RNA sequencing: current and prospective uses in metabolic research.
Previous global RNA analysis was restricted to known transcripts in species with a defined transcriptome. Next generation sequencing has transformed transcriptomics by making it possible to analyse expressed genes with an exon level resolution from any tissue in any species without any a priori knowledge of which genes that are being expressed, splice patterns or their nucleotide sequence. In addition, RNA sequencing is a more sensitive technique compared with microarrays with a larger dynamic range, and it also allows for investigation of imprinting and allele-specific expression. This can be done for a cost that is able to compete with that of a microarray, making RNA sequencing a technique available to most researchers. Therefore RNA sequencing has recently become the state of the art with regards to large-scale RNA investigations and has to a large extent replaced microarrays. The only drawback is the large data amounts produced, which together with the complexity of the data can make a researcher spend far more time on analysis than performing the actual experiment.


Fallout, radiation doses near Dounreay, and childhood leukaemia.
Possible explanations for the recently reported increased incidence of childhood leukaemia around Dounreay were examined in the light of changes in the national incidence of leukaemia that occurred during the period of exposure to fallout from international testing of nuclear weapons in the atmosphere. It was concluded that the increase could not be accounted for by an underestimate of the risk of leukaemia per unit dose of radiation at low doses and low dose rates, nor by an underestimate of the relative biological efficiency of high as compared with low linear energy transfer radiation. One possible explanation was underestimation of doses to the red bone marrow due to the discharges at Dounreay relative to the dose from fallout, though investigation of ways in which this might have occurred did not suggest anything definite. Other possible explanations included a misconception of the site of origin of childhood leukaemia, outbreaks of an infectious disease, and exposure to some other, unidentified environmental agent. These findings weigh heavily against the hypothesis that the recent increase in childhood leukaemia near Dounreay might be accounted for by radioactive discharges from nuclear plants, unless the doses to the stem cells from which childhood leukaemia originates have been grossly underestimated.


A new workflow for assigning removal credits to assess overall performance of managed aquifer recharge (MAR).
Pathogen removal in managed aquifer recharge (MAR) systems is dependent upon numerous operational, physicochemical water quality, and biological parameters. Due to the site-specific conditions affecting these parameters, guidelines for specifying pathogen removal have historically taken rather precautionary and conservative approaches in order to protect groundwater quality and public health. A literature review of regulated pathogens in MAR applications was conducted and compared to up-and-coming indicators and surrogates for pathogen assessment, all of which can be gathered into a toolbox from which regulators and operators alike can select appropriate pathogens for monitoring and optimization of MAR practices. Combined with improved knowledge of pathogen fate and transport obtained through lab- and pilot-scale studies and supported by modeling, this foundation can be used to select appropriate, site-specific pathogens for regarding a more efficient pathogen retention, ultimately protecting public health and reducing costs. This paper outlines a new 10 step-wise workflow for moving towards determining robust removal credits for pathogens based on risk management principles. This approach is tailored to local conditions while reducing overly conservative regulatory restrictions or insufficient safety contingencies. The workflow is intended to help enable the full potential of MAR as more planned water reuse systems are implemented in the coming years.


Proton NMR assignments and solution conformation of RANTES, a chemokine of the C-C type.
1H NMR has been used to investigate the structural properties of RANTES, a protein from the C-C branch of the chemotactic cytokine family that has a strong chemoattractive effect on monocytes, lymphocytes, and eosinophils. Titration of pH from 5.0 to 2.5 indicates that RANTES is extensively aggregated in solution above pH 4.0. At pH 3.7 the protein is mostly dimeric, although this species does dissociate to the monomer with a Kd of 35 microM. NMR data have been acquired and resonance assignments made for the dimeric species. Structures of the dimer have been generated by distance geometry and simulated annealing calculations that utilized 1956 intramolecular distance restraints, 120 intermolecular distance restraints, 164 dihedral angle restraints, and 68 restraints enforcing 34 hydrogen bonds (17.0 restraints per residue). The structure is well-defined (average root mean square deviation from the average structure of 0.38 +/- 0.06 and 0.53 +/- 0.12 A for backbone heavy atoms of residues 4-66 of the monomer and dimer, respectively). Each monomer consists of a C-terminal alpha-helix packing against a three-stranded antiparallel beta-sheet and two short N-terminal beta-strands; dimerization occurs between the N-terminal regions of each monomer. This quaternary structure is very different from that of the C-X-C chemokines such as interleukin-8 and melanoma growth stimulatory activity but similar to that found for the C-C chemokine macrophage inflammatory factor 1 beta. Distinct structural differences between RANTES and other chemokines at both the tertiary and quaternary level are discussed with regard to the distinct biological functions of the C-C and C-X-C members of this protein family.


Depressive Symptoms among Latino Sexual Minority Men and Latina Transgender Women in a New Settlement State: The Role of Perceived Discrimination.
Background. Little is known about the role of discrimination on depression among Latino sexual and gender identity minorities. This manuscript examined the relationship between ethnic/racial discrimination and sexual discrimination on clinically significant depressive symptoms among Latino sexual minority men (i.e., gay and bisexual men and other men who have sex with men) and Latina transgender women. Methods. A community-based participatory research partnership recruited participants (N = 186; 80.6% cisgender men) in North Carolina to a social network-based HIV intervention. Using baseline data, we quantified the amount of perceived discrimination and conducted mixed-effects logistic regression analyses to examine correlates of clinically significant depressive symptoms. Results. A high percentage of participants reported ethnic/racial discrimination (73.7%) and sexual discrimination (53.8%). In the multivariable models, ethnic/racial discrimination, sexual discrimination, masculinity, fatalism, and social support were significantly associated with clinically significant depressive symptoms. Discussion. Improving mental health requires multilevel interventions that address pertinent individual, interpersonal, and system level factors.


Role of Interleukin-17A on the Chemotactic Responses to CCL7 in a Murine Allergic Rhinitis Model.
The proinflammatory cytokine interleukin (IL)-17A is associated with eosinophil infiltration into the nasal mucosa in a mouse model of ovalbumin-induced allergic rhinitis. Chemotaxis of eosinophils is mediated primarily through C-C chemokine receptor type 3 (CCR3). However, the mechanism underlying the IL-17A-mediated enhancement of eosinophil recruitment via chemoattractants/chemokines remains unknown. In this study, we assessed the contribution of IL-17A to eosinophil-related inflammation via the CCL7/CCR3 pathway in experimental allergic rhinitis. IL-17A knockout (KO) and wild-type (WT) BALB/c mice were injected intraperitoneally and challenged intranasally with OVA to induce allergic rhinitis. Various parameters of the allergic response were evaluated, and mRNA and protein levels of CCL7 and CCR3 in nasal tissue and serum were compared between the two groups. The chemotactic response to CCL7 with or without IL-17A in bone marrow-derived eosinophils (bmEos) from BALB/c mice was measured. In the allergic rhinitis model, IL-17A deficiency significantly decreased nasal symptoms, serum IgE levels, and eosinophil recruitment to the nasal mucosa. CCL7 and CCR3 mRNA and protein levels were decreased in the nasal mucosa of IL-17A KO mice compared with the WT mice. BmEos showed a significantly increased chemotactic response to -low concentration of CCL7 in the presence of IL-17A compared with its absence. The suppression of nasal inflammation due of IL-17A deficiency in allergic rhinitis is partly responsible for the regulation of CCL7 secretion and eosinophil infiltration, which may be regulated via the CCL7/CCR3 pathway.


Altered Long Non-Coding RNA Transcriptomic Profiles in Ischemic Stroke.
A previous study described the important regulatory roles of microRNAs (miRNAs) in ischemic stroke. However, the functional significance of long non-coding RNA (lncRNAs) in ischemic stroke was largely unknown. This study aimed to identify lncRNA profiling and elucidate the regulatory mechanisms in the pathophysiology of stroke. RNA sequencing was performed on the blood of three ischemic stroke patients and three normal controls. Differential expression analysis was used to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). After further correlation and co-expression analysis, the corresponding co-expression networks and miRN-lncRNA-mRNA interaction network were then constructed. The expression of DElncRNAs and DEmRNAs was verified in Gene Expression Omnibus. RNA sequencing and subsequent bioinformatics analysis produced a total of 61 DElncRNAs (14 upregulated and 47 downregulated) and 673 DEmRNAs (432 upregulated and 241 downregulated). LOC105372881 and LOC101929707 were the most highly increased and decreased lncRNAs in ischemic stroke. LncRNA-mRNA co-expression networks were constructed according to 3,008 positively co-expressed and 607 negatively co-expressed lncRNA-mRNA pairs. The DElncRNAs may play roles in the pathways of glycolysis/gluconeogenesis, arrhythmogenic right ventricular cardiomyopathy, adherens junction, lysosome, and hematopoietic cell lineage by regulating their co-expressed mRNAs. Combined with previous data, a miRNA-lncRNA-mRNA interaction network for ischemic stroke was constructed. Based on GSE22255, the expression of six DElncRNAs (CEBPA-AS1, LINC00884, HCG27, MATN1-AS1, HCG26, and LINC01184) and 11 DEmRNAs (TREML4, AHSP, PI3, TESC, ANXA3, OAS1, OAS2, IFI6, ISG15, IFI44L, and LY6E) was similar to the current sequencing data. This study is the first to identify blood lncRNAs in human ischemic stroke using RNA sequencing. The findings may be the foundation for understanding the potential role of lncRNAs in ischemic stroke.


Spectroscopy and control of near-surface defects in conductive thin film ZnO.
The electronic structure of inorganic semiconductor interfaces functionalized with extended π-conjugated organic molecules can be strongly influenced by localized gap states or point defects, often present at low concentrations and hard to identify spectroscopically. At the same time, in transparent conductive oxides such as ZnO, the presence of these gap states conveys the desirable high conductivity necessary for function as electron-selective interlayer or electron collection electrode in organic optoelectronic devices. Here, we report on the direct spectroscopic detection of a donor state within the band gap of highly conductive zinc oxide by two-photon photoemission spectroscopy. We show that adsorption of the prototypical organic acceptor C60 quenches this state by ground-state charge transfer, with immediate consequences on the interfacial energy level alignment. Comparison with computational results suggests the identity of the gap state as a near-surface-confined oxygen vacancy.


Contribution of cell proliferation to axial elongation in the red flour beetle Tribolium castaneum.
Most arthropods generate their posterior bodies by adding segments periodically, as the embryo grows, from a posteriorly located region called the segment addition zone. This mode of segmentation is shared with vertebrates and relies on oscillatory mechanisms, where the temporal periodicity of a clock is translated into repetitive spatial patterns. This ordered anterior-to-posterior pattern is achieved at the same time as the tissue elongates, opening the question of the functional coordination between the mechanisms of segmental patterning and posterior growth. The study of these processes in different arthropods has played an important role in unravelling some of the molecular mechanisms of segment formation. However, the behavior of cells during elongation and how cellular processes affect this segmental patterning has been poorly studied. Cell proliferation together with cell rearrangements are presumed to be the major forces driving axis elongation in the red flour beetle Tribolium castaneum. However, there still no strong evidence about the role and distribution of cell proliferation within the embryo. In this study, we propose to address these questions by using whole embryo cultures and pharmacological manipulation. We show that considerable cell proliferation occurs during germband elongation, measured by incorporation of the nucleoside analog of thymidine 5-Ethynyl-2'-deoxyuridine, EdU. Moreover, proliferating cells appeared to be spread along the elongating embryo with a posterior bias at early segmentation. In addition, when we blocked cell division, treated germbands were always shorter than controls and in some cases not able to fully elongate, even when control embryos already started to retract and leg buds are evident. Finally, we found that the absence of cell proliferation has no apparent effect on segmental patterning, as evidenced by Tc-engrailed (Tc-en) gene expression.


Angular resolved light scattering for discriminating among marine picoplankton: modeling and experimental measurements.
In order to assess the capability to optically identify small marine microbes, both simulations and experiments of angular resolved light scattering (ARLS) were performed. After calibration with 30-nm vesicles characterized by a nearly constant scattering distribution for vertically polarized light (azimuthal angle=90 degrees ), ARLS from suspensions of three types of marine picoplankton (two prokaryotes and one eukaryote) in seawater was measured with a scattering device that consisted of an elliptical mirror, a rotating aperture, and a PMT. Scattered light was recorded with adequate signal-to-noise in the 40-140 degrees . Simulations modeled the cells as prolate spheroids with independently measured dimensions. For the prokaryotes, approximated as homogeneous spheroids, simulations were performed using the RM (Rayleigh-Mie) - I method, a hybrid of the Rayleigh-Debye approximation and the generalized Lorentz-Mie theory. For the picoeukaryote, an extended RM - I method was developed for a coated spheroid with different shell thickness distributions. The picoeukaryote was then modeled as a coated sphere with a spherical core. Good overall agreements were obtained between simulations and experiments. The distinctive scattering patterns of the different species hold promise for an identification system based on ARLS.


Antimalarial drugs in pregnancy: a review.
In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of antimalarial treatments in pregnancy, including artemisinin based combination therapies.


Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing?
Congenital end-plate acetylcholinesterase (AChE) deficiency (CEAD), the cause of a disabling myasthenic syndrome, arises from defects in the COLQ gene, which encodes the AChE triple-helical collagenlike-tail subunit that anchors catalytic subunits of AChE to the synaptic basal lamina. Here we describe a patient with CEAD with a nonsense mutation (R315X) and a splice-donor-site mutation at position +3 of intron 16 (IVS16+3A-->G) of COLQ. Because both A and G are consensus nucleotides at the +3 position of splice-donor sites, we constructed a minigene that spans exons 15-17 and harbors IVS16+3A-->G for expression in COS cells. We found that the mutation causes skipping of exon 16. The mutant splice-donor site of intron 16 harbors five discordant nucleotides (at -3, -2, +3, +4, and +6) that do not base-pair with U1 small-nuclear RNA (snRNA), the molecule responsible for splice-donor-site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restore normal splicing. Analysis of 1,801 native splice-donor sites reveals that presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A-->G mutations indicates that, on average, two of three nucleotides at positions +4 to +6 fail to base-pair, and that the nucleotide at +4 never base-pairs, with U1 snRNA. We conclude that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis-acting elements may also be important in assuring the fidelity of splicing.


Effect of electrochemical oxidation and reduction on cell de-adhesion at the conducting polymer-live cell interface as revealed by single cell force spectroscopy.
Cell adhesion on conducting polymers is important in organic bioelectronics, including applications such as electronically switchable surfaces and electrochemical transistors. There is a fundamental interest in understanding the conducting polymer-cellular interface though as yet no direct measurements to quantify the cell adhesion forces and energies, particularly at the molecular level, have been undertaken. Here, the authors apply electrochemical-single cell force spectroscopy (EC-SCFS) to directly quantify the de-adhesion forces between single L929 fibroblast cells and polypyrrole doped with dodecylbenzene sulfonate (PPy-DBSA) under electrical stimulation. The EC-SCFS reveals single cell de-adhesion forces of 0.65 nN on PPy-DBSA films with adsorbed fibronectin (FN) protein. Blocking experiments by introducing antibodies show that cell de-adhesion is largely due to the binding (∼60% of interactions) of cell-surface α5β1 integrin receptors. Electrochemical oxidation and reduction of PPy-DBSA during initial adsorption of fibronectin cause a significant decrease in the single cell de-adhesion forces to ∼0.4 nN, which is suggested to relate to electrical stimulation effects on reducing FN adsorption on the polymer. In contrast, when electrical stimulation is applied after protein adsorption is established and during the EC-SCFS measurements, the single cell de-adhesion is significantly enhanced on the oxidized polymer compared to the reduced and nonbiased polymer. The study highlights the use of EC-SCFS to directly quantify cell adhesion on electrode surfaces, as well as the ability to probe molecular-level interactions such as integrin receptor-FN complexes with forces of ∼50-100 pN.


Olfactory deficits in Niemann-Pick type C1 (NPC1) disease.
Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/-)) to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE) and olfactory bulb (OB). For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/-) animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/-) animals exhibit olfactory and trigeminal deficits. Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-), which is accompanied by sensory deficits.


Plasmonic Nanoassemblies: Tentacles Beat Satellites for Boosting Broadband NIR Plasmon Coupling Providing a Novel Candidate for SERS and Photothermal Therapy.
Optical theranostic applications demand near-infrared (NIR) localized surface plasmon resonance (LSPR) and maximized electric field at nanosurfaces and nanojunctions, aiding diagnosis via Raman or optoacoustic imaging, and photothermal-based therapies. To this end, multiple permutations and combinations of plasmonic nanostructures and molecular "glues" or linkers are employed to obtain nanoassemblies, such as nanobranches and core-satellite morphologies. An advanced nanoassembly morphology comprising multiple linear tentacles anchored onto a spherical core is reported here. Importantly, this core-multi-tentacle-nanoassembly (CMT) benefits from numerous plasmonic interactions between multiple 5 nm gold nanoparticles (NPs) forming each tentacle as well as tentacle to core (15 nm) coupling. This results in an intense LSPR across the "biological optical window" of 650-1100 nm. It is shown that the combined interactions are responsible for the broadband LSPR and the intense electric field, otherwise not achievable with core-satellite morphologies. Further the sub 80 nm CMTs boosted NIR-surface-enhanced Raman scattering (SERS), with detection of SERS labels at 47 × 10-9 m, as well as lower toxicity to noncancerous cell lines (human fibroblast Wi38) than observed for cancerous cell lines (human breast cancer MCF7), presents itself as an attractive candidate for use as biomedical theranostics agents.


Radiation Treatment of Organotypic Cultures from Submandibular and Parotid Salivary Glands Models Key In Vivo Characteristics.
Hyposalivation and xerostomia create chronic oral complications that decrease the quality of life in head and neck cancer patients who are treated with radiotherapy. Experimental approaches to understanding mechanisms of salivary gland dysfunction and restoration have focused on in vivo models, which are handicapped by an inability to systematically screen therapeutic candidates and efficiencies in transfection capability to manipulate specific genes. The purpose of this salivary gland organotypic culture protocol is to evaluate maximal time of culture viability and characterize cellular changes following ex vivo radiation treatment. We utilized immunofluorescent staining and confocal microscopy to determine when specific cell populations and markers are present during a 30-day culture period. In addition, cellular markers previously reported in in vivo radiation models are evaluated in cultures that are irradiated ex vivo. Moving forward, this method is an attractive platform for rapid ex vivo assessment of murine and human salivary gland tissue responses to therapeutic agents that improve salivary function.


Assessing the quality of antenatal corticosteroids in low- and middle-income countries: A systematic review.
The World Health Organization (WHO) recommends the administration of intramuscular antenatal corticosteroids to women at risk of preterm birth to prevent preterm-associated neonatal mortality and morbidity. Poor quality medicines are a major problem for health services in low- and middle-income countries (LMICs), however the quality of antenatal corticosteroids is not well understood. We aimed to conduct a systematic review of available studies describing the quality of recommended injectable antenatal corticosteroids (dexamethasone or betamethasone) in LMICs. Structured search strategy was applied to six databases (MEDLINE, EMBASE, CINAHL, International Pharmaceutical Abstracts, Global Index Medicus, WHO Medicines Quality Database), without year or language restrictions. Any primary study reporting any medicine quality parameter (Active Pharmacological Ingredient, pH and sterility) for injectable dexamethasone or betamethasone was eligible. Two authors independently screened studies for eligibility, extracted data on included studies and applied Medicine Quality Assessment Reporting Guidelines tool to assess study quality. Results were reported narratively, stratified by country of manufacture, organisation type and level of care. In total, 15,547 citations were screened with two eligible studies identified that focussed on dexamethasone quality (no studies of betamethasone were identified). One study included 19 samples from 9 LMICs, and the other included "less than 100 samples" from India. The prevalence of failed dexamethasone samples ranged from 3.14% to 32.2% due to inadequate Active Pharmacological Ingredient. A higher prevalence of failed dexamethasone samples were seen at the point of care and the public sector. Poor quality maternal and newborn health medicines can endanger women and newborns. Though available evidence on antenatal corticosteroids quality in LMICs is limited, results suggested poor quality dexamethasone may be prevalent in some countries. More primary studies are required to confirm these findings and guide policymakers on procurement of good-quality maternal and newborn health medicines.


Prognostic factors in low grade (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery.
To assess the role of surgery on survival of patients with grade II gliomas of the cerebral hemispheres. One hundred and thirty one low grade hemispheric gliomas surgically treated (biopsied patients excluded) between 1978 and 1989 were retrospectively reviewed. Thalamic, basal ganglia, callosal, or ventricular location were not considered. All tumours were World Health Organisation (WHO) grade II gliomas: 42 fibrillary and 11 gemistocytic astrocytomas, 49 oligodendrogliomas, and 29 oligoastrocytomas. Patients' ages ranged from 14 to 63 (mean 32.9, median 34) years, Karnofsky performance from 0.50 to 0.90 (mean 80.7, median 80), and postsurgical follow up of the living patients from 24 to 190 (mean 97.02, median 93) months. Postoperative external radiotherapy was performed in 49 cases. The overall survival probability at five years was 97.1%, at eight years 76.1%, and at 10 years 62.7% (median survival time 144 months). The impact on survival of the following variables was analysed: age (< 20, 21-40, and > 40 years), Karnofsky score (80-100, 70 < or = 70), histology, tumour extension (T1 < 3 cm, T2 3-5 cm, T3 > 5 cm maximum diameter), extent of surgical resection (S1 radical, S2 subtotal < 10% residual tumour, S3 partial-10%-50% residual tumour), and radiotherapy (either performed or not). A significant positive association with survival at univariate analysis was found for the age group < 20 years (P = 0.003), for total and subtotal surgical resections (S1 and S2; P < 0.001) and for the non-irradiated patients (P = 0.0049), whereas a shorter survival probability was noticed for gemistocytic astrocytomas (P < 0.001) and for tumour extension > 5 cm (T3; P = 0.0193). Karnofsky performance did not show any significant association with survival. The most relevant factor affecting survival at the multivariate analysis was the extent of surgical resection, which resulted as the only variable retaining a significant value (P = 0.001, risk factor = 2.20). The data strongly support the role of a surgical removal as extensive as possible in the treatment of these tumours.


Transradial Artery Access Complications.
Transradial access (TRA) is favored over transfemoral access for performing coronary angiography and percutaneous coronary intervention due to the reduced risk for vascular and bleeding complications and the documented survival benefit in ST-segment-elevation myocardial infarction patients who undergo primary percutaneous coronary intervention. TRA complications can be categorized as intra- or postprocedural and further categorized as related to bleeding or nonbleeding issues. Major intra- and postprocedural complications such as radial artery perforation and compartment syndrome are rare following TRA. Their occurrence, however, can be associated with morbid consequences, including requirement for surgical intervention if not identified and treated promptly. Nonbleeding complications such as radial artery spasm and radial artery occlusion are typically less morbid but occur much more frequently. Strategies to prevent TRA complications are essential and include the use of contemporary access techniques that limit arterial injury. This document summarizes contemporary techniques to prevent, identify, and manage TRA complications.


Low-molecular-weight heparins inhibit CCL21-induced T cell adhesion and migration.
The chemokine CCL21, also known as Exodus-2/6-Ckine/secondary lymphoid-tissue chemokine/T cell activator protein-4, is the most potent stimulator of T cell migration and adhesion yet described. Endothelial heparin-like glycosaminoglycans (GAGs) are thought to present chemokines at sites of inflammation, maintaining a local concentration gradient to which leukocytes can respond. In contrast, this study found that GAGs markedly inhibit the ability of CCL21 to stimulate T cell adhesion and chemotaxis. Enzymes, such as heparinase, that split GAGs into component-sulfated saccharides abrogate this inhibition, suggesting a mechanism for local tissue regulation of CCL21 function. Low-molecular-weight heparins also strongly inhibit CCL21 adhesion and chemotaxis. Therefore, low-molecular-weight heparins may be effective therapeutic agents in decreasing the pathology of T cell-infiltrative autoimmune diseases by targeting the CCL21 regulation of T cell infiltration.


Targeted box and blocks test: Normative data and comparison to standard tests.
The Box and Block Test (BBT) is a functional outcome measure that is commonly used across multiple clinical populations due to its benefits of ease and speed of implementation; reliable, objective measurement; and repetition of motion. In this study, we introduce a novel outcome measure called the targeted BBT that allows for the study of initiation, grasping, and transport of objects, and also of object release. These modifications to the existing test may increase the ecological validity of the measure while still retaining the previously stated benefits of the standard BBT. 19 able-bodied subjects performed the targeted BBT and two other standard tests. Using an integrated movement analysis framework based on motion capture and ground force data, quantitative information about how subjects completed these tests were captured. Kinematic parameters at the wrist, elbow, shoulder, thorax, and head, as well as measures of postural control, were calculated and statistically compared across the three tests. In general, the targeted BBT required significantly higher RoM at the elbow, shoulder, thorax and head when compared to standard tests. Peak angles at these joints were also higher during performance of the targeted BBT. Peak angles and RoM values for the targeted BBT were close to those found in studies of movements of able-bodied individuals performing activities of daily living. The targeted BBT allows analysis of repetitive movements, and may more closely model common real-world object manipulation scenarios in which a user is required to control a movement from pick-up to release.


Left atrial appendage occlusion.
Left atrial appendage (LAA) occlusion for stroke and thromboembolism prevention in patients with atrial fibrillation (AF) represents a significant advancement in the field of cardiovascular disease. Prevention and avoidance of the devastating consequences of thromboembolic complications from AF continues to be central in the management of these patients. The role of LAA as a nidus for thrombus formation is well documented. Multiple approaches to exclude the LAA from the circulation either percutaneously or surgically have been described and are undergoing testing. Although pharmacological therapy for stroke prevention remains the cornerstone of treatment, device and surgical exclusion of the LAA have proven to be viable alternatives in carefully selected patients. Even though current evidence show that LAA occlusion is safe and effective, approval and adoption of this strategy has been quite difficult due to paucity of randomised clinical trial data on the risk and benefit ratio, cost effectiveness and the issues of procedural risk as well as longer-term outcome. This review aims to provide an update on the current status of LAA occlusion, specifically looking at interpretation of current clinical data, available techniques and devices, issues with current devices and future direction.


Improved minicircle DNA biosynthesis for gene therapy applications.
Minicircular DNA (mcDNA) biopharmaceuticals have recently risen as a valuable alternative for the development of a next generation of bioactive therapeutics because they are more efficient and safer than standard plasmid DNA (pDNA). To date, the relatively insufficient knowledge regarding mcDNA biosynthesis is currently hindering its manufacture in suitable amounts for clinical trial evaluations. Addressing this limitation is therefore mandatory to bring forth the full therapeutic potential of this cutting-edge technology. Herein, we describe for the first time new processing parameters that improve the overall yield of mcDNA obtained from bacterial fermentations. We provide details for further in-line monitoring and optimization in view of the current good manufacturing guidelines. Our results show that by rising growth temperature to 42°C, an increase in the overall minicircle producer plasmid yield is attained, while biomass amounts are reduced. Moreover, by monitoring in real time the dynamic recombination of parental plasmids to mcDNA, we found that this event is more efficient at specific time points, regardless of the growth temperature and inductor concentration used. These are important findings since mcDNA can be recovered with higher yields at these determined key stages. Indeed, the manipulation of these parameters resulted in a 2.21-fold increase in mcDNA production compared with the established growth temperatures for this technology. Overall, our findings highlight that to achieve maximum productivity while attaining pharmaceutical-grade mcDNA preparations, process design and biosynthesis optimization must take into account key parameters such as temperature, inductor concentration, and recovery time.


Large basilar perforator pseudoaneurysm: A case report.
Basilar perforator aneurysms are rare and a communication between a basilar perforator and a separate pseudoaneurysm cavity is extremely rare. We describe a case presenting with high grade subarachnoid hemorrhage which on further investigation delineated a 2-3 mm dissecting basilar perforator aneurysm communicating superiorly into a contained 6 mm pseudoaneurysm cavity. This case illustrates an unusual neurovascular pathology with low potential for successful endovascular treatment such as coil embolization or intracranial flow diverter stenting. Conservative medical management remains the main stay of treatment for such poor surgical candidates.


Under-reporting of sexually transmitted infection with chlamydia trachomatis - a revision of surveillance system is required.
To consider whether a revision of the national chlamydia surveillance system is needed, the objectives were to estimate the proportion of laboratory confirmed cases at the Institute of Microbiology and Immunology (IMI) not reported to the National Institute of Public Health (NIPH), and to assess the completeness of reporting for individual data items. The dataset with information about the cases diagnosed at the IMI during 2007-2010, and the national chlamydia surveillance data at the NIPH, were linked using SOUNDEX code and the date of birth as unique identifier. The proportion of unreported cases was calculated. The proportions of records with missing data for individual variables were estimated for all reported cases during the same period. Chlamydia testing and reported rates for the period 2002-2010 were presented. Of 576 laboratory confirmed chlamydia cases at the IMI during 2007-2010, 201 were reported to the NIPH, corresponding to 65.1% of the overall underreporting (50.4% among dermatovenerologists, 90.1% among gynaecologist and 100% among other specialists). Item response was above 99% for demographic variables and from 69% to 81% for sexual behaviour variables. Higher testing rates corresponded to higher diagnosed rates. Surveillance data underestimated diagnosed chlamydia infection rates. Mandatory reporting of cases by laboratories with less variables, including unique identifier, gender, date of diagnosis, and reporting physician specialty, together with numbers of tests performed (for estimating testing and positivity rates) would simplify the surveillance system and eliminate underreporting of laboratory confirmed cases, while still providing necessary information for public health policies.


Surveys of soil and water reveal a goldmine of Phytophthora diversity in South African natural ecosystems.
Phytophthora species are well-known as destructive plant pathogens, especially in natural ecosystems. It is ironic, therefore, how little is known regarding the Phytophthora diversity in South African natural woody ecosystems. In this study, Phytophthora species were isolated using standard baiting techniques from 182 soil and water samples and these were identified based on ITS and coxI sequence data. The 171 resulting Phytophthora isolates resided in 14 taxa including six known species (P. multivora, P. capensis, P. cryptogea, P. frigida, P. cinnamomi, P. cinnamomi var. parvispora), the known but as yet unnamed Phytophthora sp. PgChlamydo, P. sp. emzansi, and P. sp. Kununurra and five novel taxa referred to as P. sp. stellaris, P. sp. Umtamvuna P. sp. canthium, P. sp. xWS, P. sp. xHennops. Four of the new taxa were found exclusively in water and two of these are hybrids. The most commonly isolated species from soil was P. multivora, a species recently described from Western Australia. Phytophthora frigida was isolated for the first time from stream water. With the exception of P. cinnamomi, very little is known regarding the biology, epidemiology or origin of Phytophthora in South Africa.


Incidence, Associated Factors, and Outcome of Delirium among Patients Admitted to ICUs in Oman.
The incidence of delirium is high up to 46.3% among patients admitted to ICU. Delirium is linked to negative patient outcomes like increased duration of mechanical ventilation use, prolonged ICU stay, increased mortality rate, and healthcare costs. Despite the importance of delirium and its consequences that are significant, there is a scarcity of studies which explored delirium in Oman. This study was conducted to assess the incidence of delirium, the association between the selected predisposing factors and precipitating factors with delirium, determine the predicators of delirium, and evaluate its impacts on ICU mortality and ICU length of stay among ICU patients in Oman. A multicenter prospective observational design was used. A total of 153 patients were assessed two-times a day by bedside ICU nurses through the Intensive Care Delirium Screening Checklist (ICDSC). The results revealed that the delirium incidence was 26.1%. Regression analysis showed that sepsis, metabolic acidosis, nasogastric tube use, and APACHE II score were independent predictors for delirium among ICU patients in Oman and delirium had significant impacts on ICU length of stay and mortality rate. Delirium is common among ICU patients and it is associated with negative consequences. Multidisciplinary prevention strategies should be implemented to identify and treat the modifiable risk factors.


Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.
Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%). The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.


Encounters with medical professionals: a crisis of trust or matter of respect?
In this paper I shed light on the connection between respect, trust and patients' satisfaction with their medical care. Using data collected in interviews with 49 women who had managed, or were in the process of managing, their risk of ovarian cancer using prophylactic surgery or ovarian screening, I examine their reported dissatisfaction with medical encounters. I argue that although many study participants appeared to mistrust their healthcare professionals' (HCPs) motives or knowledge base, their dissatisfaction arose not from a lack of trust, but from HCPs' failure to treat them as persons or take their concerns seriously. I conclude by describing how respect, as evidenced by "being taken seriously", is important for the development of trusting Patient-HCP relationships.


The Relationship of Varenicline Agonism of α4β2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans.
Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4β2-nAChRs occupancy, nicotine-induced change in [11C]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal. Current nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal. Varenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4β2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum. This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4β2-nAChRs and the magnitude of dopamine release following nicotine use. It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.


Subtypes of asthma based on asthma control and severity: a latent class analysis.
Asthma subtyping is a complex new field of study. Usually both etiological and outcome factors of asthma have been used simultaneously for subtyping thus making the interpretation of the results difficult. Identification of subtypes of asthma based on questionnaire data only will be useful for both treatment of asthma and for research. Our objective was to identify asthma subtypes that capture both asthma control and severity based on easily accessible variables. We applied latent class analysis for the 1995 adult asthmatics, 692 men and 1303 women, of the Northern Finnish Asthma Study (NoFAS). The classifying variables included use of asthma medication within the last 12 months, St. George's Respiratory Questionnaire score, and asthma-related healthcare use within the last 12 months. Covariates adjusted for included COPD, allergic rhinitis/allergic eczema, BMI, age and sex. All information was based on self-administered questionnaires. We identified four subtypes for women: Controlled, mild asthma (41% of participants); Partly controlled, moderate asthma (24%); Uncontrolled asthma, unknown severity (26%), and Uncontrolled, severe asthma (9%). For men we identified three subtypes: Controlled, mild asthma (31%); Poorly controlled asthma, unknown severity (53%); and Partly controlled, severe asthma (17%). For almost 96% of the subjects this subtyping was accurate. The covariates fitted in the model were based on clinical judgment and were good predictors of class membership. Our results show that it is possible to form meaningful and accurate asthma subtypes based on questionnaire data, and that separate classification should be applied for men and women.


(1S,3R,8R,11S)-11-Bromo-10-bromo-methyl-2,2-di-chloro-3,7,7-tri-methyl-tricyclo-[18.104.22.168(1,3)]dodec-9-ene.
The title compound, C16H22Br2Cl2, was synthesized from β-him-achalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol-ecule is built up from fused six- and seven-membered rings and an appended three-membered ring. The six-membered ring has a half-chair conformation, whereas the seven-membered ring displays a chair conformation. The dihedral angle between the two best plane through each ring is 59.5 (2)°. No specific inter-molecular inter-actions were discerned in the crystal packing.


Whole genome sequencing of "Faecalibaculum rodentium" ALO17, isolated from C57BL/6J laboratory mouse feces.
Intestinal microorganisms affect host physiology, including ageing. Given the difficulty in controlling for human studies of the gut microbiome, mouse models provide an alternative avenue to study such relationships. In this study, we report on the complete genome of "Faecalibaculum rodentium" ALO17, a bacterium that was isolated from the faeces of a 9-month-old female C57BL/6J mouse. This strain will be utilized in future in vivo studies detailing the relationships between the gut microbiome and ageing. The whole genome sequence of "F. rodentium" ALO17 was obtained using single-molecule, real-time (SMRT) technique on a PacBio instrument. The assembled genome consisted of 2,542,486 base pairs of double-stranded DNA with a GC content of 54.0 % and no plasmids. The genome was predicted to contain 2794 open reading frames, 55 tRNA genes, and 38 rRNA genes. The 16S rRNA gene of ALO17 was 86.9 % similar to that of Allobaculum stercoricanis DSM 13633(T), and the average overall nucleotide identity between strains ALO17 and DSM 13633(T) was 66.8 %. After confirming the phylogenetic relationship between "F. rodentium" ALO17 and A. stercoricanis DSM 13633(T), their whole genome sequences were compared, revealing that "F. rodentium" ALO17 contains more fermentation-related genes than A. stercoricanis DSM 13633(T). Furthermore, "F. rodentium" ALO17 produces higher levels of lactic acid than A. stercoricanis DSM 13633(T) as determined by high-performance liquid chromatography. The availability of the "F. rodentium" ALO17 whole genome sequence will enhance studies concerning the gut microbiota and host physiology, especially when investigating the molecular relationships between gut microbiota and ageing.


Role of transferrin and ceruloplasmin in antioxidant activity of lung epithelial lining fluid.
Lung epithelial lining fluid (ELF) is a thin layer of plasma ultrafiltrate and locally secreted substances that may provide antioxidant protection and serve as a "front-line" defense for the lower respiratory tract epithelium. To characterize the antioxidant properties of ELF, young, healthy, nonsmoking volunteers underwent bronchoalveolar lavage with determination of ELF volumes and ELF proteins. ELF (greater than 0.4 ml) is a potent inhibitor of lipid peroxidation as measured by malondialdehyde (MDA) production in an in vitro iron-dependent assay system. Two serum proteins, transferrin and ceruloplasmin, were quantitated in ELF and found to be potent inhibitors of lipid peroxidation. Other ELF components, including vitamin E, vitamin C, and albumin, did not function as antioxidants in this system. Several experimental observations suggest that ELF transferrin was more important than ceruloplasmin in inhibiting lipid peroxidation: 1) ELF concentrations of transferrin were 20-fold higher than those for ceruloplasmin; 2) ELF antioxidant activity was abolished by preincubation with Fe3+; 3) ELF antioxidant activity was minimally affected by sodium azide, which is known to inhibit ceruloplasmin ferroxidase activity; and 4) ELF ceruloplasmin ferroxidase activity was virtually nondetectable. ELF possesses a significant antioxidant activity that may be important in vivo in protecting the lung from oxidant injury.


Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.
The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.


BRCA1 as target for breast cancer prevention and therapy.
The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.


Reversal of the ΔdegP phenotypes by a novel rpoE allele of Escherichia coli.
RseA sequesters RpoE (σ(E)) to the inner membrane of Escherichia coli when envelope stress is low. Elevated envelope stress triggers RseA cleavage by the sequential action of two membrane proteases, DegS and RseP, releasing σ(E) to activate an envelope stress reducing pathway. Revertants of a ΔdegP ΔbamB strain, which fails to grow at 37°C due to high envelope stress, harbored mutations in the rseA and rpoE genes. Null and missense rseA mutations constitutively hyper-activated the σ(E) regulon and significantly reduced the major outer membrane protein (OMP) levels. In contrast, a novel rpoE allele, rpoE3, resulting from the partial duplication of the rpoE gene, increased σ(E) levels greater than that seen in the rseA mutant background but did not reduce OMP levels. A σ(E)-dependent RybB::LacZ construct showed only a weak activation of the σ(E) pathway by rpoE3. Despite this, rpoE3 fully reversed the growth and envelope vesiculation phenotypes of ΔdegP. Interestingly, rpoE3 also brought down the modestly activated Cpx envelope stress pathway in the ΔdegP strain to the wild type level, showing the complementary nature of the σ(E) and Cpx pathways. Through employing a labile mutant periplasmic protein, AcrA(L222Q), it was determined that the rpoE3 mutation overcomes the ΔdegP phenotypes, in part, by activating a σ(E)-dependent proteolytic pathway. Our data suggest that a reduction in the OMP levels is not intrinsic to the σ(E)-mediated mechanism of lowering envelope stress. They also suggest that under extreme envelope stress, a tight homeostasis loop between RseA and σ(E) may partly be responsible for cell death, and this loop can be broken by mutations that either lower RseA activity or increase σ(E) levels.


Role of transforming growth factor-beta 1 in the cellular growth response to angiotensin II.
We have shown that angiotensin II (Ang II)-induced hypertrophy of vascular smooth muscle cells is dependent on the balance between proliferative and antiproliferative growth factors, specifically basic fibroblast growth factor and transforming growth factor-beta 1 (TGF-beta 1), respectively. We now present evidence, based on two phenotypically distinct cell cultures, that the ability to secrete the biologically active form of TGF-beta 1 is central to the growth response to Ang II. Two separate cultures were examined, one in which Ang II induces hypertrophy and the other in which Ang II induces hyperplasia. Ang II induces the expression of basic fibroblast growth factor twofold to fivefold in both cultures. Furthermore, both cultures express TGF-beta 1. In the culture that responds with hypertrophy, Ang II induces the expression of the active form of TGF-beta 1 twofold to threefold. However, in the culture that responds with hyperplasia, no active TGF-beta 1 was detected either at baseline or after Ang II exposure. Interestingly, all the TGF-beta 1 present was in the inactive, latent form. In the culture that responded with hyperplasia, Ang II induced a fourfold to fivefold increase in DNA synthesis. This increase could be abolished by the addition of active TGF-beta 1. Thus in these two cultures the ability to activate TGF-beta 1 dictates the cellular response to Ang II. These results support our hypothesis that a balance of proliferative and antiproliferative autocrine signals mediates the growth control of vascular smooth muscle cells.


Glucose tolerance and insulin-resistance syndrome among St. Lawrence Island Eskimos.
Non-insulin-dependent diabetes mellitus (NIDDM) prevalence in Alaska Natives is rising but remains lower than the U.S. average. We conducted a screening study for diabetes mellitus and cardiovascular disease in a remote Yup'ik Eskimo community in Alaska. The study population included Siberian Yup'ik Eskimo residents of Gambell, Alaska, > or = age 40 years who underwent a 2 h 75 gm oral glucose tolerance test interpreted by WHO criteria. Other measurements included fasting serum insulin and lipid levels, bioimpedance body fat %, body-mass-index (BMI), waist-to-hip ratio (WHR), and blood pressure. Of 114 eligible subjects, 65 (57%) participated. These subjects had lower mean systolic or diastolic blood pressure, lower triglyceride, and higher mean HDL cholesterol levels compared to a similarly aged U.S. all races sample. The mean fasting insulin level of 50.9 pmol/L appeared low given the high mean BMI (27.2). Six subjects had NIDDM (9%, 95% CI 2%-16%) and eight had impaired glucose tolerance (IGT) (12%, 95% CI 4%-20%). Compared to normoglycemic subjects, diabetic subjects were more frequently female (83% vs 53%) and had higher mean systolic BP (138 mm Hg vs 117 mm Hg) than normoglycemic subjects. We used multiple regression to analyze associations between fasting insulin and either blood pressure or serum lipids, while adjusting for % body fat, WHR, age, sex, and antihypertensive medication use. Fasting insulin was significantly related to both diastolic blood pressure (p = .0430) and fasting serum triglyceride (p = .0182) but not to systolic BP, total cholesterol, or LDL and HDL subfractions. Although NIDDM prevalence was not high compared to non-Native U.S. residents, elements of the insulin-resistance syndrome exist in this subarctic population.


Visual problem and low back pain as initial manifestation of multiple myeloma complicating pre-existing systemic sclerosis.
Some connective tissue diseases are associated with an increased risk of developing neoplastic disorders. Association of rheumatoid arthritis and systemic lupus erythematosus with lymphoma, and of dermatomyositis with different malignancies including ovarian and lung cancer has been reported in the literature. Here, we describe a 58 years old man with systemic sclerosis (SSc) for 15 years who developed severe lumbar pain when he was admitted for intravenous infusion of prostaglandin E1 for his fingertip ulcers. He was found to have abnormal skeletal imaging. Laboratory tests including bone marrow aspiration and biopsy determined multiple myeloma causing extensive bony infiltration. The patient expired after two cycles of VAD and Bortezomide chemotherapy.


Cocrystal trimorphism as a consequence of the orthogonality of halogen- and hydrogen-bonds synthons.
True trimorphic cocrystals, i.e. multi-component molecular crystals of identical composition that exhibit three polymorphic structures, are exceedingly rare and so far no halogen-bonded cocrystal system has been reported to exhibit trimorphism. Here we describe a unique example of a trimorphic cocrystal exhibiting both hydrogen and halogen bonds in which the differences between polymorphs reveal their orthogonality, evident by the apparently independent variation of well-defined hydrogen- and halogen-bonded motifs.


A systematic review of the effectiveness of individual, community and societal level interventions at reducing socioeconomic inequalities in obesity amongst children.
Tackling childhood obesity is one of the major contemporary public health policy challenges and vital in terms of addressing socioeconomic health inequalities.We aimed to systematically review studies of the effectiveness of interventions (individual, community and societal) operating via different approaches (targeted or universal) in reducing socio-economic inequalities in obesity-related outcomes amongst children. Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence from interventions that aimed to prevent obesity, treat obesity, or improve obesity-related behaviours (diet and/or physical activity) amongst children (aged 0-18 years) in any setting and country, so long as they provided relevant information and analysis on both socioeconomic status and obesity-related outcomes. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. We located 23 studies that provided the 'best available' (strongest methodologically) international evidence. At the individual level (n = 4), there was indicative evidence that screen time reduction and mentoring health promotion interventions could be effective in reducing inequalities in obesity. For the community level interventions (n = 17), evidence was inconclusive - with some studies suggesting that school-based health promotion activities and community-based group-based programmes were effective in reducing obesity - others not. Societal level evaluations were few (n = 1). However, there was no evidence to suggest that any of these intervention types increase inequalities and several studies found that interventions could at least prevent the widening of inequalities in obesity. The majority of studies were from America and were of 6-12 year old children. The review has found only limited evidence although some individual and community based interventions may be effective in reducing socio-economic inequalities in obesity-related outcomes amongst children but further research is required, particularly of more complex, societal level interventions and amongst adolescents.


Microalgal photophysiology and macronutrient distribution in summer sea ice in the Amundsen and Ross Seas, Antarctica.
Our study addresses how environmental variables, such as macronutrients concentrations, snow cover, carbonate chemistry and salinity affect the photophysiology and biomass of Antarctic sea-ice algae. We have measured vertical profiles of inorganic macronutrients (phosphate, nitrite + nitrate and silicic acid) in summer sea ice and photophysiology of ice algal assemblages in the poorly studied Amundsen and Ross Seas sectors of the Southern Ocean. Brine-scaled bacterial abundance, chl a and macronutrient concentrations were often high in the ice and positively correlated with each other. Analysis of photosystem II rapid light curves showed that microalgal cells in samples with high phosphate and nitrite + nitrate concentrations had reduced maximum relative electron transport rate and photosynthetic efficiency. We also observed strong couplings of PSII parameters to snow depth, ice thickness and brine salinity, which highlights a wide range of photoacclimation in Antarctic pack-ice algae. It is likely that the pack ice was in a post-bloom situation during the late sea-ice season, with low photosynthetic efficiency and a high degree of nutrient accumulation occurring in the ice. In order to predict how key biogeochemical processes are affected by future changes in sea ice cover, such as in situ photosynthesis and nutrient cycling, we need to understand how physicochemical properties of sea ice affect the microbial community. Our results support existing hypothesis about sea-ice algal photophysiology, and provide additional observations on high nutrient concentrations in sea ice that could influence the planktonic communities as the ice is retreating.


In vivo mouse studies with bioluminescence tomography.
Bioluminescence tomography (BLT) is a new molecular imaging mode, which is being actively developed to reveal molecular and cellular signatures as labeled by bioluminescent probes in a living small animal. This technology can help diagnose diseases, evaluate therapies, and facilitate drug development with mouse models. In this paper, we describe in vivo mouse experiments with BLT, and propose the reconstruction procedure of bioluminescent sources from optical data measured on the body surface of the mouse using a modality fusion approach. The results show the feasibility of our methodology for localization and quantification of the bioluminescent activities in vivo.


In smooth muscle, FK506-binding protein modulates IP3 receptor-evoked Ca2+ release by mTOR and calcineurin.
Ca2+ release from the sarcoplasmic reticulum (SR) by the IP3 receptors (IP3Rs) crucially regulates diverse cell signalling processes from reproduction to apoptosis. Release from the IP3R may be modulated by endogenous proteins associated with the receptor, such as the 12 kDa FK506-binding protein (FKBP12), either directly or indirectly by inhibition of the phosphatase calcineurin. Here, we report that, in addition to calcineurin, FKPBs modulate release through the mammalian target of rapamycin (mTOR), a kinase that potentiates Ca2+ release from the IP3R in smooth muscle. The presence of FKBP12 was confirmed in colonic myocytes and co-immunoprecipitated with the IP3R. In aortic smooth muscle, however, although present, FKBP12 did not co-immunoprecipitate with IP3R. In voltage-clamped single colonic myocytes rapamycin, which together with FKBP12 inhibits mTOR (but not calcineurin), decreased the rise in cytosolic Ca2+ concentration ([Ca2+]c) evoked by IP3R activation (by photolysis of caged IP3), without decreasing the SR luminal Ca2+ concentration ([Ca2+]l) as did the mTOR inhibitors RAD001 and LY294002. However, FK506, which with FKBP12 inhibits calcineurin (but not mTOR), potentiated the IP3-evoked [Ca2+]c increase. This potentiation was due to the inhibition of calcineurin; it was mimicked by the phosphatase inhibitors cypermethrin and okadaic acid. The latter two inhibitors also prevented the FK506-evoked increase as did a calcineurin inhibitory peptide (CiP). In aortic smooth muscle, where FKBP12 was not associated with IP3R, the IP3-mediated Ca2+ release was unaffected by FK506 or rapamycin. Together, these results suggest that FKBP12 has little direct effect on IP3-mediated Ca2+ release, even though it is associated with IP3R in colonic myocytes. However, FKBP12 might indirectly modulate Ca2+ release through two effector proteins: (1) mTOR, which potentiates and (2) calcineurin, which inhibits Ca2+ release from IP3R in smooth muscle.


Can an ape create a sentence?
More than 19,000 multisign utterances of an infant chimpanzee (Nim) were analyzed for syntactic and semantic regularities. Lexical regularities were observed in the case of two-sign combinations: particular signs (for example, more) tended to occur in a particular position. These regularities could not be attributed to memorization or to position habits, suggesting that they were structurally constrained. That conclusion, however, was invalidated by videotape analyses, which showed that most of Nim's utterances were prompted by his teacher's prior utterance, and that Nim interrupted his teachers to a much larger extent than a child interrupts an adult's speech. Signed utterances of other apes (as shown on films) revealed similar non-human patterns of discourse.


Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia.
Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R was shown, by immunocytochemistry, to be present in the human infundibular nucleus/median eminence, paraventricular nucleus, lateral hypothalamic area, and perifornical area, although in the latter two regions, only a few MCH1R-containing cells were found. In addition, MCH1R staining was found in nerve fibers in the periventricular nucleus, dorsomedial and ventromedial nucleus, suprachiasmatic nucleus, and tuberomammillary nucleus. A significant 1.6 times increase in the number of MCH1R cell body staining was found in the infundibular nucleus in postmortem brain material of cachectic patients, compared with matched controls, supporting a role for this receptor in energy homeostasis in the human.


Doxycycline for osteoarthritis of the knee or hip.
Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. This is an update of a Cochrane review first published in 2009. To examine the effects of doxycycline compared with placebo or no intervention on pain and function in people with osteoarthritis of the hip or knee. We searched CENTRAL (The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, with an update performed at 16 March 2012. In addition, we checked conference proceedings, reference lists, and contacted authors. We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in people with osteoarthritis of the knee or hip. We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios (RR) for binary outcomes. We identified one additional trial (232 participants) and included two trials (663 participants) in this update. The methodological quality and the quality of reporting were considered moderate. At end of treatment, clinical outcomes were similar between the two treatment groups, with an effect size of -0.05 (95% confidence interval (CI) -0.22 to 0.13), corresponding to a difference in pain scores between doxycycline and control of -0.1 cm (95% CI -0.6 to 0.3 cm) on a 10-cm visual analogue scale, or 32% versus 29% improvement from baseline (difference 3%; 95% CI -5% to 10%). The effect size for function was -0.07 (95% CI -0.25 to 0.10), corresponding to a difference between doxycycline and control of -0.2 (95% CI -0.5 to 0.2) on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability subscale with a range of 0 to 10, or 24% versus 21% improvement (difference 3%; 95% CI -3% to 10%). The difference in changes in minimum joint space narrowing assessed in one trial was in favour of doxycycline (-0.15 mm; 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units (95% CI -0.44 to -0.02). More participants withdrew from the doxycycline group compared with placebo due to adverse events (RR 2.28; 95% CI 1.06 to 4.90). There was no evidence that participants in the doxycycline group experienced more serious adverse events than those in the placebo group, but the estimate was imprecise (RR 1.07; 95% CI 0.68 to 1.68). In this update, the strength of evidence for effectiveness outcomes was improved from low to moderate and we confirmed that the symptomatic benefit of doxycycline is minimal to non-existent, while the small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. The CIs of the summary estimates now exclude any clinically relevant difference in improvement of symptoms and the small benefit in terms of joint space narrowing does not outweigh the harms.


Harnessing the potential of chemical defenses from antimicrobial activities.
Resistance to the drugs used in the treatment of many infectious diseases is increasing, while microbial infections are being found to be responsible for more life-threatening diseases than previously thought. Despite a large investment in the invention and application of high-throughput screening techniques involving miniaturization and automation, and a diverse array of strategies for designing and constructing various chemical libraries, relatively few new drugs have resulted. Natural products, however, have been a major source of drugs for centuries. Since some of them are produced by organisms as a result of selection in favour of improved defense against competing deleterious microorganisms, in principle they would be less likely to incur resistance. Furthermore, the production of those defensive secondary metabolites is inducible because their original function is a response to environmental challenges. Moreover, symbioses, co-habitation associations between two or more different species of organisms, are universal in nature, and the production of secondary metabolites by symbiotic microbes may be an important adaptation allowing microbes to affect their hosts. Therefore, co-culture strategies, using combinations of plant cell-pathogenic microbes, plant cell-endophytes (or symbionts), and symbiont-pathogenic microbes, based on the principles of chemical defense and the known mechanisms of organism interactions, may be an efficient general approach in the search for new anti-microbial drugs.


Environmental consequences of population, affluence and technological progress for European countries: A Malthusian view.
This paper examines the short-run and long-run effects of economic, sociological and energy factors on environmental degradation in 28 European countries. In so doing, we employ Panel Vector Autoregressive (PVAR) and Fully Modified OLS (FMOLS) approaches on data from 1990 to 2014 in a STIRPAT (Stochastic Impacts by Regression on Population, Affluence, and Technology) framework. Key empirical results indicate that these factors may contribute to environmental improvement in the short run; however, there are adverse implications in the long-run. Specifically, economic factors including economic growth, trade openness and foreign direct investment cause environmental degradation in the under-analysis economies. The sociological factors as measured by the population growth and the level of urbanization also show a negative impact on the environmental degradation in the short-run but in the long run, both population size and urbanization increase environmental degradation. These findings are in line with the concerns raised by Thomas Robert Malthus in his Essay on the Principle of Population. With regards to the energy factors, it indicates that the renewable energies help the European environment by reducing the level of carbon dioxide emissions whereas the higher energy intensity is an ecological threat. Our results remain robust in the EKC framework.


Analysis of phosphorylation-dependent protein-protein interactions of histone h3.
Multiple posttranslational modifications (PTMs) of histone proteins including site-specific phosphorylation of serine and threonine residues govern the accessibility of chromatin. According to the histone code theory, PTMs recruit regulatory proteins or block their access to chromatin. Here, we report a general strategy for simultaneous analysis of both of these effects based on a SILAC MS scheme. We applied this approach for studying the biochemical role of phosphorylated S10 of histone H3. Differential pull-down experiments with H3-tails synthesized from l- and d-amino acids uncovered that histone acetyltransferase 1 (HAT1) and retinoblastoma-binding protein 7 (RBBP7) are part of the protein network, which interacts with the unmodified H3-tail. An additional H3-derived bait containing the nonhydrolyzable phospho-serine mimic phosphonomethylen-alanine (Pma) at S10 recruited several isoforms of the 14-3-3 family and blocked the recruitment of HAT1 and RBBP7 to the unmodified H3-tail. Our observations provide new insights into the many functions of H3S10 phosphorylation. In addition, the outlined methodology is generally applicable for studying specific binding partners of unmodified histone tails.


Energy dispersive X-ray diffraction (EDXRD) for operando materials characterization within batteries.
This perspective article describes the use of energy dispersive X-ray diffraction (EDXRD) to study the evolution of electrochemical energy storage materials. Using a synchrotron light source, EDXRD allows crystallographic changes in materials to be tracked from deep within large specimens, due to the use of highly penetrating X-rays and the ability to define a well-controlled diffraction gauge volume in space. Herein we provide an overview of battery work performed using the EDXRD technique, as developed at beamline X17B1 at the National Synchrotron Light Source (NSLS), and continued at beamline 6BM-A at the Advanced Photon Source (APS), beamline I12 at the Diamond Light Source, and beamline 7T-MPW-EDDI at the Berlin Electron Storage Ring Society for Synchrotron Radiation (BESSY II). The High Energy Engineering X-Ray Scattering (HEX) beamline currently under construction at the National Synchrotron Light Source II (NSLS-II) by Brookhaven National Lab and the State of New York will further expand capability for and access to this technique. The article begins with a general introduction to the technique of EDXRD, including a description of the photon energy and d-spacing relationship and a discussion of the gauge volume. The primary topic of the review, battery characterization by EDXRD, includes discussion of batteries of differing materials chemistries (lithium-based batteries and aqueous batteries) which store energy by different mechanisms (insertion and conversion materials). A discussion of high temperature batteries is also included.


Internet addiction in Chinese adolescents in Hong Kong: assessment, profiles, and psychosocial correlates.
Internet addiction behavior was examined in 6,121 Chinese primary and secondary school students in Hong Kong based on the assessment frameworks of Ivan Goldberg and Kimberly Young. Results showed that scales derived from both frameworks (CIA-Goldberg Scale and CIA-Young Scale) were internally consistent and evidence supporting their validity was found. Descriptive statistical analyses revealed that roughly one-fifth of the respondents could be classified as Internet addicted based on either scale. Further analyses showed that Internet-addicted and -nonaddicted respondents differed in their Internet use and related behavior. Logistic regression analyses showed that engagement in certain on-line activities (such as playing on-line games and downloading software) and replacement of pastimes activities (such as watching TV and going out with friends) with Internet activities predicted a higher probability of Internet addiction.


Monitoring Lung Cancer Screening Use and Outcomes at Four Cancer Research Network Sites.
Lung cancer screening registries can monitor screening outcomes and improve quality of care. To describe nascent lung cancer screening programs and share efficient data collection approaches for mandatory registry reporting in four integrated health care systems of the National Cancer Institute-funded Cancer Research Network. We documented the distinctive characteristics of lung cancer screening programs, and we provide examples of strategies to facilitate data collection and describe early challenges and possible solutions. In addition, we report preliminary data on use and outcomes of screening with low-dose computed tomography at each of the participating sites. Programs varied in approaches to confirming patient eligibility, ordering screening low-dose computed tomographic scans, and coordinating follow-up care. Most data elements were collected from structured fields in electronic health records, but sites also made use of standardized order templates, local procedure codes, identifiable hashtags in radiology reports, and natural language processing algorithms. Common challenges included incomplete documentation of tobacco smoking history, difficulty distinguishing between scans performed for screening versus diagnosis or surveillance, and variable adherence with use of standardized templates. Adherence with eligibility criteria as well as the accuracy and completeness of data collection appeared to depend at least partly on availability of personnel and other resources to support the successful implementation of screening. To maximize the effectiveness of lung cancer screening, minimize the burden of data collection, and facilitate research and quality improvement, clinical workflow and information technology should be purposefully designed to ensure that patients meet eligibility criteria and receive appropriate follow-up testing.


Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin following single-dose subcutaneous injection in black-tailed prairie dogs (Cynomys ludovicianus).
OBJECTIVE To determine plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin following single-dose SC administration to black-tailed prairie dogs (Cynomys ludovicianus). ANIMALS 8 captive healthy 6-month-old sexually intact male black-tailed prairie dogs. PROCEDURES Enrofloxacin (20 mg/kg) was administered SC once to 6 prairie dogs and IV once to 2 prairie dogs. A blood sample was collected from each animal immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin. Plasma enrofloxacin and ciprofloxacin concentrations were quantified with ultraperformance liquid chromatography-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. RESULTS Enrofloxacin was biotransformed to ciprofloxacin in the prairie dogs used in the study. For total fluoroquinolones (enrofloxacin and ciprofloxacin), the mean (range) of peak plasma concentration, time to maximum plasma concentration, and terminal half-life after SC administration were 4.90 μg/mL (3.44 to 6.08 μg/mL), 1.59 hours (0.5 to 2.00 hours), and 4.63 hours (4.02 to 5.20 hours), respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that administration of enrofloxacin (20 mg/kg, SC, q 24 h) in black-tailed prairie dogs may be appropriate for treatment of infections with bacteria for which the minimum inhibitory concentration of enrofloxacin is ≤ 0.5 μg/mL. However, clinical studies are needed to determine efficacy of such enrofloxacin treatment.


Soluble human CD4 elicits an antibody response in rhesus monkeys that inhibits simian immunodeficiency virus replication.
Rhesus monkeys infected with the simian immunodeficiency virus of macaques (SIVmac) demonstrate significant virologic and clinical improvement as a result of treatment with human recombinant soluble CD4 (rsCD4). We show that human rsCD4 does not efficiently inhibit SIVmac replication in bone marrow macrophages of rhesus monkeys and does not significantly augment bone marrow hematopoietic colony formation in vitro. However, plasma of human rsCD4-treated rhesus monkeys does exhibit significant anti-SIVmac activity in vitro. Plasma of these animals efficiently blocks SIVmac replication in peripheral blood lymphocytes and bone marrow macrophages. It also increases granulocyte/macrophage colony formation in vitro by bone marrow cells of SIVmac-infected monkeys. This plasma and the IgG fraction of plasma from a rhesus monkey immunized with human rsCD4 in adjuvant demonstrate reactivity with a soluble form of the rhesus monkey CD4 molecule, exhibit binding to CD4+ but not CD8+ concanavalin A-activated rhesus monkey peripheral blood lymphocytes, and precipitate the CD4 molecule from surface-labeled activated rhesus monkey peripheral blood lymphocytes. Moreover, anti-viral activity is demonstrable in the IgG fraction of plasma from a human rsCD4-immunized monkey. These studies raise the possibility that a modified human CD4 molecule serving as an immunogen might elicit an antibody response that could potentially induce a beneficial therapeutic response in human immunodeficiency virus-infected individuals.


High-density lipoprotein as a therapeutic target: a systematic review.
High-density lipoprotein cholesterol (HDL-C) is a cardiovascular risk factor that is gaining substantial interest as a therapeutic target. To review the current and emerging strategies that modify high-density lipoproteins (HDLs). Systematic search of English-language literature (1965-May 2007) in MEDLINE and the Cochrane database, using the key words HDL-C and apolipoprotein A-I and the subheadings reverse cholesterol transport, CVD [cardiovascular disease] prevention and control, drug therapy, and therapy; review of presentations made at major cardiovascular meetings from 2003-2007; and review of ongoing trials from ClinicalTrials.gov and current guidelines from major cardiovascular societies. Study selection was prioritized to identify randomized controlled trials over meta-analyses over mechanistic studies; identified studies also included proof-of-concept studies and key phase 1 through 3 trials of novel agents. Study eligibility was assessed by 2 authors; disagreements were resolved by consensus with the third. Of 754 studies identified, 31 randomized controlled trials met the inclusion criteria. Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels. At present there is modest evidence to support aggressively increasing HDL-C levels in addition to what is achieved by lifestyle modification alone. Ongoing clinical trials that target specific pathways in HDL metabolism may help expand cardiovascular treatment options.


Effectiveness of a coral-derived surfacing material for reducing sediment production on unpaved roads, Schoffield barracks, Oahu, Hawaii.
This study evaluated the effectiveness of two application rates of a coral-derived surfacing material for both traffic and nontraffic road conditions using simulated rainfall (110-120 mm h(-1) for 30-90 min) on 0.75-m (wide) x 5.0-m (long) plots of similar slope (roughly 0.1 m m(-1)). The coral is a locally available material that has been applied to unpaved roads surfaces on Schoffield Barracks, Oahu, Hawaii (USA), where this experiment was conducted. The simulations show that compared with a bare control plot, the coral-based surface application rates of 80 and 160 kg m(-2) (equivalent to only 10- and 20-mm thicknesses) reduced road sediment production by 75% and 95%, respectively, for nontraffic conditions. However, after two passes of the research vehicle during wet conditions, sediment production rates for the two coral treatments were not significantly different from those on the bare road plots. The overall effectiveness of the coral-derived surfacing material is unsatisfactory, primarily because the on-road surface thickness associated with the application rates tested was too small. These rates were selected to bracket those applied to training roads in the study area. Furthermore, the composition of the coral-based material does not facilitate the development of a sealed, erosion-resistant surface. When applied at the low rates tested, the coral material breaks down under normal traffic conditions, thereby losing its ability to counter shearing forces exerted by overland flow on long hillslopes where erosion measures are most needed. These simulations, combined with observations on roads in the study area, indicate that this material is not an appropriate road surfacing material for the site-at least for the low application rates examined. These results are preliminary; extended testing of higher applications rates at the hillslope scale under natural climate and traffic conditions is needed to better judge the effectiveness of this material over time.


Highly sensitive SnO2 sensor via reactive laser-induced transfer.
Gas sensors based on tin oxide (SnO2) and palladium doped SnO2 (Pd:SnO2) active materials are fabricated by a laser printing method, i.e. reactive laser-induced forward transfer (rLIFT). Thin films from tin based metal-complex precursors are prepared by spin coating and then laser transferred with high resolution onto sensor structures. The devices fabricated by rLIFT exhibit low ppm sensitivity towards ethanol and methane as well as good stability with respect to air, moisture, and time. Promising results are obtained by applying rLIFT to transfer metal-complex precursors onto uncoated commercial gas sensors. We could show that rLIFT onto commercial sensors is possible if the sensor structures are reinforced prior to printing. The rLIFT fabricated sensors show up to 4 times higher sensitivities then the commercial sensors (with inkjet printed SnO2). In addition, the selectivity towards CH4 of the Pd:SnO2 sensors is significantly enhanced compared to the pure SnO2 sensors. Our results indicate that the reactive laser transfer technique applied here represents an important technical step for the realization of improved gas detection systems with wide-ranging applications in environmental and health monitoring control.


Reliability of Tibialis Anterior Muscle Voluntary Activation Using the Interpolated Twitch Technique and the Central Activation Ratio in People with Stroke.
Voluntary activation (VA) is measured by applying supramaximal electrical stimulation to a muscle during a maximal voluntary contraction (MVC). The amplitude of the evoked muscle twitch is used to determine any VA deficit, and indicates incomplete central neural drive to the motor units. People with stroke experience VA deficits and greater levels of central fatigue, which is the decrease in VA that occurs following exercise. This study investigated the between-session reliability of VA and central fatigue of the tibialis anterior muscle (TA) in people with chronic stroke (n = 12), using the interpolated twitch technique (ITT), adjusted-ITT, and central activation ratio (CAR) methods. On two separate sessions, supramaximal electrical stimulation was applied to the TA when it was at rest and maximally activated, at the start and end of a 30-s isometric dorsiflexor MVC. The most reliable measures of VA were obtained using the CAR calculation on transformed data, which produced an ICC of 0.92, and a lower bound confidence interval in the good range (95% CI 0.77 to 0.98). Reliability was lower for the CAR calculation on non-transformed data (ICC 0.82, 95% CI 0.63 to 0.91) and the ITT and adjusted-ITT calculations on transformed data (ICCs 0.82, 95% CIs 0.51 to 0.94), which had lower bound confidence intervals in the moderate range. The two ITT calculations on non-transformed data demonstrated the poorest reliability (ICCs 0.62, 95% CI 0.25 to 0.74). Central fatigue measures demonstrated very poor reliability. Thus, the reliability for VA in people with chronic stroke ranged from good to poor, depending on the calculation method and statistical analysis method, whereas the reliability for central fatigue was very poor.


Carbonic anhydrase 2-like a and 15a are involved in acid-base regulation and Na+ uptake in zebrafish H+-ATPase-rich cells.
H(+)-ATPase-rich (HR) cells in zebrafish gills/skin were found to carry out Na+ uptake and acid-base regulation through a mechanism similar to that which occurs in mammalian proximal tubular cells. However, the roles of carbonic anhydrases (CAs) in this mechanism in zebrafish HR cells are still unclear. The present study used a functional genomic approach to identify 20 CA isoforms in zebrafish. By screening with whole mount in situ hybridization, only zca2-like a and zca15a were found to be expressed in specific groups of cells in zebrafish gills/skin, and further analyses by triple in situ hybridization and immunocytochemistry demonstrated specific colocalizations of the two zca isoforms in HR cells. Knockdown of zca2-like a caused no change in and knockdown of zca15a caused an increase in H+ activity at the apical surface of HR cells at 24 h postfertilization (hpf). Later, at 96 hpf, both the zca2-like a and zca15a morphants showed decreased H+ activity and increased Na+ uptake, with concomitant upregulation of znhe3b and downregulation of zatp6v1a (H+-ATPase A-subunit) expressions. Acclimation to both acidic and low-Na+ fresh water caused upregulation of zca15a expression but did not change the zca2-like a mRNA level in zebrafish gills. These results provide molecular physiological evidence to support the roles of these two zCA isoforms in Na+ uptake and acid-base regulation mechanisms in zebrafish HR cells.


Presynaptic modulation of cortical synaptic activity by calcineurin.
Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.


A Multisensory Approach to Present Phonemes as Language Through a Wearable Haptic Device.
Communication is an important part of our daily interactions; however, communication can be hindered, either through visual or auditory impairment, or because usual communication channels are overloaded. When standard communication channels are not available, our sense of touch offers an alternative sensory modality for transmitting messages. Multi-sensory haptic cues that combine multiple types of haptic sensations have shown promise for applications, such as haptic communication, that require large discrete cue sets while maintaining a small, wearable form factor. This article presents language transmission using a multi-sensory haptic device that occupies a small footprint on the upper arm. In our approach, phonemes are encoded as multisensory haptic cues consisting of vibration, radial squeeze, and lateral skin stretch components. Participants learned to identify haptically transmitted phonemes and words after training across a four day training period. A subset of our participants continued their training to extend word recognition free response. Participants were able to identify words after four days using multiple choice with an accuracy of 89% and after eight days using free response with an accuracy of 70%. These results show promise for the use of multisensory haptics for haptic communication, demonstrating high word recognition performance with a small, wearable device.