. Cases younger than 18 yr of age were also excluded from the study. The status of patients was investigated at 2, 5, and 7 yr after diagnosis. We identified 2024 cases with SH, a prevalence of 0.63% and an incidence of 29 per 100,000 in 2008. Most SH cases without thyroid treatment remained as SH at 2 (81.8%), 5 (67.5%), and 7 yr (63.0%) after diagnosis. Few patients (0.5-0.7%) developed hyperthyroidism at 2, 5, and 7 yr. The percentage of SH cases reverting to normal increased with time: 17.2% (2 yr), 31.5% (5 yr), and 35.6% (7 yr), and this was more common in SH patients with baseline TSH between 0.1 and 0.4 mU/liter. Very few SH patients develop frank hyperthyroidism, whereas a much larger proportion revert to normal, and many remain with SH.


2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study.
Migraineurs experience a spectrum of headaches: migraine, migrainous, and episodic tension-type as defined by the International Headache Society (IHS). To evaluate the effectiveness of sumatriptan, 50-mg tablets, in treating the spectrum of headaches in IHS-diagnosed migraineurs. Migraineurs with severe disability (Headache Impact Questionnaire score 250 or greater) were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients treated up to 10 headaches with sumatriptan, 50 mg, or placebo (4:1). Headache features, recorded prior to treatment, were used to classify each headache using IHS criteria. Headache response (moderate or severe pain reduced to mild or no pain) and pain-free response were recorded at 2 and 4 hours postdose (primary endpoint). Because patients treated multiple attacks, statistical methods controlling for within-subject correlation were used. Two hundred forty-nine migraineurs treated 1576 moderate or severe headaches: migraine (n = 1110), migrainous (n = 103), and tension-type (n = 363). Sumatriptan was superior to placebo for headache response 4 hours postdose (primary endpoint) across all headache types (migraine, 66% versus 48%; P<.001; migrainous, 71% versus 39%; P<.01; tension-type, 78% versus 50%, P<.001). Sumatriptan was also superior to placebo for pain-free response 4 hours postdose for migraine (41% versus 24%, P<.001) and tension-type headaches (56% versus 36%, P =.001). Sumatriptan provided superior pain-free response 2 hours postdose for migraine (18% versus 7%, P<.0001) and tension-type headache (28% versus 14%, P =.0005) compared with placebo. Sumatriptan, 50-mg tablets, are effective for the full spectrum of headaches experienced by patients with disabling migraine due to a sumatriptan-responsive mechanism.


Pregnancy-related mortality in Africa and Asia: evidence from INDEPTH Health and Demographic Surveillance System sites.
Women continue to die in unacceptably large numbers around the world as a result of pregnancy, particularly in sub-Saharan Africa and Asia. Part of the problem is a lack of accurate, population-based information characterising the issues and informing solutions. Population surveillance sites, such as those operated within the INDEPTH Network, have the potential to contribute to bridging the information gaps. To describe patterns of pregnancy-related mortality at INDEPTH Network Health and Demographic Surveillance System sites in sub-Saharan Africa and southeast Asia in terms of maternal mortality ratio (MMR) and cause-specific mortality rates. Data on individual deaths among women of reproductive age (WRA) (15-49) resident in INDEPTH sites were collated into a standardised database using the INDEPTH 2013 population standard, the WHO 2012 verbal autopsy (VA) standard, and the InterVA model for assigning cause of death. These analyses are based on reports from 14 INDEPTH sites, covering 14,198 deaths among WRA over 2,595,605 person-years observed. MMRs varied between 128 and 461 per 100,000 live births, while maternal mortality rates ranged from 0.11 to 0.74 per 1,000 person-years. Detailed rates per cause are tabulated, including analyses of direct maternal, indirect maternal, and incidental pregnancy-related deaths across the 14 sites. As expected, these findings confirmed unacceptably high continuing levels of maternal mortality. However, they also demonstrate the effectiveness of INDEPTH sites and of the VA methods applied to arrive at measurements of maternal mortality that are essential for planning effective solutions and monitoring programmatic impacts.


The mitochondrial genotype can influence nuclear gene expression in yeast.
Isochromosomal, respiratory-deficient yeast strains, such as a mit-, a hypersuppressive petite, and a petite lacking mitochondrial DNA, are phenotypically identical in spite of differences in their mitochondrial genomes. Subtractive hybridizations of complementary DNA's to polyadenylated RNA isolated from derepressed cultures of these strains reveal the presence of nuclear-encoded transcripts whose abundance varies not only between them and their respiratory-competent parent, but among the respiratory-deficient strains themselves. Transcripts of some nuclear-encoded mitochondrial proteins, like cytochrome c and the alpha and beta subunits of the mitochondrial adenosine triphosphatase, whose abundance is affected by glucose or heme, do not vary. In the absence of major metabolic variables, yeast cells seem to respond to the quality and quantity of mitochondrial DNA and modulate the levels of nuclear-encoded RNA's, perhaps as a means of intergenomic regulation.


Rat islet mitochondrial adenine nucleotide translocase and the regulation of insulin secretion.
Employing a preparation of rat islet mitochondria, phosphoenolpyruvate has been shown to interact with the mitochondrial adenine nucleotide translocase. Thus, phosphoenolpyruvate inhibited mitochondrial uptake of [14C]ADP and exchanged with intramitochondrial [14C]ATP. A concentration-dependent inhibition of islet mitochondrial 45Ca2+ accumulation was seen when mitochondria were exposed to phosphoenolpyruvate with half-maximal inhibition observed at a phosphoenolpyruvate concentration of 0.2 mM. In experiments employing whole islets, phosphoenolpyruvate content was shown to be significantly elevated at both 1 and 30 min after an increase in the medium glucose concentration from 2 to 20 mM. In these experiments, the estimated islet concentrations of phosphoenolpyruvate fell in the range of maximal sensitivity of the islet adenine nucleotide translocase to phosphoenolpyruvate-induced inhibition of Ca2+ accumulation. It is concluded that increased concentrations of islet phosphoenolpyruvate resulting from increased extracellular glucose concentration may act to trigger or promote glucose-stimulated insulin secretion by modifying the distribution of Ca2+ between the islet cytosolic and mitochondrial compartments in a transport reaction catalyzed by the adenine nucleotide translocase.


PCK2 activation mediates an adaptive response to glucose depletion in lung cancer.
Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C₃-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C₃-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.


Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning.
The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.


Boll weevil found in pre-columbian cotton from Mexico.
A well-preserved, teneral adult female boll weevil, Anthonomus grandis Bohemnan (broad sense), was discovered in fragments of a cultivated cotton boll found in Guila Nacquitz Cave, Level A, dated about A.D. 900, near Mitla, Oaxaca, Mexico. This find antedates any previously known association of the boll weevil with cultivated cotton by about 900 years and negates the contention that this association began in the 18th century. The specimen is intermediate in form between Anthonomus grandis grandis Boheman and the thurberia weevil, Anthonomus grandis thurberiae Pierce.


Does elevated CO2 alter silica uptake in trees?
Human activities have greatly altered global carbon (C) and Nitrogen (N) cycling. In fact, atmospheric concentrations of carbon dioxide (CO2) have increased 40% over the last century and the amount of N cycling in the biosphere has more than doubled. In an effort to understand how plants will respond to continued global CO2 fertilization, long-term free-air CO2 enrichment experiments have been conducted at sites around the globe. Here we examine how atmospheric CO2 enrichment and N fertilization affects the uptake of silicon (Si) in the Duke Forest, North Carolina, a stand dominated by Pinus taeda (loblolly pine), and five hardwood species. Specifically, we measured foliar biogenic silica concentrations in five deciduous and one coniferous species across three treatments: CO2 enrichment, N enrichment, and N and CO2 enrichment. We found no consistent trends in foliar Si concentration under elevated CO2, N fertilization, or combined elevated CO2 and N fertilization. However, two-thirds of the tree species studied here have Si foliar concentrations greater than well-known Si accumulators, such as grasses. Based on net primary production values and aboveground Si concentrations in these trees, we calculated forest Si uptake rates under control and elevated CO2 concentrations. Due largely to increased primary production, elevated CO2 enhanced the magnitude of Si uptake between 20 and 26%, likely intensifying the terrestrial silica pump. This uptake of Si by forests has important implications for Si export from terrestrial systems, with the potential to impact C sequestration and higher trophic levels in downstream ecosystems.


Analysis of angiogenesis related factors in glioblastoma, peritumoral tissue and their derived cancer stem cells.
The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1α, HIF2α, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro. Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the "angiogenic switch" and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.


Definition of a minimal region of deletion of chromosome 7 in uterine leiomyomas by tiling-path microarray CGH and mutation analysis of known genes in this region.
Somatic interstitial deletions of chromosome segment 7q22-q31 in uterine leiomyomas are a frequent event, thought to be indicative of a tumor suppressor gene in the region. Previous LOH and CGH studies have refined this region to 7q22.3-q31, although the target gene has not been identified. Here, we have used tiling-path resolution microarray CGH to further refine the region and to identify homozygous deletions in fibroids. Furthermore, we have screened all manually annotated genes in the region for mutations. We have refined the minimum deleted region at 7q22.3-q31 to 2.79 Mbp and identified a second region of deletion at 7q34. However, we identified no pathogenic coding variation.


Marine biodiversity and the chessboard of life.
Species richness is greater in places where the number of potential niches is high. Consequently, the niche may be fundamental for understanding the arrangement of life and especially, the establishment and maintenance of the well-known Latitudinal Biodiversity Gradient (LBG). However, not all potential niches may be occupied fully in a habitat, as measured by niche vacancy/saturation. Here, we theoretically reconstruct oceanic biodiversity and analyse modeled and observed data together to examine patterns in niche saturation (i.e. the ratio between observed and theoretical biodiversity of a given taxon) for several taxonomic groups. Our results led us to hypothesize that the arrangement of marine life is constrained by the distribution of the maximal number of species' niches available, which represents a fundamental mathematical limit to the number of species that can co-exist locally. We liken this arrangement to a type of chessboard where each square on the board is a geographic area, itself comprising a distinct number of sub-squares (species' niches). Each sub-square on the chessboard can accept a unique species of a given ecological guild, whose occurrence is determined by speciation/extinction. Because of the interaction between the thermal niche and changes in temperature, our study shows that the chessboard has more sub-squares at mid-latitudes and we suggest that many clades should exhibit a LBG because their probability of emergence should be higher in the tropics where more niches are available. Our work reveals that each taxonomic group has its own unique chessboard and that global niche saturation increases when organismal complexity decreases. As a result, the mathematical influence of the chessboard is likely to be more prominent for taxonomic groups with low (e.g. plankton) than great (e.g. mammals) biocomplexity. Our study therefore reveals the complex interplay between a fundamental mathematical constraint on biodiversity resulting from the interaction between the species' ecological niche and fluctuations in the environmental regime (here, temperature), which has a predictable component and a stochastic-like biological influence (diversification rates, origination and clade age) that may alter or blur the former.


The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology.
The neuropathological features of schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity. Semaphorin 3A (sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with schizophrenia and 16 controls. In adults, sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay (+28%; P<0.05) and immunohistochemistry (+45%; P<0.01). We also measured reelin mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend reduction in the subjects with schizophrenia (-26%; P=0.07) and, notably, was negatively correlated with sema3A. Sema3A also correlated negatively with synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect, sema3A appears to contribute to the synaptic pathology of schizophrenia, perhaps via ongoing effects of persistent sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.


The generalization of upper atmospheric wind and temperature based on the Voigt line shape profile.
The principle of probing the upper atmospheric wind field, which is the Voigt profile spectral line shape, is presented for the first time. By the Fourier Transform of Voigt profile, with the Imaging Spectroscope and the Doppler effect of electromagnetic wave, the distribution and calculation formulae of the velocity field, temperature field, and pressure field of the upper atmosphere wind field are given. The probed source is the two major aurora emission lines originated from the metastable O(1S) and O(1D) at 557.7nm and 630.0nm. From computer simulation and error analysis, the Voigt profile, which is the correlation of the Gaussian profile and Lorentzian profile, is closest to the actual airglow emission lines.


Detecting asymmetries in balance control with system identification: first experimental results from Parkinson patients.
Cognitive processes can influence balance in various ways, but not all changes in postural performance can easily be identified with the naked clinical eye. Various studies have shown that dynamic posturography is able to detect more subtle changes in balance control. For patients with Parkinson's disease (which is typically an asymmetric disease), changes in the symmetry of balance control might provide a sensitive measure of cognitive influences on balance. Here, we describe a new posturography technique that combines dynamic platform perturbations with system identification techniques to detect such asymmetries in balance control of two patients with Parkinson's disease. Results were compared to those of six healthy controls. Our pilot data show clear asymmetries in dynamic balance control, even though patients themselves were not aware of this and had no subjective problems with stability or standing. We also found asymmetries in weight bearing, but the asymmetries in dynamic balance contribution were larger. Finally, asymmetries in weight bearing and dynamic balance in patients were not tightly coupled as in healthy controls. Future studies could incorporate this approach when examining the influence of mental decline on postural regulation.


Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage.
TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.


'Selfie'- boon or a bane? A study from a private medical college in Southern India.
Taking selfies is spreading like a mania across the globe. It may positively or negatively affect the self-esteem of an individual. The present study was undertaken to assess the proportion of medical undergraduates and teaching faculty involved in taking selfies, to compare the pattern of selfie taking among medical undergraduates and teaching faculty and to assess the self-esteem score among them. The subject consisted of medical undergraduates and teaching faculty of Kasturba Medical College, Mangalore. A cross-sectional study was carried out. A semi-structured questionnaire was prepared. Self-esteem was assessed by using the Rosenberg Self-esteem Scale. Information obtained was analyzed using SPSS 11.5. The study included 366 participants of the study population. The Rosenberg Self-esteem Scale conclude that 96% of the faculty and 84% of the students have normal self-esteem. Around 52.73% of them agree that they find selfie taking can be addictive, 43.72% of them agree that selfie taking can have disastrous effects, sometimes even life threatening and 57.92% of them agree that they enjoy the habit of selfie taking and find entertainment in it. It was found that most undergraduates and teaching faculty indulge in the act of selfie taking. Students tend to take selfies to share their current lifestyle, whereas faculty take selfies for convenience. It is found that selfies does not affect the self-esteem of an individual as the majority of the population were found to have normal self-esteem.


Validation of an Objective Keratoconus Detection System Implemented in a Scheimpflug Tomographer and Comparison With Other Methods.
To validate a recently developed program for automatic and objective keratoconus detection (Keratoconus Assistant [KA]) by applying it to a new population and comparing it with other methods described in the literature. KA uses machine learning and 25 Pentacam-derived parameters to classify eyes into subgroups, such as keratoconus, keratoconus suspect, postrefractive surgery, and normal eyes. To validate this program, it was applied to 131 eyes diagnosed separately by experienced corneal specialists from 2 different centers (Fondation Rothschild, Paris, and Antwerp University Hospital [UZA]). The agreement of the KA classification with 7 other indices from the literature was assessed using interrater reliability and confusion matrices. The agreement of the 2 clinical classifications was also assessed. For keratoconus, KA agreed in 92.6% of cases with the clinical diagnosis by UZA and in 98.0% of cases with the diagnosis by Rothschild. In keratoconus suspect and forme fruste detection, KA agreed in 65.2% (UZA) and 100% (Rothschild) of cases with the clinical assessments. This corresponds with a moderate agreement with a clinical assessment (κ = 0.594 and κ = 0.563 for Rothschild and UZA, respectively). The agreement with the other classification methods ranged from moderate (κ = 0.432; Score) to low (κ = 0.158; KISA%). Both clinical assessments agreed substantially (κ = 0.759) with each other. KA is effective at detecting early keratoconus and agrees with trained clinical judgment. As keratoconus detection depends on the method used, we recommend using multiple methods side by side.


Candida mannan: chemistry, suppression of cell-mediated immunity, and possible mechanisms of action.
The ability of Candida albicans to establish an infection involves multiple components of this fungal pathogen, but its ability to persist in host tissue may involve primarily the immunosuppressive property of a major cell wall glycoprotein, mannan. Mannan and oligosaccharide fragments of mannan are potent inhibitors of cell-mediated immunity and appear to reproduce the immune deficit of patients with the mucocutaneous form of candidiasis. However, neither the exact structures of these inhibitory species nor their mechanisms of action have yet been clearly defined. Different investigators have proposed that mannan or mannan catabolites act upon monocytes or suppressor T lymphocytes, but research from unrelated areas has provided still other possibilities for consideration. These include interference with cytokine activities, lymphocyte-monocyte interactions, and leukocyte homing. To stimulate further research of the immunosuppressive property of C. albicans mannan, we have reviewed (i) the relationship of mannan to other antigens and virulence factors of the fungus; (ii) the chemistry of mannan, together with methods for preparation of mannan and mannan fragments; and (iii) the historical evidence for immunosuppression by Candida mannan and the mechanisms currently proposed for this property; and (iv) we have speculated upon still other mechanisms by which mannan might influence host defense functions. It is possible that understanding the immunosuppressive effects of mannan will provide clues to novel therapies for candidiasis that will enhance the efficacy of both available and future anti-Candida agents.


Retinal imaging: what the neurologist needs to know.
With the advent of confocal microscopy and optical coherence tomography, high-resolution multimodal imaging of the retina and optic nerve head can now be obtained routinely, providing new diagnostic clues in a variety of neuro-ophthalmological conditions. In this review, we provide an overview of these imaging advances and their clinical applications.


Nanodiamond-Based Composite Structures for Biomedical Imaging and Drug Delivery.
Nanodiamond particles are widely recognized candidates for biomedical applications due to their excellent biocompatibility, bright photoluminescence based on color centers and outstanding photostability. Recently, more complex architectures with a nanodiamond core and an external shell or nanostructure which provides synergistic benefits have been developed, and their feasibility for biomedical applications has been demonstrated. This review is aimed at summarizing recent achievements in the fabrication and functional demonstrations of nanodiamond-based composite structures, along with critical considerations that should be taken into account in the design of such structures from a biomedical point of view. A particular focus of the review is core/shell structures of nanodiamond surrounded by porous silica shells, which demonstrate a remarkable increase in drug loading efficiency; as well as nanodiamonds decorated with carbon dots, which have excellent potential as bioimaging probes. Other combinations are also considered, relying on the discussed inherent properties of the inorganic materials being integrated in a way to advance inorganic nanomedicine in the quest for better health-related nanotechnology.


Drug use in pregnancy: Knowledge of drug dispensers and pregnant women in Dar es Salaam, Tanzania.
More than 90% of pregnant women take prescription or non-prescription drugs at some time during pregnancy. In general, unless absolutely necessary, drugs should not be used during pregnancy because many of them are harmful to the fetus. Appropriate dispensing is one of the steps for rational drug use; so, it is necessary that drug dispensers should have relevant and updated knowledge and skills regarding drug use in pregnancy. To assess the knowledge of drug dispensers and pregnant women regarding drug use in pregnancy, focusing on four commonly used drugs that are teratogenic or cause unwanted effects to the fetus and babies. The study was conducted in two parts: consumers' perception and providers' practice. It was a cross-sectional study involving visits to 200 private retail community pharmacies (as simulated client) within Temeke, Ilala and Kinondoni municipals in Dar es Salaam, Tanzania. The second part of the study was conducted at the antenatal clinics of the three municipal hospitals in Dar es Salaam. A semi-structured questionnaire was used to gather information from pregnant women. In total, 200 pregnant women were interviewed. Out of 200 drug dispensers, 86 (43%) were willing to dispense artemether-lumefantrine (regardless of the age of pregnancy), 56 (29%) were willing to dispense sodium valproate, 104 (52%) were willing to dispense captopril and 50 (25%) were willing to dispense tetracycline. One hundred and thirty-three (66.5%) pregnant women reported that they hesitated to take medications without consulting their physicians, 47 (23.5%) indicated that it was safe to take medications during pregnancy, while 123 (61.5%) mentioned that it was best to consult a doctor, while 30 (15%) did not have any preference. Sixty-three (31.5%) women reported that they were aware of certain drugs that are contraindicated during pregnancy. It is evident that most drug dispensers have low knowledge regarding the harmful effects of drugs during pregnancy. Drug dispensing personnel should be considered part of the therapeutic chain and, if appropriately trained, they will play a very important role in promoting rational use of medicines.


A broader view on jamming: from spring networks to circle packings.
Jamming occurs when objects like grains are packed tightly together (e.g. grain silos). It is highly cooperative and can lead to phenomena like earthquakes, traffic jams, etc. In this paper we point out the paramount importance of the underlying contact network for jammed systems; the network must have one contact in excess of isostaticity and a finite bulk modulus. Isostatic means that the number of degrees of freedom is exactly balanced by the number of constraints. This defines a large class of networks that can be constructed without the necessity of packing particles together compressively (either in the lab or computationally). One such construction, which we explore here, involves setting up the Delaunay triangulation of a Poisson disk sampling and then removing edges to maximize the bulk modulus until the isostatic plus one edge is reached. This construction works in any dimensions and here we give results in 2D where we also show how such networks can be transformed into disk packs.


DNAzyme logic-controlled biofuel cells for self-powered biosensors.
The integration of a biosensor employing a DNAzyme logic system within a biofuel cell is presented. The self-powered DNAzyme logic biosensor conforms with INH logic operation and generates power output in accordance with a truth table. The new concept of logic-activated DNAzyme by the input signals has wide-ranging implications in the self-powered diagnostics domain.


Quality of Care Indicators in Patients with Acute Pancreatitis.
Acute pancreatitis (AP) is a common and expensive condition. Improving quality of care in AP is vital to minimizing cost and improving patient outcomes. However, there has been little work accomplished toward developing and validating explicit quality indicators (QIs) in AP. To define quality of care in patients with AP by developing explicit QIs using standardized techniques. We used the UCLA/RAND Delphi panel approach to combine a comprehensive literature review with the collective judgment of experts to identify a defined set of process measures for AP. We produced 164 candidate QIs after a comprehensive literature review. After Delphi review, 75 had a median rating ≥ 7. We excluded 11 QIs where the disagreement index exceeded 1.0 and combined indicators overlapping in content to produce a final list of 22 QIs. Overall, 8 QIs related to diagnosis, prevention, or determination of etiology, 2 QIs focused on determination of severity, 3 QIs captured fluid resuscitation, 2 QIs measured nutrition, 1 QI use of antibiotics, and 6 QIs captured endoscopic or surgical management. We have developed 22 QIs spanning the spectrum of AP management including diagnosis, risk stratification, and pharmacological and endoscopic therapy. These QIs will facilitate future quality improvement by practitioners and organizations who treat patients with AP and further identify areas that are amenable to improvement to enhance patient care. We anticipate that this QI set will represent the first step in determining a framework for demonstrating value in the care of patients with AP.


Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats.
In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.


Assessing Heat-Related Mortality Risks among Rural Populations: A Systematic Review and Meta-Analysis of Epidemiological Evidence.
Most epidemiological studies of high temperature effects on mortality have focused on urban settings, while heat-related health risks in rural areas remain underexplored. To date there has been no meta-analysis of epidemiologic literature concerning heat-related mortality in rural settings. This study aims to systematically review the current literature for assessing heat-related mortality risk among rural populations. We conducted a comprehensive literature search using PubMed, Web of Science, and Google Scholar to identify articles published up to April 2018. Key selection criteria included study location, health endpoints, and study design. Fourteen studies conducted in rural areas in seven countries on four continents met the selection criteria, and eleven were included in the meta-analysis. Using the random effects model, the pooled estimates of relative risks (RRs) for all-cause and cardiovascular mortality were 1.030 (95% CI: 1.013, 1.048) and 1.111 (95% CI: 1.045, 1.181) per 1 °C increase in daily mean temperature, respectively. We found excess risks in rural settings not to be smaller than risks in urban settings. Our results suggest that rural populations, like urban populations, are also vulnerable to heat-related mortality. Further evaluation of heat-related mortality among rural populations is warranted to develop public health interventions in rural communities.


Encapsulation of implicit and explicit memory in sequence learning.
Contrasts between implicit and explicit knowledge in the serial reaction time (SJRT) paradigm have been challenged because they have depended on a single dissociation; intact implicit knowledge in the absence of corresponding explicit knowledge. In the SRT task, subjects respond with a corresponding keypress to a cue that appears in one of four locations. The cue follows a repeating sequence of locations, and subjects can exhibit knowledge of the repeating sequence through increasingly rapid performance (an implicit test) or by being able to recognize the sequence (an explicit test). In our study, amnesic patients were given extensive SRT training. Their implicit and explicit test performance was compared to the performance of control subjects who memorized the training sequence. Compared with control subjects, amnesic patients exhibited superior performance on the implicit task and impaired performance on the explicit task. This crossover interaction suggests that implicit and explicit knowledge of the embedded sequence are separate and encapsulated and that they presumably depend on different brain systems.


Molecular phylogeny of Crematogaster subgenus Decacrema ants (Hymenoptera: Formicidae) and the colonization of Macaranga (Euphorbiaceae) trees.
To elucidate the evolution of one of the most species-rich ant-plant symbiotic systems, the association between Crematogaster (Myrmicinae) and Macaranga (Euphorbiaceae) in South-East Asia, we conducted a phylogenetic analysis of the ant partners. For the phylogenetic analysis partial mitochondrial cytochrome oxidase I and II were sequenced and Maximum Parsimony analysis was performed. The analyzed Crematogaster of the subgenus Decacrema fell into three distinct clades which are also characterized by specific morphological and ecological traits (queen morphology, host-plants, and colony structure). Our results supported the validity of our currently used morphospecies concept for Peninsula Malaysia. However, on a wider geographic range (including North and North-East Borneo) some morphospecies turned out to be species complexes with genetically quite distinct taxa. Our phylogenetic analysis and host association studies do not indicate strict cocladogenesis between the subgenus Decacrema and their Macaranga host-plants because multiple ant taxa occur on quite distinct host-plants belonging to different clades within in the genus Macaranga. These results support the view that host-shifting or host-expansion is common in the ants colonizing Macaranga. Additionally, the considerable geographic substructuring found in the phylogenetic trees of the ants suggests that allopatric speciation has also played a role in the diversification and the current distribution of the Decacrema ants.


Factors influencing effect of mammography screening in a university workplace.
The purpose of this study was to examine the relationship between theoretically identified variables and participation in mammography screening in a university workplace. A sample of 1093 women 50 and over returned a questionnaire following the offer of a free workplace breast cancer screening. Anderson's Behavioral Model of Health Services Use identified factors predisposing and enabling women to have mammograms. Predisposing variables included attitudes and experience related to mammography. Enabling variables included income, willingness to pay for mammography, health insurance coverage, and regular source of health care. Comparisons were made among: (i) those who were screened in the workplace, (ii) those who were screened elsewhere, and (iii) those who were not screened. Differences in perceived barriers, perceived benefits, practice of breast self-examination (BSE), and education surfaced. Results indicated, among other things, that women who were older, had no more than 12 years of education, had a family member with breast cancer, and were proficient with breast self-examination were more likely to have participated in the university work-site screening.


Time-resolved Förster-resonance-energy-transfer DNA assay on an active CMOS microarray.
We present an active oligonucleotide microarray platform for time-resolved Förster-resonance-energy-transfer (TR-FRET) assays. In these assays, immobilized probe is labeled with a donor fluorophore and analyte target is labeled with a fluorescence quencher. Changes in the fluorescence decay lifetime of the donor are measured to determine the extent of hybridization. In this work, we demonstrate that TR-FRET assays have reduced sensitivity to variances in probe surface density compared with standard fluorescence-based microarray assays. Use of an active array substrate, fabricated in a standard complementary metal-oxide-semiconductor (CMOS) process, provides the additional benefits of reduced system complexity and cost. The array consists of 4096 independent single-photon avalanche diode (SPAD) pixel sites and features on-chip time-to-digital conversion. We demonstrate the functionality of our system by measuring a DNA target concentration series using TR-FRET with semiconductor quantum dot donors.


Octave-spanning carrier-envelope phase stabilized visible pulse with sub-3-fs pulse duration.
The visible second harmonic of the idler output from a noncollinear optical parametric amplifier was compressed using adaptive dispersion control with a deformable mirror. The amplifier was pumped by and seeded in the signal path by a common 400 nm second-harmonic pulse from a Ti:sapphire regenerative amplifier. Thus, both the idler output and the second harmonic of the idler were passively carrier-envelope phase stabilized. The shortest pulse duration achieved was below 3 fs.


Formation of the 'Great Unconformity' as a trigger for the Cambrian explosion.
The transition between the Proterozoic and Phanerozoic eons, beginning 542 million years (Myr) ago, is distinguished by the diversification of multicellular animals and by their acquisition of mineralized skeletons during the Cambrian period. Considerable progress has been made in documenting and more precisely correlating biotic patterns in the Neoproterozoic-Cambrian fossil record with geochemical and physical environmental perturbations, but the mechanisms responsible for those perturbations remain uncertain. Here we use new stratigraphic and geochemical data to show that early Palaeozoic marine sediments deposited approximately 540-480 Myr ago record both an expansion in the area of shallow epicontinental seas and anomalous patterns of chemical sedimentation that are indicative of increased oceanic alkalinity and enhanced chemical weathering of continental crust. These geochemical conditions were caused by a protracted period of widespread continental denudation during the Neoproterozoic followed by extensive physical reworking of soil, regolith and basement rock during the first continental-scale marine transgression of the Phanerozoic. The resultant globally occurring stratigraphic surface, which in most regions separates continental crystalline basement rock from much younger Cambrian shallow marine sedimentary deposits, is known as the Great Unconformity. Although Darwin and others have interpreted this widespread hiatus in sedimentation on the continents as a failure of the geologic record, this palaeogeomorphic surface represents a unique physical environmental boundary condition that affected seawater chemistry during a time of profound expansion of shallow marine habitats. Thus, the formation of the Great Unconformity may have been an environmental trigger for the evolution of biomineralization and the 'Cambrian explosion' of ecologic and taxonomic diversity following the Neoproterozoic emergence of animals.


Abundance of commercially important reef fish indicates different levels of over-exploitation across shelves of the U.S. Virgin Islands.
The United States Virgin Islands are comprised of two separate insular platforms separated by the deep water Anegada Passage. Although managed by the same regulations, as one fishery, several physical and spatial differences exist between the two northern shelf islands, St. Thomas and St. John, and isolated St. Croix. Based on two long-term fisheries independent datasets, collected by the U.S. Virgin Islands Territorial Coral Reef Monitoring Program and the National Oceanographic and Atmospheric Administration Center for Coastal Monitoring and Assessment, there were significant differences between the northern USVI and St. Croix in both the occurrence and size of several species of large and commercially important reef fishes. These fishes are primarily apex piscivores and generally the first species over-exploited in small-scale fisheries. The disparities between the fish communities on the two island shelves cannot be explained solely by differences in habitat (coral cover, rugosity) or fisheries management, such as relative amount of marine protected area in local waters. They are instead probably caused by a combination of several other interrelated factors including water depth, fishing methodology, fishable area, and the presence or absence of viable fish spawning areas. This study considers those aspects, and illustrates the need for management of island artisanal fisheries that is tailored to the physical and spatial constraints imposed by insular platforms.


A novel chimeric DNA vaccine: enhancement of preventive and therapeutic efficacy of DNA vaccine by fusion of Mucin 1 to a heat shock protein 70 gene.
Intensive efforts to improve vaccines against cancer are currently outgoing. Mucin 1 (Muc1) is a tumor-specific antigen that is overexpressed and heavily glycosylated in a variety of adenocarcinomas. In the present study, the efficacy of an anticancer DNA vaccination strategy was demonstrated using Muc1 fusion vaccines. To enhance antigen presentation and tumor-suppressive efficacy, a chimeric Muc1 vaccine was designed, encoding the transmembrane- and C-terminal domain-deleted Muc1 gene (∆TM) fused to the human HSP70 gene. To confirm the expression and secretion of fusion protein, cell culture supernatants were subjected to Western blotting. We found secreted Muc1 ΔTM-HSP0 fusion protein in the supernatants. These results demonstrate that the Muc1 ΔTM-HSP0 construct can be efficiently expressed and secreted from transfected cells. When the chimeric Muc1 vaccine was administered to mice, antigen-specific cellular immune responses were observed. Notably, we observed that antigen-specific lymphocyte proliferation and cytotoxic responses were effectively induced only in the group of mice that had been vaccinated with the chimeric Muc1 vaccine. Concurrent with the Muc1-specific tumor-suppressive effect, the growth of established Muc1-expressing B16 mouse melanoma cells was also significantly inhibited by vaccination with the chimeric Muc1 vaccine. The growth of B16 mouse melanoma cells expressing human Muc1 in C57BL/6 mice was effectively suppressed by the Muc1-HSP70 chimeric DNA vaccine. Our results reveal that the antitumor efficacy of the chimeric DNA vaccine was improved by the presence of HSP/70.


The impact of rheumatoid arthritis on foot function in the early stages of disease: a clinical case series.
Foot involvement occurs early in rheumatoid arthritis but the extent to which this impacts on the structure and function leading to impairment and foot related disability is unknown. The purpose of this study was to compare clinical disease activity, impairment, disability, and foot function in normal and early rheumatoid arthritis (RA) feet using standardised clinical measures and 3D gait analysis. Twelve RA patients with disease duration < or =2 years and 12 able-bodied adults matched for age and sex underwent 3D gait analysis to measure foot function. Disease impact was measured using the Leeds Foot impact Scale (LFIS) along with standard clinical measures of disease activity, pain and foot deformity. For this small sample, the mean differences between the groups and associated confidence intervals were calculated using the t distribution Moderate-to-high foot impairment and related disability were detected amongst the RA patients. In comparison with age- and sex-matched controls, the patients with early RA walked slower (1.05 m/s Vs 1.30 m/s) and had a longer double-support phase (19.3% Vs 15.8%). In terminal stance, the heel rise angle was reduced in the patients in comparison with normal (-78.9 degrees Vs -85.7 degrees). Medial arch height was lower and peak eversion in stance greater in the RA patients. The peak ankle plantarflexion power profile was lower in the patients in comparison with the controls (3.4 W/kg Vs 4.6 W/kg). Pressure analysis indicated that the RA patients had a reduced lesser toe contact area (7.6 cm2 Vs 8.1 cm2), elevated peak forefoot pressure (672 kPa Vs 553 kPa) and a larger mid-foot contact area (24.6 cm2 Vs 19.4 cm2). Analysis detected small but clinically important changes in foot function in a small cohort of RA patients with disease duration <2 years. These were accompanied by active joint disease and impairment and disability.


Allium sativum potentiates suicide gene therapy for murine transitional cell carcinoma.
This study evaluated the synergistic effect of Allium sativum (AS) with suicide gene therapy for transitional cell carcinoma (TCC) of the bladder. Subcutaneous TCCs were established in syngeneic C3H/He mice with 1 x 10(5) MBT-2 cells. AS liquid extract was injected at the site of tumor transplantation on Day 1 for three weeks (Experiment I) and into the established tumors weekly for five weeks (Experiment II) in combination with or without gene therapy using a replication-defective adenoviral vector containing a herpes simplex virus thymidine kinase (HSV-TK) gene under the transcriptional control of Rous sarcoma virus (RSV) promoter (Ad-RSV-TK, 5 x 10(8) plaque-forming units) plus ganciclovir (20 mg/kg/day i.p.). AS demonstrated a statistically significant reduction in incidence of TCC (cumulative dose 25 mg of AS). Combination AS-suicide gene therapy significantly inhibited the tumor growth compared with the controls, which was evidenced by apoptosis on histomorphological and immunohistochemical studies. These results suggest that AS had a definite antitumor effect in inhibiting tumorigenesis and growth of TCC in a murine model. AS treatment combined with suicide gene therapy had significant additive antitumor effects on TCC and may provide a novel and effective treatment modality for TCC of the bladder.


Birds, primates, and spoken language origins: behavioral phenotypes and neurobiological substrates.
Vocal learners such as humans and songbirds can learn to produce elaborate patterns of structurally organized vocalizations, whereas many other vertebrates such as non-human primates and most other bird groups either cannot or do so to a very limited degree. To explain the similarities among humans and vocal-learning birds and the differences with other species, various theories have been proposed. One set of theories are motor theories, which underscore the role of the motor system as an evolutionary substrate for vocal production learning. For instance, the motor theory of speech and song perception proposes enhanced auditory perceptual learning of speech in humans and song in birds, which suggests a considerable level of neurobiological specialization. Another, a motor theory of vocal learning origin, proposes that the brain pathways that control the learning and production of song and speech were derived from adjacent motor brain pathways. Another set of theories are cognitive theories, which address the interface between cognition and the auditory-vocal domains to support language learning in humans. Here we critically review the behavioral and neurobiological evidence for parallels and differences between the so-called vocal learners and vocal non-learners in the context of motor and cognitive theories. In doing so, we note that behaviorally vocal-production learning abilities are more distributed than categorical, as are the auditory-learning abilities of animals. We propose testable hypotheses on the extent of the specializations and cross-species correspondences suggested by motor and cognitive theories. We believe that determining how spoken language evolved is likely to become clearer with concerted efforts in testing comparative data from many non-human animal species.


Geometric nomenclature and classification of RNA base pairs.
Non-Watson-Crick base pairs mediate specific interactions responsible for RNA-RNA self-assembly and RNA-protein recognition. An unambiguous and descriptive nomenclature with well-defined and nonoverlapping parameters is needed to communicate concisely structural information about RNA base pairs. The definitions should reflect underlying molecular structures and interactions and, thus, facilitate automated annotation, classification, and comparison of new RNA structures. We propose a classification based on the observation that the planar edge-to-edge, hydrogen-bonding interactions between RNA bases involve one of three distinct edges: the Watson-Crick edge, the Hoogsteen edge, and the Sugar edge (which includes the 2'-OH and which has also been referred to as the Shallow-groove edge). Bases can interact in either of two orientations with respect to the glycosidic bonds, cis or trans relative to the hydrogen bonds. This gives rise to 12 basic geometric types with at least two H bonds connecting the bases. For each geometric type, the relative orientations of the strands can be easily deduced. High-resolution examples of 11 of the 12 geometries are presently available. Bifurcated pairs, in which a single exocyclic carbonyl or amino group of one base directly contacts the edge of a second base, and water-inserted pairs, in which single functional groups on each base interact directly, are intermediate between two of the standard geometries. The nomenclature facilitates the recognition of isosteric relationships among base pairs within each geometry, and thus facilitates the recognition of recurrent three-dimensional motifs from comparison of homologous sequences. Graphical conventions are proposed for displaying non-Watson-Crick interactions on a secondary structure diagram. The utility of the classification in homology modeling of RNA tertiary motifs is illustrated.


Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury.
Susceptibility to ischemic damage to the subcortical white matter of the brain has a strong genetic basis. Dysregulation of matrix metalloproteinases (MMPs) contributes to loss of cerebrovascular integrity and white matter injury. We investigated whether sequence variation in the genes encoding MMP3 and MMP9 is associated with variation in leukoaraiosis volume, determined by magnetic resonance imaging, in non-Hispanic whites and African-Americans using family-based association tests. Seven hundred and fifty-six white and 671 African-American individuals from sibships ascertained through two or more siblings with hypertension were genotyped for 7 and 8 haplotype-tagging polymorphisms in the MMP3 and MMP9 genes, respectively. MMP3 sequence variation was significantly associated with variation in leukoaraiosis volume in Whites. Two common haplotypes with opposing relationships to leukoaraiosis volume were identified. MMP9 sequence variation was also significantly associated with variation in leukoaraiosis volume in both African-Americans and Whites. Different haplotypes contributed to these associations in the two racial groups. These findings add to the growing body of evidence from animal models and human clinical studies suggesting a role of MMPs in ischemic white matter injury. They provide the basis for further investigation of the role of these genes in susceptibility and/or progression to clinical disease.


Research progress on electronic phase separation in low-dimensional perovskite manganite nanostructures.
Perovskite oxide manganites with a general formula of R1-x AxMnO3 (where R is a trivalent rare-earth element such as La, Pr, Sm, and A is a divalent alkaline-earth element such as Ca, Sr, and Ba) have received much attention due to their unusual electron-transport and magnetic properties, which are indispensable for applications in microelectronic, magnetic, and spintronic devices. Recent advances in the science and technology have resulted in the feature sizes of microelectronic devices based on perovskite manganite oxides down-scaling into nanoscale dimensions. At the nanoscale, low-dimensional perovskite manganite oxide nanostructures display novel physical properties that are different from their bulk and film counterparts. Recently, there is strong experimental evidence to indicate that the low-dimensional perovskite manganite oxide nanostructures are electronically inhomogeneous, consisting of different spatial regions with different electronic orders, a phenomenon that is named as electronic phase separation (EPS). As the geometry sizes of the low-dimensional manganite nanostructures are reduced to the characteristic EPS length scale (typically several tens of nanometers in manganites), the EPS is expected to be strongly modulated, leading to quite dramatic changes in functionality and more emergent phenomena. Therefore, reduced dimensionality opens a door to the new functionalities in perovskite manganite oxides and offers a way to gain new insight into the nature of EPS. During the past few years, much progress has been made in understanding the physical nature of the EPS in low-dimensional perovskite manganite nanostructures both from experimentalists and theorists, which have a profound impact on the oxide nanoelectronics. This nanoreview covers the research progresses of the EPS in low-dimensional perovskite manganite nanostructures such as nanoparticles, nanowires/nanotubes, and nanostructured films and/or patterns. The possible physical origins of the EPS are also discussed from the signatures of electronic inhomogeneities as well as some theoretical scenarios, to shed light on understanding this phenomenon. Finally, the perspectives to the future researches in this area are also outlined.


Mandibular corpus bone strain in goats and alpacas: implications for understanding the biomechanics of mandibular form in selenodont artiodactyls.
The goal of this study is to clarify the functional and biomechanical relationship between jaw morphology and in vivo masticatory loading in selenodont artiodactyls. We compare in vivo strains from the mandibular corpus of goats and alpacas to predicted strain patterns derived from biomechanical models for mandibular corpus loading during mastication. Peak shear strains in both species average 600-700 microepsilon on the working side and approximately 450 microepsilon on the balancing side. Maximum principal tension in goats and alpacas is directed at approximately 30 degrees dorsocaudally relative to the long axis of the corpus on the working side and approximately perpendicular to the long axis on the balancing side. Strain patterns in both species indicate primarily torsion of the working-side corpus about the long axis and parasagittal bending and/or lateral transverse bending of the balancing-side corpus. Interpretation of the strain patterns is consistent with comparative biomechanical analyses of jaw morphology suggesting that in goats, the balancing-side mandibular corpus is parasagittally bent whereas in alpacas it experiences lateral transverse bending. However, in light of higher working-side corpus strains, biomechanical explanations of mandibular form also need to consider that torsion influences relative corpus size and shape. Furthermore, the complex combination of loads that occur along the selenodont artiodactyl mandibular corpus during the power stroke has two implications. First, added clarification of these loading patterns requires in vivo approaches for elucidating biomechanical links between mandibular corpus morphology and masticatory loading. Second, morphometric approaches may be limited in their ability to accurately infer masticatory loading regimes of selenodont artiodactyl jaws.


OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.
Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing. Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.


The role of age in post-cardiac arrest therapy in an elderly patient population.
We investigated the effect of age on post-cardiac arrest treatment outcomes in an elderly population, based on a local database and a systemic review of the literature. Data were collected retrospectively from medical charts and reports. Sixty-one comatose patients, cooled to 32-34 °C for 24 h, were categorized into three groups: younger group (≤65 years), older group (66-75 years), and very old group (>75 years). Circumstances of cardiopulmonary resuscitation (CPR), patients' characteristics, post-resuscitation treatment, hemodynamic monitoring, neurologic outcome and survival were compared across age groups. Kruskal-Wallis test, Chi-square test and binary logistic regression (BLR) were applied. In addition, a literature search of PubMed/Medline database was performed to provide a background. Age was significantly associated with having a cardiac arrest on a monitor and a history of hypertension. No association was found between age and survival or neurologic outcome. Age did not affect hemodynamic parameter changes during target temperature management (TTM), except mean arterial pressure (MAP). Need of catecholamine administration was the highest among very old patients. During the literature review, seven papers were identified. Most studies had a retrospective design and investigated interventions and outcome, but lacked unified age categorization. All studies reported worse survival in the elderly, although old survivors showed a favorable neurologic outcome in most of the cases. There is no evidence to support the limitation of post-cardiac arrest therapy in the aging population. Furthermore, additional prospective studies are needed to investigate the characteristics and outcome of post-cardiac arrest therapy in this patient group.


Chemoprevention of oral squamous cell carcinomas.
Among individuals with a history of head and neck cancer and tobacco abuse the risk of second primary cancers in the upper aerodigestive tract is high. Chemoprevention of oral squamous cell carcinomas is based on two conditions: Premalignant mucosa lesions are treated with chemopreventive agents in order to prevent malignant conversion (primary prevention). In secondary prevention of oral cancer, after curative therapy patients are treated by chemoprevention in order to reduce the rate of second primaries. This paper presents a comprehensive clinical review of oral cancer prevention studies, highlighting the agents mostly used, such as beta-carotene, alpha-tocopherol, ascorbic acid, and retinoids. Although most intervention trials showed good overall response with these substances, high relapse rates and serious side effects, in most cases related to the retinoid compounds were noticed. In addition, in all prospective randomized chemoprevention trials (CARET, ATBC and PHS) no significant evidence of benefit for supplementation with alpha-tocopherol, beta-carotene or retinyl palmitate was reported.


Math learning disorder: incidence in a population-based birth cohort, 1976-82, Rochester, Minn.
To report the incidence of math learning disorder (Math LD) among school-aged children, overall and by gender. To compare incidence estimates obtained by using three different methods to identify Math LD cases. To assess the extent to which children manifest Math LD alone, versus Math LD with comorbid reading disorder. This is a population-based, retrospective, birth cohort study. Subjects included all children born 1976-82 who remained in Rochester, Minn after age 5 (N = 5718). Using records from all public and private schools, medical facilities, and private tutorial services, all individually administered intelligence quotient and achievement tests and extensive medical, educational, and socioeconomic information were abstracted. Math LD was established using research criteria based on 3 formulas (regression-based discrepancy, nonregression-based discrepancy, low achievement). Cumulative incidence rates of Math LD by age 19 years varied from 5.9% to 13.8% according to the formula used. Boys were more likely to be affected than girls, with relative risk ratios from 1.6 to 2.2 depending on the formula applied. Many children with Math LD (35% to 56.7%, depending on the formula used to define Math LD) did not have a comorbid reading disorder. These results, from a community-based birth cohort, suggest that Math LD is common among schoolchildren, and is significantly more frequent among boys than girls, regardless of definition. Many children with Math LD do not have an associated reading disorder.


Depressive symptoms and work role satisfaction in mothers of toddlers.
To determine the incidence of depressive symptoms in mothers of toddlers in community pediatric practice. The interaction of employment and work role satisfaction with depressive symptoms was also investigated. Depression screening measures were completed by 233 mothers of toddlers (aged 12 to 24 months) at health supervision visits in two community pediatric practices in New Hampshire. Depression was evaluated with a depressive symptom screening inventory modified by Barrett, Oxman, and Gerber from the Hopkins Symptom Checklist for use in primary care population. Data were obtained on parents' socioeconomic variables, hours worked, and whether the mother was satisfied with her current role of being employed or not employed. Depressive symptoms were present in 42% of mothers. Rates of depressive symptoms were similar in employment groups but varied significantly with work role satisfaction. When both employment and satisfaction were considered, mothers who were dissatisfied were 3.7 times more likely to be depressed. After controlling for work role satisfaction, mothers working part time were half as likely to be depressed as mothers working full time and not employed. Depressive symptoms are a major problem for mothers of toddlers in middle class pediatric practice. Work role satisfaction and employment status together are related to depressive symptoms.


Two ways of experimental infection of Ixodes ricinus ticks (Acari: Ixodidae) with spirochetes of Borrelia burgdorferi sensu lato complex.
A previously reported procedure for the introduction of Borrelia spirochetes into tick larvae by immersion in a suspension of spirochetes was tested on Ixodes ricinus (L.) ticks and three of the most medically important European Borrelia genomic species, B. burgdorferi sensu stricto, B. garinii and B. afzelii. The procedure was compared with "classical" infection of nymphs by feeding on infected mice. Both methods yielded comparable results (infection rate 44-65%) with the exception of B. afzelii, which produced better results using the immersion method (44%) compared with feeding on infected mice (16%). Nymphs infected by the immersion method at the larval stage were able to transmit the infection to naïve mice as shown by serology and PCR detection of spirochetal DNA in organs. The immersion method is faster than feeding on infected mice and provides more reproducible conditions for infection. It can be exploited for studies on both pathogen transmission and Borrelia-vector interactions.


CNS amyloid proteins in neurodegenerative diseases.
The amyloid plaques found in neurodegenerative diseases show considerable morphologic diversity. Two amyloidogenic proteins have been isolated from the brains of humans and animals with neurodegenerative diseases--beta-protein from Alzheimer's disease (AD) and Down's syndrome, and prion protein (PrP) from scrapie and Creutzfeldt-Jakob disease (CJD). Using monoclonal antibodies to a synthetic peptide corresponding to a portion of beta-protein and rabbit antiserum to hamster scrapie PrP 27-30, we examined in situ amyloid plaques on sections from cases of neurodegenerative diseases, including cases with a spectrum of plaque types. Anti-beta-peptide stained cerebrovascular and plaque core amyloid in all AD cases as well as cerebrovascular amyloid and senile plaque core amyloid in five elderly CJD cases. Anti-PrP stained plaques in CJD, kuru, and Gerstmann-Sträussler syndrome cases but not cerebrovascular amyloid or plaques in AD. Dual localization experiments showed that in cases with a mixture of plaque types, the antibodies identified different populations of plaques that showed anatomic heterogeneity. Colocalization of the two proteins was not observed in any plaque type. The data suggest that in neurodegenerative diseases two major plaque types exist, which have different etiologic origins. Our results emphasize the need for classification of CNS amyloids based not on their morphology but on the macromolecular components comprising these pathologic polymers.


Two regulators of Vibrio parahaemolyticus play important roles in enterotoxicity by controlling the expression of genes in the Vp-PAI region.
Vibrio parahaemolyticus is an important pathogen causing food-borne disease worldwide. An 80-kb pathogenicity island (Vp-PAI), which contains two tdh (thermostable direct hemolysin) genes and a set of genes for the type III secretion system (T3SS2), is closely related to the pathogenicity of this bacterium. However, the regulatory mechanisms of Vp-PAI's gene expression are poorly understood. Here we report that two novel ToxR-like transcriptional regulatory proteins (VtrA and VtrB) regulate the expression of the genes encoded within the Vp-PAI region, including those for TDH and T3SS2-related proteins. Expression of vtrB was under control of the VtrA, as vector-expressed vtrB was able to recover a functional protein secretory capacity for T3SS2, independent of VtrA. Moreover, these regulatory proteins were essential for T3SS2-dependent biological activities, such as in vitro cytotoxicity and in vivo enterotoxicity. Enterotoxic activities of vtrA and/or vtrB deletion strains derived from the wild-type strain were almost absent, showing fluid accumulation similar to non-infected control. Whole genome transcriptional profiling of vtrA or vtrB deletion strains revealed that the expression levels of over 60 genes were downregulated significantly in these deletion mutant strains and that such genes were almost exclusively located in the Vp-PAI region. These results strongly suggest that VtrA and VtrB are master regulators for virulence gene expression in the Vp-PAI and play critical roles in the pathogenicity of this bacterium.


Cutting edge: the ontogeny and function of Va14Ja18 natural T lymphocytes require signal processing by protein kinase C theta and NF-kappa B.
The rapid and robust immunoregulatory cytokine response of Va14Ja18 natural T (iNKT) cells to glycolipid Ags determines their diverse functions. Unlike conventional T cells, iNKT lymphocyte ontogeny absolutely requires NF-kappa B signaling. However, the precise role of NF-kappa B in iNKT cell function and the identity of upstream signals that activate NF-kappa B in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-kappa B signaling, we demonstrate that iNKT cell function requires NF-kappa B in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase C theta, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase C theta implies that signals emanating from the TCR activate NF-kappa B during iNKT cell development and function. Thus, we conclude that NF-kappa B signaling plays a crucial role at distinct levels of iNKT cell biology.


Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey.
To evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in a series of patients with inherited complete IFN-gamma receptor 1 (IFNgammaR1) deficiency. We report 8 patients who received altogether 11 HSCT from family donors, including 10 HLA-identical (5 siblings and 5 relatives) and 1 HLA-haplo-identical donors. Five grafts were T-cell depleted, and conditioning regimens varied in intensity. Four patients died within 8 months after HSCT. Two of these deaths were due to specific complications related to mycobacterial infection. There was no or very low (2%) donor cell engraftment in 2 survivors. Only 2 patients are in full remission of mycobacterial disease 5 years after HSCT. These are the only patients who received non-T-cell-depleted grafts from an HLA-identical sibling after a fully myeloablative conditioning regimen. HSCT can lead to prolonged remission of mycobacterial disease in children with complete IFNgammaR1 deficiency. However, optimal control of mycobacterial infection before HSCT and the use of a non-T-cell-depleted transplant from an HLA-identical sibling after a fully myeloablative conditioning regimen are recommended.


The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors.
The class A scavenger receptor (cA-SR) family is a group of five evolutionarily related innate immune receptors. The cA-SRs are known for their promiscuous ligand binding; as they have been shown to bind bacteria, such as Streptococcus pneumoniae and Escherichia coli, as well as different modified forms of low-density lipoprotein. Three of the five family members possess a scavenger receptor cysteine-rich (SRCR) domain while the remaining two receptors lack the domain. Previous work has suggested that the macrophage-associated receptor with collagenous structure (MARCO) shares a recent common ancestor with the non-SRCR-containing receptors; however, the origin of the SRCR domain within the cA-SRs remains unknown. We hypothesize that the SRCR domains of the cA-SRs have a common origin that predates teleost fish. Using the newly available sequence data from sea lamprey and ghost shark genome projects, we have shown that MARCO shares a common ancestor with the SRCR-containing proteins. In addition, we explored the evolutionary relationships within the SRCR domain by reconstructing the ancestral SRCR domains of the cA-SRs. We identified a motif that is highly conserved between the cA-SR SRCR domains and the ancestral SRCR domain that consist of WGTVCDD. We also show that the GRAEVYY motif, a functionally important motif within MARCO, is poorly conserved in the other cA-SRs and in the reconstructed ancestral domain. Further, we identified three sites within MARCO's SRCR domain, which are under positive selection. Two of these sites lie adjacent to the conserved WGTVCDD motif, and may indicate a potential biological function for these sites. Together, these findings indicate a common origin of the SRCR domain within the cA-SRs; however, different selective pressures between the proteins may have caused MARCOs SRCR domain to evolve to contain different functional motifs when compared to the other SRCR-containing cA-SRs.


Dubious decision evidence and criterion flexibility in recognition memory.
When old-new recognition judgments must be based on ambiguous memory evidence, a proper criterion for responding "old" can substantially improve accuracy, but participants are typically suboptimal in their placement of decision criteria. Various accounts of suboptimal criterion placement have been proposed. The most parsimonious, however, is that subjects simply over-rely on memory evidence - however faulty - as a basis for decisions. We tested this account with a novel recognition paradigm in which old-new discrimination was minimal and critical errors were avoided by adopting highly liberal or conservative biases. In Experiment 1, criterion shifts were necessary to adapt to changing target probabilities or, in a "security patrol" scenario, to avoid either letting dangerous people go free (misses) or harming innocent people (false alarms). Experiment 2 added a condition in which financial incentives drove criterion shifts. Critical errors were frequent, similar across sources of motivation, and only moderately reduced by feedback. In Experiment 3, critical errors were only modestly reduced in a version of the security patrol with no study phase. These findings indicate that participants use even transparently non-probative information as an alternative to heavy reliance on a decision rule, a strategy that precludes optimal criterion placement.


Antibiotic prophylaxis to prevent spontaneous bacterial peritonitis in people with liver cirrhosis: a network meta-analysis.
Approximately 2.5% of all hospitalisations in people with liver cirrhosis are for spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is associated with significant short-term mortality; therefore, it is important to prevent spontaneous bacterial peritonitis in people at high risk of developing it. Antibiotic prophylaxis forms the mainstay preventive method, but this has to be balanced against the development of drug-resistant spontaneous bacterial peritonitis, which is difficult to treat, and other adverse events. Several different prophylactic antibiotic treatments are available; however, there is uncertainty surrounding their relative efficacy and optimal combination. To compare the benefits and harms of different prophylactic antibiotic treatments for prevention of spontaneous bacterial peritonitis in people with liver cirrhosis using a network meta-analysis and to generate rankings of the different prophylactic antibiotic treatments according to their safety and efficacy. We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to November 2018 to identify randomised clinical trials in people with cirrhosis at risk of developing spontaneous bacterial peritonitis. We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis undergoing prophylactic treatment to prevent spontaneous bacterial peritonitis. We excluded randomised clinical trials in which participants had previously undergone liver transplantation, or were receiving antibiotics for treatment of spontaneous bacterial peritonitis or other purposes. We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We included 29 randomised clinical trials (3896 participants; nine antibiotic regimens (ciprofloxacin, neomycin, norfloxacin, norfloxacin plus neomycin, norfloxacin plus rifaximin, rifaximin, rufloxacin, sparfloxacin, sulfamethoxazole plus trimethoprim), and 'no active intervention' in the review. Twenty-three trials (2587 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, with or without other features of decompensation, having ascites with low protein or previous history of spontaneous bacterial peritonitis. The follow-up in the trials ranged from 1 to 12 months. Many of the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Overall, approximately 10% of trial participants developed spontaneous bacterial peritonitis and 15% of trial participants died. There was no evidence of differences between any of the antibiotics and no intervention in terms of mortality (very low certainty) or number of serious adverse events (very low certainty). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the trials reported health-related quality of life or the proportion of people with serious adverse events. There was no evidence of differences between any of the antibiotics and no intervention in terms of proportion of people with 'any adverse events' (very low certainty), liver transplantation (very low certainty), or the proportion of people who developed spontaneous bacterial peritonitis (very low certainty). The number of 'any' adverse events per participant was fewer with norfloxacin (rate ratio 0.74, 95% CrI 0.59 to 0.94; 4 trials, 546 participants; low certainty) and sulfamethoxazole plus trimethoprim (rate ratio 0.19, 95% CrI 0.02 to 0.81; 1 trial, 60 participants; low certainty) versus no active intervention. There was no evidence of differences between the other antibiotics and no intervention in the number of 'any' adverse events per participant (very low certainty). There were fewer other decompensation events with rifaximin versus no active intervention (rate ratio 0.61, 65% CrI 0.46 to 0.80; 3 trials, 575 participants; low certainty) and norfloxacin plus neomycin (rate ratio 0.06, 95% CrI 0.00 to 0.33; 1 trial, 22 participants; low certainty). There was no evidence of differences between the other antibiotics and no intervention in the number of decompensations events per participant (very low certainty). None of the trials reported health-related quality of life or development of symptomatic spontaneous bacterial peritonitis. One would expect some correlation between the above outcomes, with interventions demonstrating effectiveness across several outcomes. This was not the case. The possible reasons for this include sparse data and selective reporting bias, which makes the results unreliable. Therefore, one cannot draw any conclusions from these inconsistent differences based on sparse data. There was no evidence of any differences in the subgroup analyses (performed when possible) based on whether the prophylaxis was primary or secondary. the source of funding for five trials were organisations who would benefit from the results of the study; six trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 18 trials was unclear. Based on very low-certainty evidence, there is considerable uncertainty about whether antibiotic prophylaxis is beneficial, and if beneficial, which antibiotic prophylaxis is most beneficial in people with cirrhosis and ascites with low protein or history of spontaneous bacterial peritonitis. Future randomised clinical trials should be adequately powered, employ blinding, avoid postrandomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, health-related quality of life, and decompensation events.


Acetabular Subchondral Bone Decortication and Its Role in the Outcome of Cemented Total Hip Replacement in Young Patients.
Long-term fixation of cemented acetabular components can be problematic in younger active patients. Our technique is put forward to improve outcomes and maximize implant survivorship in this particular patient population. We report on a cohort of young adult patients (less than 55 years old) with cemented total hip replacement (THR) using a novel technique in preparing and cementing the acetabulum with a minimum follow-up of 10 years (mean follow-up, 14 years). Retrospectively collected data on clinical and radiological outcomes were reviewed. Sixty-five THRs were performed with the minimum study follow-up period. Average age for patients was 44 years old (range, 19-55 years). The mean Hip Disability and Osteoarthritis Outcome Score for patients at final appointment was 92.7. Radiographs taken at an average of 14 years after operation showed 63 of 65 hips showed no evidence of any radiological loosening. Cup survivorship was 100% at the end of the study period. Our technique of preparing the acetabulum in combination with cement fixation is reproducible with excellent results in a cohort of patients prone to early aseptic loosening of the acetabular component.


Endoscopic augmented reality navigation system for endonasal transsphenoidal surgery to treat pituitary tumors: technical note.
Endoscopes have been commonly used in transsphenoidal surgery to treat pituitary tumors, to compensate for the narrow surgical field. Although many navigation systems have been introduced for neurosurgical procedures, there have been few reports of navigation systems for endoscopic operations. This report presents our recently developed, endoscopic, augmented reality (AR) navigation system. The technology is based on the principles of AR environment technology. The system consisted of a rigid endoscope with light-emitting diodes, an optical tracking system, and a controller. The operation of the optical tracking system was based on two sets of infrared light-emitting diodes, which measured the position and orientation of the endoscope relative to the patient's head. We used the system during endonasal transsphenoidal operations to treat pituitary tumors in 12 recent cases. Anatomic, "real," three-dimensional, virtual images of the tumor and nearby anatomic structures (including the internal carotid arteries, sphenoid sinuses, and optic nerves) were superimposed on real- time endoscopic live images. The system also indicated the positions and directions of the endoscope and the endoscopic beam in three-dimensional magnetic resonance imaging or computed tomographic planes. Furthermore, the colors of the wire-frame images of the tumor changed according to the distance between the tip of the endoscope and the tumor. These features were superior to those of conventional navigation systems, which are available only for operating microscopes. The endoscopic AR navigation system allows surgeons to perform accurate, safe, endoscope-assisted operations to treat pituitary tumors; it is particularly useful for reoperations, in which midline landmarks may be absent. We consider the AR navigation system to be a promising tool for safe, minimally invasive, endonasal, transsphenoidal surgery to treat pituitary tumors.


Spectroelectrochemical analysis of the mechanism of (photo)electrochemical hydrogen evolution at a catalytic interface.
Multi-electron heterogeneous catalysis is a pivotal element in the (photo)electrochemical generation of solar fuels. However, mechanistic studies of these systems are difficult to elucidate by means of electrochemical methods alone. Here we report a spectroelectrochemical analysis of hydrogen evolution on ruthenium oxide employed as an electrocatalyst and as part of a cuprous oxide-based photocathode. We use optical absorbance spectroscopy to quantify the densities of reduced ruthenium oxide species, and correlate these with current densities resulting from proton reduction. This enables us to compare directly the catalytic function of dark and light electrodes. We find that hydrogen evolution is second order in the density of active, doubly reduced species independent of whether these are generated by applied potential or light irradiation. Our observation of a second order rate law allows us to distinguish between the most common reaction paths and propose a mechanism involving the homolytic reductive elimination of hydrogen.


Characterization of Sp1, AP-1, CBF and KRC binding sites and minisatellite DNA as functional elements of the metastasis-associated mts1/S100A4 gene intronic enhancer.
The mts1/S100A4 gene encodes a small acidic calcium-binding protein that is expressed in a cell-specific manner in development, tumorigenesis and certain tissues of adult mice. A composite enhancer that is active in murine mammary adenocarcinoma cells was previously identified in the first intron of the mts1/S100A4 gene. Here we present a detailed analysis of the structure and function of this enhancer in the Mts1/S100A4-expressing CSML100 and non-expressing CSML0 mouse adenocarcinoma cell lines. In CSML100 cells the enhancer activity is composed of at least six cis-elements interacting with Sp1 and AP-1 family members and CBF/AML/PEBP2 and KRC transcription factors. In addition, a minisatellite-like DNA sequence significantly contributes to the enhancer activity via interaction with abundant proteins, which likely have been described previously under the name minisatellite-binding proteins. Extensive mutational analysis of the mts1/S100A4 enhancer revealed a cooperative function of KRC and the factors binding minisatellite DNA. This is the first example of an enhancer where two nuclear factors earlier implicated in different recombination processes cooperate to activate transcription. In Mts1/S100A4-negative CSML0 cells the strength of the enhancer was 7- to 12.5-fold lower compared to that in CSML100 cells, when referred to the activities of three viral promoters. In CSML0 cells the enhancer could be activated by exogenous AP-1 and CBF transcription factors.


Riding the knowledge translation roundabout: lessons learned from the Canadian Institutes of Health Research Summer Institute in knowledge translation.
Funding the education and training of the next generation of health researchers is a key mandate of the Canadian Institutes of Health Research (CIHR) knowledge translation (KT) portfolio. The field of KT is growing daily; thus, the training and development of a new generation of KT researchers is essential. Using curriculum documents, participant evaluations, and self-reflection, this paper describes a unique Summer Institute hosted by the CIHR in Cornwall, Ontario, Canada. We outline the key aspects of a successful training initiative that could inform organizations and agencies worldwide with an interest in or who have a mandate for KT. This work provides potential funders, faculty, and students with an inside look into the purpose, process, and outcomes of such training initiatives. National and international KT organizations, research institutions, and funding agencies are encouraged to consider replicating the training model employed here, as investment into KT personnel will foster the advancement of the field within and beyond local borders. 'To the individual who devotes his/her life to science, nothing can give more happiness than when the results immediately find practical application. There are not two sciences. There is science and the application of science, and these two are linked as the fruit is to the tree.' - Louis Pasteur, 1871 (from presentation by Ian Graham, 2008 CIHR Knowledge Translation Summer Institute).


Production of activated carbon from poultry feathers for waste water treatment.
Contamination of water bodies by heavy metal ions is a challenge many developing nations like Zimbabwe face, with negative environmental and socio-economic repercussions. Treating affected bodies usually requires a costly consignment of chemicals and activated carbon. This research investigates the possible use of an abundant waste resource - poultry feathers - to make activated carbon for heavy metal ion removal. Poultry consumption in this nation generates more than five million tonnes of feathers a year, with very few uses of this by-product. This research was carried out to evaluate the effectiveness of activated carbon synthesized from poultry feathers with sodium hydroxide as the activating agent. It was tested for removing heavy metal ions from waste water at Lake Chivero and the experimental work done showed that it had a removal efficiency as high as 97%, with a high affinity for lead ions as compared with chromium ions. Upon characterization, the activated carbon showed an iodine number of 520 mg and it worked best at a pH value of 8. The efficiency removal also increased with increasing adsorbent concentration as well as contact time up to a period where these factors ceased to be the limiting factors of the reaction.


SAFETEL randomised controlled feasibility trial of a safety planning intervention with follow-up telephone contact to reduce suicidal behaviour: study protocol.
There are no evidence-based interventions that can be administered in hospital settings following a general hospital admission after a suicide attempt. To determine whether a safety planning intervention (SPI) with follow-up telephone support (SAFETEL) is feasible and acceptable to patients admitted to UK hospitals following a suicide attempt. Three-phase development and feasibility study with embedded process evaluation. Phase I comprises tailoring an SPI with telephone follow-up originally designed for veterans in the USA, for use in the UK. Phase II involves piloting the intervention with patients (n=30) who have been hospitalised following a suicide attempt. Phase III is a feasibility randomised controlled trial of 120 patients who have been hospitalised following a suicide attempt with a 6-month follow-up. Phase III participants will be recruited from across four National Health Service hospitals in Scotland and randomised to receive either the SPI with telephone follow-up and treatment as usual (n=80) or treatment as usual only (n=40). The primary outcomes are feasibility outcomes and include the acceptability of the intervention to participants and intervention staff, the feasibility of delivery in this setting, recruitment, retention and intervention adherence as well as the feasibility of collecting the self-harm re-admission to hospital outcome data. Statistical analyses will include description of recruitment rates, intervention adherence/use, response rates and estimates of the primary outcome event rates, and intervention effect size (Phase III). Thematic analyses will be conducted on interview and focus group data. The East of Scotland Research Ethics Service (EoSRES) approved this study in March 2017 (GN17MH101 Ref: 17/ES/0036). The study results will be disseminated via peer-reviewed publication and conference presentations. A participant summary paper will also be disseminated to patients, service providers and policy makers alongside the main publication. ISRCTN62181241.