[Management of erectile dysfunction in patients with preexisting cardiovascular disease].
Erectile dysfunction (ED) is common among patients with cardiovascular diseases (CVD). Sexual problems usually precede the onset of CVD and should, therefore, be considered as a risk factor for cardiac events. Similarly, patients with preexisting CVD are at increased risk of experiencing ED. Therefore, ED and CVD might be considered as two different clinical manifestations of the same systemic disease. Moreover, these conditions share many common pathophysiological mechanisms. Patients with preexisting CVD and ED should be stratified according to their cardiovascular risk. Sexual activity is safe in patients at low risk of CVD and these individuals might be treated with pro-erectile medications. On the other hand, men at high risk of CVD should be reassessed and the cardiac condition should be stabilized before they might have sexual attempts. Recent evidence suggests that lifestyle changes, administration of phosphodiesterase type-5 inhibitors, and testosterone supplementation might improve sexual function and reduce the risk of experiencing CVD during follow-up.


Local and non-local effects on surface-mediated stereoscopic depth.
The magnitude and precision of stereoscopic depth between two probes is often determined by the disparity each has to a common background. If stereoscopic slant of the background is underestimated, a bias is introduced in the PSE of the probes (G. Mitchison & G. Westheimer, 1984). Using random dot stimuli, we show here how more remote surfaces can influence probe PSE via their influence on perceived background surface slant. The bias was reduced when frontal flanking surfaces were placed above and below the background surface, increasing its perceived slant. In a similar experiment, the flankers were slanted and the central background surface was frontal. For flankers alone, probe bias did not diminish up to a 4.4° separation of flankers and probes. When the central surface was present, the effect of the flankers on probe bias was mediated by this surface and diminished with flanker separation, presumably because of the diminishing contrast slant of the background surface. Stereoscopic depth between probes is thus influenced by a common background surface, by neighboring surfaces acting (contiguously or non-contiguously) on the background surface, and by distant surfaces acting directly on the probes.


Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis.
Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.


Sexual risk taking among transgender male-to-female youths with different partner types.
We examined associations between partner types (categorized as main, casual, or commercial) and sexual risk behaviors of sexually active male-to-female (transgender female) youths. We interviewed 120 transgender female youths aged 15 to 24 years recruited from clinics, community-based agencies, club and bar venues, referrals, and the streets of Los Angeles, California, and Chicago, Illinois. Sexual risk behaviors varied by partner type. Transgender female youths were less likely to use condoms during receptive anal intercourse with their main partner and were less likely to use condoms with a main partner while under the influence of substances. Youth participants were also more likely to talk to a main partner about their HIV status. Our data identified no demographic or social factors that predicted condom use during receptive anal intercourse by partner type. Research and interventions that focus on understanding and mitigating risk behaviors by partner type, especially those that tackle the unique risks incurred with main partners, may make important contributions to risk reduction among transgender female youths.


Microtubule organization and function in epithelial cells.
Microtubules are essential for many aspects of polarity in multicellular organisms, ranging from the asymmetric distribution of cell-fate determinants in the one-cell embryo to the transient polarity generated in migrating fibroblasts. Epithelial cells exhibit permanent cell polarity characterized by apical and basolateral surface domains of distinct protein and lipid composition that are segregated by tight junctions. They are also endowed with a microtubule network that reflects the asymmetry of their cell surface: microtubule minus-ends face the apical- and microtubule plus-ends the basal domain. Strikingly, the formation of distinct surface domains during epithelial differentiation is accompanied by the re-organization of microtubules from a uniform array focused at the centrosome to the noncentrosomal network that aligns along the apico-basolateral polarity axis. The significance of this coincidence for epithelial morphogenesis and the signaling mechanisms that drive microtubule repolymerization in developing epithelia remain major unresolved questions that we are only beginning to address. Studies in cultured polarized epithelial cells have established that microtubules serve as tracks that facilitate targeted vesicular transport. Novel findings suggest, moreover, that microtubule-based transport promotes protein sorting, and even the generation of transport carriers in the endo- and exocytic pathways.


Delineating the plastic waste status in the State of Qatar: Potential opportunities, recovery and recycling routes.
The Qatar's national vision (QNV2030) underlines an unequivocal commitment to maintaining harmony between the three inter-dependent pillars of sustainable development: economic growth, social development and environmental management. Nonetheless, it seems that the country is set on a trajectory of unparalleled and rapid development that most waste management and environmental experts would, possibly, characterise as unsustainable; in addition it seems to repeat many of the "errors" that have been made in other parts of the world, including, for example, a lack of developed recycling and waste management infrastructure. The average Municipal Solid Waste (MSW) generation rate per capita in the Gulf Co-operation countries (GCC) reaches almost 1.5 kg/person/d, with the State of Qatar being close to 1.4 kg/person/d during the past years, thereby ranking the Gulf States as some of the highest waste generating countries globally. Plastics, accounting for approx. 13-14% of the total MSW (in these countries), present both a significant amount as well as a valuable resource to be recovered. In the present work, the authors attempt to delineate the plastic recovery status, based on the current waste management and recycling infrastructure existing and operating in Qatar, outlying the drawbacks, but at the same time highlighting the potential opportunities and benefits in developing the waste management and recovery sector in the country.


Evidence-based occupational therapy for people with dementia and their families: What clinical practice guidelines tell us and implications for practice.
The first evidence-based Clinical Practice Guidelines and Principles of Care for People with Dementia in Australia have been released. The Guidelines detail a number of important evidence-based recommendations for occupational therapists. The aim of this paper is (1) to provide an overview of Guideline development, and (2) to describe the evidence supporting a recommendation for occupational therapy. Common characteristics of effective occupational therapy programmes for people with dementia are described. Guideline development involved adaptation of existing high-quality guidelines developed overseas and 17 systematic reviews to ensure that the most recent high-quality evidence was included. One of the systematic reviews involved examining the evidence for interventions to promote independence in people with dementia. Specifically, we looked at the evidence for occupational therapy and its effect on activities of daily living, quality of life and carer impact. A total of 109 recommendations are included in the Guidelines. Occupational therapy was found to significantly increase independence in activities of daily living and improve quality of life. Effective occupational therapy programmes involve: environmental assessment, problem solving strategies, carer education and interactive carer skills training. Occupational therapists working with people with dementia in community settings should ensure that their time is spent on those aspects of intervention that are shown to be effective.


Expression of an IRF-3 fusion protein and mouse estrogen receptor, inhibits hepatitis C viral replication in RIG-I-deficient Huh 7.5 cells.
Interferon Regulatory Factor-3 (IRF-3) plays a central role in the induction of interferon (IFN) production and succeeding interferon-stimulated genes (ISG) expression en route for restraining hepatitis C virus (HCV) infection. Here, we established a stable Huh7.5-IRF3ER cell line expressing a fusion protein of IRF-3 and mouse estrogen receptor (ER) to examine IFN production and anti-HCV effects of IRF-3 in retinoic acid inducible-gene-I (RIG-I) deficient Huh 7.5 cells. Homodimerization of the IRF-3ER fusion protein was detected by Western blotting after treatment with the estrogen receptor agonist 4-hydrotamoxifen (4-HT) in Huh7.5-IRF3ER cells. Expression of IFN-α, IFN-β, and their inhibitory effects on HCV replication were demonstrated by real-time polymerase chain reaction (PCR). Peak expression of IFN-α and IFN-β was achieved 24-hours post 4-HT treatment, coinciding with the appearance of phosphorylated signal transducer and activator of transcription (STAT) proteins. Additionally, HCV viral replication declined in time-dependent fashion. In previous studies, a novel IFN-mediated pathway regulating expression of 1-8U and heterogeneous nuclear ribonucleoprotein M (hnRNP M) inhibited HCV internal ribosomal entry site (IRES)-dependent translation. When expression of ISGs such as 1-8U and hnRNP M were measured in 4-HT-treated Huh7.5-IRF3ER cells, both genes were positively regulated by activation of the IRF-3ER fusion protein. In conclusion, the anti-HCV effects of IRF-3ER homodimerization inhibited HCV RNA replication as well as HCV IRES-dependent translation in Huh7.5-IRF3ER cells. The results of this study indicate that IRF-3ER homodimerization is a key step to restore IFN expression in Huh7.5-IRF3ER cells and in achieving its anti-HCV effects.


Impact of renal surgery for cortical neoplasms on lipid metabolism.
To examine the incidence of and risk factors for development of hyperlipidaemia in patients undergoing radical nephrectomy (RN) or partial nephrectomy (PN) for renal cortical neoplasms, as hyperlipidaemia is a major source of morbidity in chronic kidney disease (CKD). We conducted a two-centre retrospective analysis of 905 patients (mean age 57.5 years, mean follow-up 78 months), who underwent RN (n = 610) or PN (n = 295) between July 1987 and June 2007. Demographics, preoperative and postoperative hyperlipidaemia were recorded. De novo hyperlipidaemia was defined as that ocurring ≥6 months after surgery in cases where laboratory values met National Cholesterol Education Program Adult Treatment Panel III definitions. The Kaplan-Meier method was used to assess freedom from de novo hyperlipidaemia. Multivariable analysis was conducted to determine the risk factors for de novo hyperlipidaemia. There were no significant differences with respect to demographics, preoperative glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) (P = 0.123) and hyperlipidaemia (P = 0.144). Tumour size (cm) was significantly larger in the RN group vs the PN group (7.0 vs 3.7; P < 0.001). Significantly greater postoperative GFR <60 mL/min/1.73 m(2) was noted in the RN group (45.7 vs 18%, P < 0.001). Significantly, more de novo hyperlipidaemia developed in the RN group than in the PN group (23 vs 6.4%; P < 0.001). The mean time to development of hyperlipidaemia was longer for PN than for RN (54 vs 44 months; P = 0.03). Five-year freedom from de novo hyperlipidaemia probability was 76% for RN vs 96% for PN (P < 0.001). Multivariable analysis showed that RN (odds ratio [OR] 2.93; P = 0.0107), preoperative GFR <60 mL/min/1.73 m(2) (OR 1.98; P = 0.037) and postoperative GFR <60 mL/min/1.73 m(2) (OR 7.89; P < 0.001) were factors associated with hyperlipidaemia development. Patients who underwent RN had a significantly higher incidence of and shorter time to development of de novo hyperlipidaemia. RN and pre- and postoperative eGFR <60 mL/min/1.73 m(2) were associated with development of hyperlipidaemia. Further follow-up and prospective investigation are necessary to confirm these findings.


The renin-angiotensin system and the developing retinal vasculature.
To determine the location and activity of renin-angiotensin system (RAS) components in the developing rat retina and whether the RAS influences retinal vascularization. Transgenic Ren-2 rats, which overexpress the RAS, and Sprague-Dawley (SD) rats were studied at postnatal day (P)1, P7, P14, P21, and P90. Immunohistochemistry was performed for angiotensinogen, prorenin, angiotensin II (Ang II), and the angiotensin type 1 (AT(1)) and 2 (AT(2)) receptors. Retinal active renin and prorenin were measured by radioimmunoassay, and the density of angiotensin-converting enzyme (ACE) by autoradiography. At P1 to P7, Ren-2 and SD rats were administered either the ACE inhibitor lisinopril (10 mg/kg per day, intraperitoneally [IP]) or the AT(1) receptor antagonist losartan (10 mg/kg per day, IP), and vessel length and density were measured. At all time points, RAS components were localized to blood vessels and cells in the ganglion cell layer. At P1, Ang II and both the AT(1) and AT(2) receptors were on hyaloid vessels. ACE binding increased in intensity from P1 to P90. Retinal renin was mainly activated and was 5- to 15-fold higher in Ren-2 than in SD rats. In Ren-2 rats, the growing vasculature extended farther into the retinal periphery than in SD rats and was unchanged with either lisinopril or losartan. Vascular density was increased in the periphery of Ren-2 rats compared with SD rats and was reduced with lisinopril but not with losartan. In the developing rat retina, a complete RAS is mainly found in blood vessels and cells in the ganglion cell layer, where it may influence the early stages of vascularization.


Lipoprotein-associated phospholipase A2 is associated with atherosclerotic stroke risk: the Northern Manhattan Study.
Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown. Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors. Serum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% non-Hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk. LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI 1.17-2.04). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR = 1.43, 95% CI 0.23-8.64; 3rd quartile HR = 4.47, 95% CI 0.93-21.54; 4th quartile HR = 5.07, 95% CI 1.07-24.06). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p = 0.01); LpPLA2-mass was associated with increased risk of LAA among non-Hispanic Whites (adjusted HR per SD 1.44, 95% CI 0.98-2.11), but not other race-ethnic groups. LpPLA2-mass levels were associated with risk of atherosclerotic stroke among non-Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them.


A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.
The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.


Mechanisms responsible for the promoter-specific effects of myocardin.
Understanding the mechanism of smooth muscle cell (SMC) differentiation will provide the foundation for elucidating SMC-related diseases such as atherosclerosis, restenosis, and asthma. Recent studies have demonstrated that the interaction of SRF with the co-activator myocardin is a critical determinant of smooth muscle development. It has been proposed that the specific transcriptional activation of smooth muscle-restricted genes (as opposed to other SRF-dependent genes) by myocardin results from the presence of multiple CArG boxes in smooth muscle genes that facilitate myocardin homodimer formation. This proposal was further tested in the current study. Our results show that the SMC-specific telokin promoter, which contains only a single CArG box, is strongly activated by myocardin. Furthermore, myocardin and a dimerization defective mutant myocardin induce expression of endogenous telokin but not c-fos in 10T1/2 fibroblast cells. Knocking down myocardin by small interfering RNA decreased telokin promoter activity and expression in A10 SMCs. A series of telokin and c-fos promoter chimeric and mutant reporter genes was generated to determine the mechanisms responsible for the promoter-specific effects of myocardin. Data from these experiments demonstrated that the ets binding site in the c-fos promoter partially blocks the activation of this promoter by myocardin. However, the binding of ets factors alone was not sufficient to explain the promoter-specific effects of myocardin. Elements 3' of the CArG box in the c-fos promoter act in concert with the ets binding site to block the ability of myocardin to activate the promoter. Conversely, elements 5' and 3' of the CArG box in the telokin promoter act in concert with the CArG box to facilitate myocardin stimulation of the promoter. Together these data suggest that the promoter specificity of myocardin is dependent on complex combinatorial interactions of multiple cis elements and their trans binding factors.


Utilisation and Determinants of Epidermal Growth Factor Receptor Mutation Testing in Patients with Non-small Cell Lung Cancer in Routine Clinical Practice: A Global Systematic Review.
Epidermal growth factor receptor (EGFR) mutation testing is recommended for selecting patients with non-squamous non-small cell lung cancer (NSCLC) for EGFR tyrosine kinase inhibitor drug treatment. The objective of this article was to systematically review available evidence on the utilisation and determinants of EGFR mutation testing of patients with NSCLC in routine clinical practice. Searches were made of five electronic databases (Web of Science, MEDLINE [Ovid], Science Direct, EMBASE and Scopus), bibliographies of relevant articles, studies that cited included studies and relevant cancer websites. Studies were included if they: (1) reported the rate of uptake of EGFR testing in patients with NSCLC; (2) were conducted in routine clinical practice settings; (3) were published in English prior to July 2017; and (4) had full text available. Studies were appraised using the STROBE and the National Institutes of Health (National Heart, Lung and Blood Institute) checklists. Eighteen eligible studies were identified for this systematic review, published between 2011 and 2017, from the USA (n = 7), Canada (n = 2), Republic of Korea (n = 2), Norway (n = 1), Sweden (n = 1), Germany (n = 1), Spain (n = 1), New Zealand (n = 1), China (n = 1) and multiple countries from the Asia-Pacific region (n = 1). Overall, testing for EGFR mutations was undertaken in 16,146 of 52,257 study patients (31%), although testing rates varied widely between different studies (from 7.8% to 78.3%). Single institution retrospective audits reported higher rates of testing (median 65.7%, range 31.3-78.3%) than population-based retrospective cohort analyses (median 23%, range 11-69%) and multi-institutional cross-sectional practitioner surveys (median 19.8%, range 7.8-31.8%). Nine studies reported increasing rates of testing over the study period but maximum testing rates remained less than 75% in most studies. Factors associated with higher testing uptake rates included: female sex; younger age; former/no smoking; advanced stage of lung cancer; adenocarcinoma histology; better mobility; radiation therapy; available tissue specimen; and private insurance. Among 16,146 tested patients, EGFR mutations were detected in 4328 patients (26.8%). However, estimates of mutation prevalence were biased by incomplete and selective testing in many studies. The uptake of EGFR mutation testing of patients with NSCLC is suboptimal in many parts of the world. Incomplete uptake of testing is fuelled by selective testing referral practices, sample limitations, and funding constraints.


MassSorter: a tool for administrating and analyzing data from mass spectrometry experiments on proteins with known amino acid sequences.
Proteomics is the study of the proteome, and is critical to the understanding of cellular processes. Two central and related tasks of proteomics are protein identification and protein characterization. Many small laboratories are interested in the characterization of a small number of proteins, e.g., how posttranslational modifications change under different conditions. We have developed a software tool called MassSorter for administrating and analyzing data from peptide mass fingerprinting experiments on proteins with known amino acid sequences. It is meant for small scale mass spectrometry laboratories that are interested in posttranslational modifications of known proteins. Several experiments can be compared simultaneously, and the matched and unmatched peak values are clearly indicated. The hits can be sorted according to m/z values (default) or according to the sequence of the protein. Filters defined by the user can mark autolytic protease peaks and other contaminating peaks (keratins, proteins co-migrating with the protein of interest, etc.). Unmatched peaks can be further analyzed for unexpected modifications by searches against a local version of the UniMod database. They can also be analyzed for unexpected cleavages, a highly useful feature for proteins that undergo maturation by proteolytic cleavage, creating new N- or C-terminals. Additional tools exist for visualization of the results, like sequence coverage, accuracy plots, different types of statistics, 3D models, etc. The program and a tutorial are freely available for academic users at http://www.bioinfo.no/software/massSorter. MassSorter has a number of useful features that can promote the analysis and administration of MS-data.


Treatment of severe psychiatric illness in a day hospital.
Severity of psychiatric illness was assessed using standardised clinical and social measures in 69 in-patients and 41 day patients admitted consecutively from the community. Day and in-patients differed little in terms of psychiatric symptoms and social disability, especially if compulsory admissions were excluded. Protection of self or others was a common reason for in-patient admission given by clinicians, who were otherwise prepared to treat seriously ill patients in the day hospital. Very few of the day patients had to be transferred to the in-patient facility, and at three months and one year the two groups showed similar improvements. It is concluded that day treatment is feasible for some seriously ill psychiatric patients, but a random-allocation study is required to assess more completely the efficacy of day treatment, and define the characteristics of those who require in-patient admission.


Expression and activity of epidermal growth factor receptor in late fetal rat lung is cell- and sex-specific.
Epidermal growth factor (EGF) augments late fetal lung maturation by advancing the ontogeny of fetal lung development and by stimulating surfactant synthesis. Previous studies have indicated that fibroblastalveolar epithelial cell communications mediate surfactant synthesis in the fetal lung and EGF acts through such a mechanism. We investigated the hypothesis that is differential activity and expression of the epidermal growth factor receptor (EGF-R) in fetal lung fibroblasts during the canalicular stage of lung development mediates EGF effects. To test this hypothesis, we examined fetal rat lung fibroblasts (FLFs) and type II cells of late gestation (canalicular and saccular stages; 17-22 days) by EGF-R binding techniques, SDS-PAGE, and Western blot analysis. Specific EGF binding increased 181% in day 18 female FLFs, with male FLFs exhibiting a similar increase on day 19. In contrast, specific EGF binding was low in type II cells, did not increase during late gestation, and there were no sex-specific differences. SDS-PAGE and Western blot analysis revealed a predominant 170-kDa EGF-R band in fibroblasts that increased with gestation (peak = 19 days), and was stronger in females. Immunoprecipitation of EGF-treated cells demonstrated the tyrosine kinase activity of the identified receptor. In contrast, type II cells showed minimal signal that did not increase until day 21 of gestation. We also examined whole fetal lung sections by immunohistochemistry to determine cell-specific expression of the EGF-R in vivo. Immunohistochemistry revealed specific EGF-R staining in columnar and cuboidal epithelia of small conducting airways and in mesenchyme of epithelial-mesenchymal borders (including subepithelial mesenchyme). In contrast, alveolar epithelia showed minimal staining, while subalveolar mesenchyme EGF-R staining peaked at day 19 of gestation. We conclude that cell-specific and sex-specific differences in EGF-R binding and EGF-R immunolocalization appears in the fetal lung at a developmental stage that is critical for alveolar epithelial cell differentiation. The results suggest a role for EGF-R activation in late fetal alveolar epithelial cell maturation, which is mediated through mesenchymal-epithelial cell communication.


Evaluation of CdTe/CdS/ZnS core/shell/shell quantum dot toxicity on three-dimensional spheroid cultures.
In this work, three-dimensional (3D) spheroid cultures of human adipose-derived mesenchymal stem cells (hAD-MSCs), with tissue-mimetic morphology through well developed cell-cell and cell-matrix interactions and distinct diffusion/transport characteristics, were assessed for dose-dependent toxic effects of red-emitting CdTe/CdS/ZnS quantum dots (Qdots). Morphological investigations and time-resolved microscopy analysis in addition to cell metabolic activity studies revealed that 3D spheroid cultures are more resistant to Qdot-induced cytotoxicity in comparison to conventional 2D cultures. The obtained results suggest the presence of two distinct cell populations in 2D cultures with different sensitivity to Qdots, however that effect wasn't observed in 3D spheroids. Our investigations were aimed to improve the prediction of nanotoxicity of Qdot on tissue-level and provide the essential screening steps prior to any in vivo application. Moreover, penetration ability of highly fluorescent Qdots to densely-packed spheroids will fortify the biological application of developed Qdots in tissue-like structures.


Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels.
Antimicrobial resistance is an increasing concern in ICUs worldwide. Infection with an antibiotic resistant (ABR) strain of an organism is associated with greater mortality than infection with the non-resistant strain, but there are few data assessing whether being admitted to an intensive care unit (ICU) with high levels of antimicrobial resistance is associated with a worse outcome than being admitted to an ICU with low rates of resistance. The aim of this study was, therefore, to compare the characteristics of infections and antibiotic treatments and patient outcomes in patients admitted to ICUs in countries considered as having high levels of antibiotic resistance and those admitted to ICUs in countries considered as having low levels of antibiotic resistance. Data from the large, international EPIC II one-day point prevalence study on infections in patients hospitalized in ICUs were used. For the current study, we compared the data obtained from patients from two groups of countries: countries with reported MRSA rates of ≥ 25% (highABR: Greece, Israel, Italy, Malta, Portugal, Spain, and Turkey) and countries with MRSA rates of < 5% (lowABR: Denmark, Finland, Netherlands, Norway, and Sweden). On the study day, 1187/2204 (53.9%) patients in the HighABR ICUs were infected and 255/558 (45.7%) in the LowABR ICUs (P < 0.01). Patients in the HighABR ICUs were more severely ill than those in the LowABR ICUs, as reflected by a higher SAPS II score (35.6 vs 32.7, P < 0.05) and had longer median ICU (12 days vs 5 days) and hospital (24 days vs 16 days) lengths of stay. They also had higher crude ICU (20.0% vs 15.4%) and hospital (27.0% vs 21.5%) mortality rates (both P < 0.05). However, after multivariable adjustment and matched pair analysis there were no differences in ICU or hospital mortality rates between High or LowABR ICU patients overall or among those with infections. Being hospitalized in an ICU in a region with high levels of antimicrobial resistance is not associated per se with a worse outcome.


Baseline age and time to major fracture in younger postmenopausal women.
This study aims to estimate the incidence of first hip or clinical vertebral fracture or major osteoporotic (hip, clinical vertebral, proximal humerus, or wrist) fracture in postmenopausal women undergoing their first bone mineral density (BMD) test before age 65 years. We studied 4,068 postmenopausal women, aged 50 to 64 years without hip or clinical vertebral fracture or antifracture treatment at baseline, who were participating in the Women's Health Initiative BMD cohort study. BMD tests were performed between October 1993 and April 2005, with fracture follow-up through 2012. Outcomes were the time for 1% of women to sustain a hip or clinical vertebral fracture and the time for 3% of women to sustain a major osteoporotic fracture before initiating treatment, adjusting for clinical risk factors and accounting for competing risks. Women without osteoporosis and women with osteoporosis on their first BMD test were analyzed separately. During a maximum of 11.2 years of concurrent BMD and fracture follow-up, the adjusted estimated time for 1% of women to have a hip or clinical vertebral fracture was 12.8 years (95% CI, 8.0-20.4) for women aged 50 to 54 years without baseline osteoporosis, 7.6 years (95% CI, 4.8-12.1) for women aged 60 to 64 years without baseline osteoporosis, and 3.0 years (95% CI, 1.3-7.1) for all women aged 50 to 64 years with baseline osteoporosis. Results for major osteoporotic fracture were similar. Because of very low rates of major osteoporotic fracture, postmenopausal women aged 50 to 64 years without osteoporosis on their first BMD test are unlikely to benefit from frequent rescreening before age 65 years.


The Src family of protein tyrosine kinases: regulation and functions.
Most of the nine members of the Src family of tyrosine kinases are restricted in their expression, often to cells of the haematopoietic lineage, while some, particularly Src, Fyn and Yes, are more ubiquitously expressed. We have been studying the functions of Src, Fyn and Yes in fibroblasts. We have shown that stimulation of quiescent fibroblasts with platelet-derived growth factor (PDGF) causes Src, Fyn and Yes to become activated, and to associate transiently with the PDGF receptor. To address the role of Src, Fyn and Yes in the response to PDGF, we have used a dominant negative approach, in which cells were engineered to express catalytically inactive forms of Src kinases. These cells were unable to enter S phase in response to PDGF, and we therefore conclude that Src family tyrosine kinases are required in order for the PDGF receptor to transmit a mitogenic signal. It has previously been shown that the kinase activity of Src is negatively regulated by phosphorylation of tyr 527 in its carboxy-terminal tail. A kinase, Csk, that phosphorylates tyr 527 has recently been identified. We expressed Src in yeast to test the model that phosphorylation of tyr 527 represses activity by promoting intramolecular association between the tail and the SH2 domain. Inducible expression of Src in S. pombe caused cell death. Co-expression of Csk counteracted this effect. Src proteins mutated in the SH2 domain were as lethal as wild-type Src, but were insensitive to Csk. We interpret these results in favour of an SH2 domain: phosphorylated tail interaction repressing Src activity. (ABSTRACT TRUNCATED AT 250 WORDS)


Probing the electronic structures of Con (n = 1-5) clusters on γ-Al2O3 surfaces using first-principles calculations.
The electronic structure of the oxide-supported nanoclusters based on metal-support interactions including charge and spin reorganization plays a crucial role in the catalytic activity at the interface region. In this work, by using density functional theory periodic calculations, we theoretically investigated the stability, nucleation and electronic properties of cobalt clusters Con (n = 1-5) supported on γ-Al2O3 surfaces including dehydrated (100) and hydrated (110) surfaces. In Con/γ-Al2O3(100) (n = 1-5) and Con/γ-Al2O3(110) (n = 1 and 2), the Con clusters prefer to adsorb on the surface. However, for Con/γ-Al2O3(110) (n = 3-5), the Con clusters bind to surface hydroxyl groups directly. Our results revealed that due to the metal-support interaction, small Co clusters strongly adsorb onto the surfaces. Nucleation energy disclosed that the critical cluster sizes are 4 and 3 for the dehydrated (100) and hydrated (110) surfaces, respectively, suggesting that the presence of γ-Al2O3 surfaces remarkably affects and even prevents the sintering process of small Co clusters. More importantly, the charge analysis showed that both metal cluster and support play important roles in the charge state of clusters.


Green-fluorescent protein fusions for efficient characterization of nuclear targeting.
The green-fluorescent protein (GFP) from Aequorea victoria has been shown to be a convenient and flexible reporter molecule within a variety of eukaryotic systems, including higher plants. It is particularly suited for applications in vivo, since the mechanism of fluorophore formation involves an intramolecular autoxidation and does not require exogenous co-factors. Unlike standard histochemical procedures of fixation and staining required for analysis of the cellular or tissue-specific expression of other popular reporter molecules, such as the beta-glucuronidase (GUS) marker, analysis of GFP can be done in living cells with no specific pretreatments. This implies that GFP might also be particularly suited for studies of intracellular protein targeting. In this paper, the use of GUS is compared with that of GFP for the analysis of nuclear targeting in tobacco. A novel oligopeptide motif from a tobacco protein is described which confers nuclear localization of GUS. The use of this oligopeptide and two from potyviral proteins to target GFP to the nucleus is examined. An essential modification of GFP is described, which specifically increases its molecular weight to eliminate its passive penetration into the nucleus. Three examples of the targeting of these enlarged GFP molecules to the nucleus are illustrated. GFP, in combination with confocal microscopy, offers significant advantages over traditional methods of studying nuclear targeting.


Diversity and ecology survey of mosquitoes potential vectors in Belgian equestrian farms: A threat prevention of mosquito-borne equine arboviruses.
Emergence of West Nile Virus was recently recorded in several European countries, which can lead to severe health problems in horse populations. Europe is also at risk of introduction of mosquito-borne equine alphavirus from Americas. Prevention of these arboviruses requires a clear understanding of transmission cycles, especially their vectors. To characterize mosquito fauna, their ecology and identify potential vectors of equine arboviruses in Belgium, entomological surveys of six equestrian farms located in the Wolloon Region were conducted during 2011-2012. The harvest of mosquitoes was based on larval sampling (272 samples from 111 breeding sites) and monthly adults trapping (CO2-baited traps, Mosquito Magnet Liberty Plus). Among 51,493 larvae and 319 adult mosquitoes collected, morphological identification showed the presence of 11 species: Anopheles claviger (Meigen), An. maculipennis s.l. (Meigen), An. plumbeus (Stephens), Culex hortensis (Ficalbi), Cx. territans (Walker), Cx. pipiens s.l. L., Cx. torrentium (Martini), Coquillettidia richiardii (Ficalbi), Culiseta annulata (Schrank), Aedes cantans (Meigen), Ae. geniculatus (Olivier). Molecular identification of Cx. pipiens species complex allowed the detection of three molecular forms, Pipiens (92.3%), Molestus (4.6%) and Hybrid (3.1%). Larvae of Cx. pipiens sl and Cx. torrentium were omnipresent and the most abundant species. Water troughs, ponds and slurry (liquid manure) were the most favorable breeding sites of mosquito larvae. Based upon behavior and ecology of the identified mosquito species, Studied Belgian equestrian farms seem to provide a suitable environment and breeding sites for the proliferation of potential vectors of arboviruses and those being a real nuisance problem for horses and neighboring inhabitants.


Drug suicide: a sex-equal cause of death in 16 European countries.
There is a lack of international research on suicide by drug overdose as a preventable suicide method. Sex- and age-specific rates of suicide by drug self-poisoning (ICD-10, X60-64) and the distribution of drug types used in 16 European countries were studied, and compared with other self-poisoning methods (X65-69) and intentional self-injury (X70-84). Data for 2000-04/05 were collected from national statistical offices. Age-adjusted suicide rates, and age and sex distributions, were calculated. No pronounced sex differences in drug self-poisoning rates were found, either in the aggregate data (males 1.6 and females 1.5 per 100,000) or within individual countries. Among the 16 countries, the range (from some 0.3 in Portugal to 5.0 in Finland) was wide. 'Other and unspecified drugs' (X64) were recorded most frequently, with a range of 0.2-1.9, and accounted for more than 70% of deaths by drug overdose in France, Luxembourg, Portugal and Spain. Psychotropic drugs (X61) ranked second. The X63 category ('other drugs acting on the autonomic nervous system') was least frequently used. Finland showed low X64 and high X61 figures, Scotland had high levels of X62 ('narcotics and hallucinogens, not elsewhere classified') for both sexes, while England exceeded other countries in category X60. Risk was highest among the middle-aged everywhere except in Switzerland, where the elderly were most at risk. Suicide by drug overdose is preventable. Intentional self-poisoning with drugs kills as many males as females. The considerable differences in patterns of self-poisoning found in the various European countries are relevant to national efforts to improve diagnostics of suicide and appropriate specific prevention. The fact that vast majority of drug-overdose suicides came under the category X64 refers to the need of more detailed ICD coding system for overdose suicides is needed to permit better design of suicide-prevention strategies at national level.


Recent advances in the development of farnesoid X receptor agonists.
Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.


Emotional intelligence and social interaction.
Two studies found positive relationships between the ability to manage emotions and the quality of social interactions, supporting the predictive and incremental validity of an ability measure of emotional intelligence, the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). In a sample of 118 American college students (Study 1), higher scores on the managing emotions subscale of the MSCEIT were positively related to the quality of interactions with friends, evaluated separately by participants and two friends. In a diary study of social interaction with 103 German college students (Study 2), managing emotions scores were positively related to the perceived quality of interactions with opposite sex individuals. Scores on this subscale were also positively related to perceived success in impression management in social interactions with individuals of the opposite sex. In both studies, the main findings remained statistically significant after controlling for Big Five personality traits.


A validation study of the Eurostat harmonised European time use study (HETUS) diary using wearable technology.
The central aim was to examine the accuracy of the full range of daily activities recorded in self-report time-use diaries against data from two objective passive data collection devices (wearable camera and accelerometer) serving as criterion reference instruments. This enabled systematic checks and comparisons on the timing, sequence and duration of activities recorded from the three data sources. Participants (n = 148) were asked to complete a single-day self-report paper time-use diary designed for use in the Harmonised European Time Use Study (HETUS), while simultaneously wearing a camera that continuously recorded images of their activities, and an accelerometer tracking physical movement. In a reconstruction interview shortly after the data collection period, participants viewed the camera images to help researchers interpret the image sequences. Of the initial 148 recruits (multi-seed snowball sample, 59% women, aged 18-91, 43% > 40) 131 returned usable diary and camera records (of whom 124 also provided a usable whole-day accelerometer record. We compare time allocation estimates from the diary and camera records, and also match the diary and camera records to the simultaneously recorded accelerometer vector magnitudes. The data were examined at three analytic levels: aggregate, individual diarist and timeslot. The most important finding is that the estimates of mean daily time devoted to 8 of the 10 main activities differ by < 10% in the camera and diary records. The single case of major divergence (eating) can be explained by a systematic difference between the procedures followed by the self-reporting diarist and the observer coding the camera records. There are more substantial differences at the respondent level, paired t-tests showing significant differences in time spent in the 4/10 categories. 45% of all variation in the accelerometer vector magnitudes in the timeslots is explained by camera and diary records. Detailed activity classifications perform much better than METs as predictors of actigraphy. The comparison of the diary with the camera and accelerometer records strongly supports using diary methodology for studying the full range of daily activity, particularly at aggregate levels. Accelerometer data could be combined with diary measures to improve estimation of METs equivalents for various types of active and sedentary behaviour.


Spatial light modulation techniques for system application to multipath delay estimation.
Three electronically addressed spatial light modulators (SLM's) are tested for their utility in forming optical taps onto an acousto-optic delay line. The SLM's are characterized as devices within a specific optical signal-processing application rather than as independent components. The signal-processing architecture described here uses a programmable tapped delay line for estimating multipath delays. Overall system performance specifications necessitate the SLM requirements. These requirements are compared with the measured performance characteristics of a magneto-optic SLM, a liquid-crystal display, and an acousto-optic deflector used as an SLM. The magneto-optic SLM and the liquid-crystal display are found to provide insufficient contrast and system light efficiency. The acousto-optic-based SLM is found to provide the best overall SLM performance for this particular optical signal processing application.


Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment.
Vaginal atrophy occurring during menopause is closely related to the dramatic decrease in ovarian estrogens due to the loss of follicular activity. Particularly, significant changes occur in the structure of the vaginal mucosa, with consequent impairment of many physiological functions. In this study, carried out on bioptic vaginal mucosa samples from postmenopausal, nonestrogenized women, we present microscopic and ultrastructural modifications of vaginal mucosa following fractional carbon dioxide (CO2) laser treatment. We observed the restoration of the vaginal thick squamous stratified epithelium with a significant storage of glycogen in the epithelial cells and a high degree of glycogen-rich shedding cells at the epithelial surface. Moreover, in the connective tissue constituting the lamina propria, active fibroblasts synthesized new components of the extracellular matrix including collagen and ground substance (extrafibrillar matrix) molecules. Differently from atrophic mucosa, newly-formed papillae of connective tissue indented in the epithelium and typical blood capillaries penetrating inside the papillae, were also observed. Our morphological findings support the effectiveness of fractional CO2 laser application for the restoration of vaginal mucosa structure and related physiological trophism. These findings clearly coupled with striking clinical relief from symptoms suffered by the patients before treatment.


The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.
Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome-derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1-mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome-derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe-dependent metabolism, as well as interorganismal communication between the host and microbiome.


Comparative morphology of the mechanosensory lateral line system in a clade of New Zealand triplefin fishes.
The mechanoreceptive lateral line system in fishes detects hydrodynamic stimuli and plays a critical role in many fundamental behaviours, including orientation to water currents and the detection of stationary objects, prey and predators. Interspecific variation in lateral line structure may result from a process of functional adaptation, with the background level of hydrodynamic activity proposed as an important selective pressure. Here we use the eight species of the ecologically diverse New Zealand marine triplefin fish of the genus Forsterygion and one species from the sister genus Notoclinops to investigate interspecific differences in lateral line morphology and to assess the relationship between lateral line characteristics and exposure to wave energy (fetch/depth ratio). Overall, the results show that lateral line traits are divergent between species, and these differences could in part be related to the wave exposure of the habitats that the species occupy. Specifically, numbers of canal neuromasts differed significantly between species, and most canal groupings increased in neuromast number with fetch/depth ratio, while the number and area of some superficial neuromast groupings decreased significantly with exposure. Distribution of superficial neuromasts along the trunk in the semi-pelagic and paedomorphic species F. maryannae differed from the other, demersal species, which may be associated with the unique lifestyle of this species and/or developmental processes. Canal architecture also differed considerably between species, but displayed no relationship with fetch/depth ratio. The results from this study indicate that some interspecific differences in lateral line organs may be a by-product of selection for habitat divergence. Future work should explore additional causal factors that might have influenced the evolution of lateral morphology in these species, including phylogenetic and allometric effects.


Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis.
Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle. The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32 MJ/day, range of -0.21 to 1.66 MJ/day, p<0.05). The individual increases in energy expenditure correlated to state 4 respiration (p<0.02, R(2) = 0.50). This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilities for mitochondrial uncoupling as an alternative therapeutic target in the treatment of obesity.


Participation in a trial in the emergency situation: a qualitative study of patient experience in the UK WOLLF trial.
Patients can struggle to make sense of trials in emergency situations. This study examines patient experience of participating in the United Kingdom, Wound management of Open Lower Limb Fractures (UK WOLLF) study, a trial of standard wound management versus Negative Pressure Wound Therapy (NPWT). The aim of the study was to understand the patient's lived experience of taking part in a trial of wound dressings. Interviews drawing on Phenomenology were undertaken with a purposive sample of 20 patients, on average 12 days into their hospital stay from July 2012-July 2013. The participants were vulnerable due to the emotional and physical impact of injury. They expressed their trial experience through the theme of being compromised identified in categories of being dependent, being trusting, being grateful and being without experience. Participants felt dependent on and trusted the team to make the right decisions for them and not cause them harm. Their hopes for future recovery were also invested within the expertise of the team. Despite often not being well enough to consent to the study prior to surgery, they wished to be involved as much as possible. In agreeing to take part they expressed gratitude for their care, wanted to be helpful to others and considered the trial interventions to be a small component in relation to the enormity of their injury and broader treatment. In making sense of the trial they felt they could not understand the interventions without experience of them but if they received NPWT they developed a strong technological preference for this intervention. Patients prefer to be involved in studies within the limits of their capacity, despite not being able to provide informed consent. A variety of sources of knowledge may enable participants to feel that they have a better understanding of the interventions. Professional staff need to be aware of the situated nature of decision making where participants invest their hopes for recovery in the team. Current Controlled Trials, ID: ISRCTN33756652 . Registered on 24 February 2012.


Modified Viscotrabeculotomy with Microcatheter: Our Technique and Experience in the Surgical management of Glaucoma.
To present the results of our case series with a technique we defined as "modified viscotrabeculotomy" which incorporates the benefits of 360° of trabeculotomy and viscodilation and viscodissection of canal of Schlemm using a microcatheter. This study was designed as a prospective interventional case series and was conducted in Cerrahpasa Medical School Ophthalmology Clinic. Forty-one eyes of 30 patients diagnosed with congenital glaucoma (CG) underwent modified viscotrabeculotomy surgery following initial preoperative examination. The main outcome measure was the surgical success of the procedure, which is determined by an intraocular pressure (IOP) of <18 mm Hg without medication or resurgery; qualified success is defined as an IOP of <18 mm Hg under general anesthesia with an additional need for medications. The differences in IOP measurements were analyzed using paired analysis of variance (ANOVA) with repeated measures. The mean preoperative IOP of the patients was 32.27 ± 4.89 mm Hg. The IOP values at the 1st, 3rd, 6th postoperative months, and at the last visit were 13.41 ± 2.25 mm Hg, 13.70 ± 1.78 mm Hg, 12.47 ± 1.57 mm Hg, and 12.26 ± 1.81 mm Hg, respectively. The difference between the preoperative IOP values and postoperative IOP values was statistically significant (p < 0.001). The qualified surgical success rate was 94.4% after a mean follow-up of 27.95 ± 8.25 months (range 15-45 months). Modified viscotrabeculotomy is a safe and effective treatment in the management of CG. Tamçelik N, Capar O, Atalay E. Modified Viscotrabeculotomy with Microcatheter: Our Technique and Experience in the Surgical management of Glaucoma. J Curr Glaucoma Pract 2019;13(3):88-93.


Alginate inhibits iron absorption from ferrous gluconate in a randomized controlled trial and reduces iron uptake into Caco-2 cells.
Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n = 15) were given a test meal of 200 g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p = 0.003). Sub-group B (n = 9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p = 0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p = 0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p = 0.009) and 35% (p = 0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p < 0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification. ClinicalTrials.gov NCT01528644.


Increased resistance against citrus canker mediated by a citrus mitogen-activated protein kinase.
Mitogen-activated protein kinases (MAPK) play crucial roles in plant immunity. We previously identified a citrus MAPK (CsMAPK1) as a differentially expressed protein in response to infection by Xanthomonas aurantifolii, a bacterium that causes citrus canker in Mexican lime but a hypersensitive reaction in sweet oranges. Here, we confirm that, in sweet orange, CsMAPK1 is rapidly and preferentially induced by X. aurantifolii relative to Xanthomonas citri. To investigate the role of CsMAPK1 in citrus canker resistance, we expressed CsMAPK1 in citrus plants under the control of the PR5 gene promoter, which is induced by Xanthomonas infection and wounding. Increased expression of CsMAPK1 correlated with a reduction in canker symptoms and a decrease in bacterial growth. Canker lesions in plants with higher CsMAPK1 levels were smaller and showed fewer signs of epidermal rupture. Transgenic plants also revealed higher transcript levels of defense-related genes and a significant accumulation of hydrogen peroxide in response to wounding or X. citri infection. Accordingly, nontransgenic sweet orange leaves accumulate both CsMAPK1 and hydrogen peroxide in response to X. aurantifolii but not X. citri infection. These data, thus, indicate that CsMAPK1 functions in the citrus canker defense response by inducing defense gene expression and reactive oxygen species accumulation during infection.


Vitamin D receptor gene polymorphisms and prognosis of breast cancer among African-American and Hispanic women.
Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). Although African-Americans have the lowest levels of serum vitamin D, there is a dearth of information on VDR gene polymorphisms and breast cancer among African-Americans and Hispanics. This study examines whether VDR gene polymorphisms are associated with breast cancer in these cohorts. Blood was collected from 232 breast cancer patients (Cases) and 349 non-cancer subjects (Controls). Genotyping for four polymorphic variants of VDR (FokI, BsmI, TaqI and ApaI) was performed using the PCR-RFLP method. An increased association of the VDR-Fok1 f allele with breast cancer was observed in African-Americans (OR = 1.9, p = 0.07). Furthermore, the FbTA, FbtA and fbtA haplotypes were associated with breast cancer among African-Americans (p<0.05). Latinas were more likely to have the VDR-ApaI alleles (Aa or aa) (p = 0.008). The VDR-ApaI aa genotype was significantly associated with poorly-differentiated breast tumors (p = 0.04) in combined Cases. Kaplan-Meier survival analysis showed decreased 5-year disease-free-survival (DFS) in breast cancer patients who had the VDR-Fok1 FF genotype (p<0.05). The Cox regression with multivariate analysis revealed the independent predictor value of the VDR-FokI polymorphism for DFS. The other three variants of VDR (BsmI, TaqI and ApaI) were not associated with disease outcome. VDR haplotypes are associated with breast cancer in African-Americans, but not in Hispanic/Latinas. The VDR-FokI FF genotype is linked with poor prognosis in African-American women with breast cancer.


Methylmercury-induced microtubule depolymerization leads to inhibition of tubulin synthesis.
Methylmercury (MeHg) specifically depolymerizes microtubules and inhibits cell proliferation in mouse glioma cells. The effect of microtubule depolymerization by MeHg on tubulin synthesis was studied. Tubulin synthesis analyzed by two-dimensional electrophoresis using [35S]methionine as a tracer was markedly inhibited in mouse glioma cells exposed to 5 x 10(-6)M MeHg for 3 hr, which completely depolymerized microtubules. Under this condition, density of the protein bands other than tubulin in autoradiogram remained unchanged on gradient urea-polyacrylamide gels. Furthermore, the decrease in tubulin mRNA level was relevant to that in tubulin synthesis, although actin mRNA levels remained unchanged. In addition, specific transcription rates of beta-tubulin genes appeared to be unaffected under the same experimental condition as above. Thus, it is concluded that the disruption of microtubules by MeHg resulted in the inhibition of the synthesis of tubulin itself through autoregulatory repression in post-transcriptional processes as in the case of colchicine treatment.


MitraClip and Transcatheter Aortic Valve Implantation (TAVI): State of the Art 2015.
The feasibility, safety, and efficacy of transcatheter heart valve (THV) therapies such as MitraClip and transcatheter aortic valve implantation (TAVI) have made them valid therapeutic options in high-risk or inoperable patients with heart failure (HF). Randomized controlled trials (RCTs) demonstrated noninferiority and superiority in terms of efficacy for 12 months of TAVI versus surgical replacement and optimal medical therapy, respectively. With regard to MitraClip, noninferiority was first demonstrated in four subgroups at 12 months and then later at 4-year follow-up. This difference in clinical outcomes between the two therapies is consistent with the discrepancy in the level of recommendation and class of evidence for TAVI and MitraClip according to recent international guidelines (IB vs. IIbC, respectively). Data from ongoing RCTs and national registries will help establish the reciprocal role and hierarchy among THV therapies, surgery, and medical treatment in patients with HF.


Mpox Knowledge, Attitudes, & Practices Among Persons Presenting for JYNNEOS Vaccination - District of Columbia, August-October 2022.
More than 30,000 mpox cases have been confirmed in the United States since May 2022. Mpox cases have disproportionally occurred among adult gay, bisexual, and other men who have sex with men (MSM), transgender persons, and Black and Hispanic/Latino persons. We examined knowledge, attitudes, and practices regarding mpox vaccination among adults presenting for vaccination to inform prevention efforts. We collected mixed-methods data from a convenience sample of adults presenting for JYNNEOS vaccination at three DC Health mpox vaccine clinics during August-October 2022. Survey and interview topics included knowledge about mpox symptoms and vaccine protection, beliefs about vaccine access, and trusted sources of information. In total, 352 participants completed self-administered surveys and 62 participants completed an in-depth interview (IDI). Three main themes emerged from survey and interview data. First, most participants had a general understanding about mpox, but gaps remained in comprehensive understanding about mpox symptoms, modes of transmission, vaccine protection, personal risk, and vaccine dosing strategies. Second, participants had high trust in public health agencies. Third, participants wanted more equitable and less stigmatizing access to mpox vaccine services. Non-stigmatizing, inclusive, and clear communication from trusted sources, including public health agencies, is needed to address mpox knowledge gaps and increase vaccine access and uptake in affected communities. Mpox outreach efforts should continue innovative approaches, including person-level risk assessment tools, to address community needs.


Identification of clinically predictive metagenes that encode components of a network coupling cell shape to transcription by image-omics.
The associations between clinical phenotypes (tumor grade, survival) and cell phenotypes, such as shape, signaling activity, and gene expression, are the basis for cancer pathology, but the mechanisms explaining these relationships are not always clear. The generation of large data sets containing information regarding cell phenotypes and clinical data provides an opportunity to describe these mechanisms. Here, we develop an image-omics approach to integrate quantitative cell imaging data, gene expression, and protein-protein interaction data to systematically describe a "shape-gene network" that couples specific aspects of breast cancer cell shape to signaling and transcriptional events. The actions of this network converge on NF-κB, and support the idea that NF-κB is responsive to mechanical stimuli. By integrating RNAi screening data, we identify components of the shape-gene network that regulate NF-κB in response to cell shape changes. This network was also used to generate metagene models that predict NF-κB activity and aspects of morphology such as cell area, elongation, and protrusiveness. Critically, these metagenes also have predictive value regarding tumor grade and patient outcomes. Taken together, these data strongly suggest that changes in cell shape, driven by gene expression and/or mechanical forces, can promote breast cancer progression by modulating NF-κB activation. Our findings highlight the importance of integrating phenotypic data at the molecular level (signaling and gene expression) with those at the cellular and tissue levels to better understand breast cancer oncogenesis.


Ultrasmall hybrid protein-copper sulfide nanoparticles for targeted photoacoustic imaging of orthotopic hepatocellular carcinoma with a high signal-to-noise ratio.
Although photoacoustic imaging combined with second near infrared (NIR II) molecular probes for tumor diagnosis has drawn tremendous attention during the past few decades, the targeted photoacoustic imaging of orthotopic hepatocellular carcinoma (HCC) still remains a challenge due to high liver vascularization and non-specificity of probes in liver tumors. Herein, we report on cyclic arginine-glycine-aspartic acid (cRGD) peptide conjugated ultrasmall CuS nanoparticles (CuS@BSA-RGD NPs) which encapsulate bovine serum albumin (BSA) and possess high optical absorption at 1064 nm. The encapsulation of BSA results in great biocompatibility of CuS@BSA-RGD NPs along with excellent photostability and physiological stability. The cRGD conjugation enables the improvement of tumor uptake of CuS@BSA-RGD NPs by virtue of its positive tumor cell targeting capability. The efficient accumulation of CuS@BSA-RGD NPs in the tumor over time after intravenous administration to orthotopic HCC bearing mice was achieved, which resulted in highly sensitive photoacoustic visualization of the tumor region. Toxicity studies indicate that CuS@BSA-RGD NPs exhibited negligible systemic toxicity in vivo. The results demonstrate that the CuS@BSA-RGD NPs might hold great promise for future imaging and diagnosis of cancer.


Evaluation of hemostatic and fibrinolytic markers in dogs with ascites attributable to right-sided congestive heart failure.
To determine whether dogs with ascites secondary to right-sided congestive heart failure (CHF) have bleeding disorders associated with hypofibrinogenemia and discordant plasma fibrin-fibrinogen degradation products (FDPs) and D-dimer assay results (ie, a circulating concentration of FDPs higher than the reference range and a circulating concentration of D-dimer within the reference range). Retrospective case-control study. 80 client-owned dogs. Dogs with ascites secondary to right-sided CHF (group 1; n = 20), unhealthy dogs without cardiac disease (group 2; 40), and dogs with left-sided CHF (group 3; 20) were included in the study. Urine bile acids-to-creatinine concentration ratios were calculated as a marker of liver function. Differences among groups regarding coagulation profile analysis results and prevalence of discordant FDPs and D-dimer assay results were determined. No significant differences were detected among the 3 groups regarding urine bile acids-to-creatinine concentration ratios. Plasma fibrinogen concentration was significantly lower for group 1 versus groups 2 or 3. Prevalence of discordant FDPs and D-dimer assay results was significantly higher for group 1 versus groups 2 or 3. Eighteen group 1 dogs had discordant FDPs and D-dimer assay results. Ten of these dogs had concurrent hypofibrinogenemia, 2 of which had clinical signs of bleeding. Only 10 dogs in groups 2 or 3 had discordant FDPs and D-dimer assay results; none of these dogs had hypofibrinogenemia or clinical signs of bleeding. Dogs with right-sided CHF and ascites may be at increased risk for primary hyperfibrinogenolysis (ie, hypofibrinogenemia and discordant FDPs and D-dimer assay results).


Therapeutic vaccines for allergic disease.
Allergic diseases are highly prevalent worldwide and affect all age groups, contributing to a high personal and socioeconomic burden. Treatment with an "allergy vaccine" or allergen immunotherapy aims to provide long-lasting benefits by inducing unresponsiveness to the relevant antigen. The consequences of the therapy are considered disease modifying and range from dampening of the immediate immune responses to the reduction of secondary tissue remodeling. Furthermore, allergen immunotherapy interventions have a potential to slow or cease the development of additional allergic manifestations with a long-term overall effect on morbidity and quality of life. Here, we review proposed mechanisms underlying the therapeutic effects of immunotherapy for allergic diseases. Further, we discuss both standard and novel approaches and possible future directions in the development of allergen immunotherapy.


Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.
Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification 'Compulsive Sexual Behavior Disorder' is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD - cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.


A neuron-specific deletion of the microRNA-processing enzyme DICER induces severe but transient obesity in mice.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.


Mapping early environment using communication deviance: A longitudinal study of maternal sensitivity toward 6-month-old children.
Communication deviance (CD) reflects features of the content or manner of a person's speech that may confuse the listener and inhibit the establishment of a shared focus of attention. The construct was developed in the context of the study of familial risks for psychosis based on hypotheses regarding its effects during childhood. It is not known whether parental CD is associated with nonverbal parental behaviors that may be important in early development. This study explored the association between CD in a cohort of mothers (n = 287) at 32 weeks gestation and maternal sensitivity with infants at 29 weeks in a standard play procedure. Maternal CD predicted lower overall maternal sensitivity (B = -.385; p < .001), and the effect was somewhat greater for sensitivity to infant distress (B = -.514; p < .001) than for sensitivity to nondistress (B = -.311; p < .01). After controlling for maternal age, IQ and depression, and for socioeconomic deprivation, the associations with overall sensitivity and sensitivity to distress remained significant. The findings provide new pointers to intergenerational transmission of vulnerability involving processes implicated in both verbal and nonverbal parental behaviors.


Acanthocephalan Parasites of the Oarfish, Regalecus russelii (Regalecidae), With A Description of A New Species of Gymnorhadinorhynchus (Acanthocephala: Gymnorhadinorhynchidae).
Oarfish are rarely seen and seldom studied, which makes their parasite fauna even more enigmatic. Necropsy of 12 oarfish, Regalecus russelii (Regalecidae) (Cuvier, 1816), from Japan yielded 2 species of acanthocephalans. One species was found in 2 oarfish and a total of 76 specimens was collected, but only a single, immature specimen of the second species was found. The former represents an undescribed species from the order Echinorhynchida and is described here. Morphological and phylogenetic analyses of the small subunit ( SSU) rDNA place this species in the family Gymnorhadinorhynchidae, and genus Gymnorhadinorhynchus which is characterized by a cylindrical proboscis with longitudinal rows of hooks, basal circle of enlarged hooks, asymmetry of hook shape, 4 cement glands, and a spineless trunk. Diagnostic characters of this species within the genus are the number of longitudinal rows of hooks (14), smaller body size (males: 4.8-6.6 mm and females: 5.3-6.3 mm) and a number of molecular autapomorphies including a number of long insertions in both the SSU and large subunit rDNA (LSU). A single immature female of Bolbosoma sp. (Palaeacanthocephala: Plagiorhynchidae) was also found with its anterior end embedded in the mucosa of the pyloric ceca. The characters of this specimen are not consistent with any other known species of Bolbosoma; however, because only 1 immature specimen with a partially invaginated proboscis was recovered, it was not designated as a new species.


Evidence for lesion bypass by yeast replicative DNA polymerases during DNA damage.
The enzyme ribonucleotide reductase, responsible for the synthesis of deoxyribonucleotides (dNTP), is upregulated in response to DNA damage in all organisms. In Saccharomyces cerevisiae, dNTP concentration increases approximately 6- to 8-fold in response to DNA damage. This concentration increase is associated with improved tolerance of DNA damage, suggesting that translesion DNA synthesis is more efficient at elevated dNTP concentration. Here we show that in a yeast strain with all specialized translesion DNA polymerases deleted, 4-nitroquinoline oxide (4-NQO) treatment increases mutation frequency approximately 3-fold, and that an increase in dNTP concentration significantly improves the tolerance of this strain to 4-NQO induced damage. In vitro, under single-hit conditions, the replicative DNA polymerase epsilon does not bypass 7,8-dihydro-8-oxoguanine lesion (8-oxoG, one of the lesions produced by 4-NQO) at S-phase dNTP concentration, but does bypass the same lesion with 19-27% efficiency at DNA-damage-state dNTP concentration. The nucleotide inserted opposite 8-oxoG is dATP. We propose that during DNA damage in S. cerevisiae increased dNTP concentration allows replicative DNA polymerases to bypass certain DNA lesions.


Non-contact acquisition of brain function using a time-extracted compact camera.
A revolution in functional brain imaging techniques is in progress in the field of neurosciences. Optical imaging techniques, such as high-density diffuse optical tomography (HD-DOT), in which source-detector pairs of probes are placed on subjects' heads, provide better portability than conventional functional magnetic resonance imaging (fMRI) equipment. However, these techniques remain costly and can only acquire images at up to a few measurements per square centimetre, even when multiple detector probes are employed. In this study, we demonstrate functional brain imaging using a compact and affordable setup that employs nanosecond-order pulsed ordinary laser diodes and a time-extracted image sensor with superimposition capture of scattered components. Our technique can simply and easily attain a high density of measurement points without requiring probes to be attached, and can directly capture two-dimensional functional brain images. We have demonstrated brain activity imaging using a phantom that mimics the optical properties of an adult human head, and with a human subject, have measured cognitive brain activation while the subject is solving simple arithmetical tasks.


Association between LH receptor regulation and ovarian hyperstimulation syndrome in a rodent model.
Ovarian hyperstimulation syndrome (OHSS) is a common complication of ovarian stimulation associated with the administration of human chorionic gonadotropin (hCG) during assisted reproduction. We have determined the expression of luteinizing hormone receptor (Lhcgr) mRNA, vascular endothelial growth factor (VEGF), and its transcription factor, HIF1α, during the periovulatory period in a rodent model of OHSS and compared these results with normal ovulatory periods. These results showed that the downregulation of Lhcgr mRNA in response to conditions that mimic preovulatory LH surge was significantly impaired in the OHSS group compared to the complete downregulation seen in the control group. Most importantly, the downregulation of luteinizing hormone receptor mRNA expression following hCG administration was sustained in the control group up to 48 h, whereas it remained at significantly higher levels in the OHSS group. This impairment of hCG-induced Lhcgr downregulation in the OHSS group was accompanied by significantly elevated levels of VEGF and its transcription factor, HIF1α. Furthermore, the downregulation of Lhcgr that occurs in response to a preovulatory LH surge in normal cycles was accompanied by low levels of VEGF. This study shows that, while downregulation of Lhcgr as well as low VEGF levels are seen in response to a preovulatory LH surge in normal ovarian cycle, impaired Lhcgr downregulation and elevated VEGF levels were found in the OHSS group.


Global, regional, and national burden of meningitis and its aetiologies, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories. We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category. In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000-277 000) and 2·51 million (2·11-2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400-145 000) and 1·28 million incident cases (0·947-1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6-8·4) per 100 000 population in 1990 to 3·3 (2·8-3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1-19·2]), followed by N meningitidis (13·6% [12·7-14·4]) and K pneumoniae (12·2% [10·2-14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5-81·8]), followed by N meningitidis (72·3% [64·4-78·5]) and viruses (58·2% [47·1-67·3]). Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment. Bill & Melinda Gates Foundation.


Searching for stimulus-driven shifts of attention.
Several types of dynamic cues (e.g., abrupt onsets, motion) draw attention in visual search tasks even when they are irrelevant. Although these stimuli appear to capture attention in a stimulus-driven fashion, typical visual search tasks might induce an intentional strategy to focus on dynamic events. Because observers can only begin their search when the search display suddenly appears, they might orient to any dynamic display change (Folk, Remington, & Johnston, 1992; Gibson & Kelsey, 1998). If so, the appearance of capture might result from task-induced biases rather than from the properties of the stimulus. In fact, such biases can even create the appearance of stimulus-driven capture by stimuli that typically do not capture attention (Gibson & Kelsey, 1998). The possibility of task-induced, top-down biases plagues the interpretation of all previous studies claiming stimulus-driven attention capture by dynamic stimuli. In two experiments, we attempt to eliminate potential task-induced biases by removing any need to monitor for display changes. In the first experiment, search displays did not change on most trials. In the second experiment, although new search displays appeared on each trial, we ensured that observers never saw the changes, by making them during large saccades. In both cases, dynamic events still received search priority, suggesting that some dynamic stimuli capture attention in a stimulus-driven fashion.


Isoflavones in coffee: influence of species, roast degree, and brewing method.
This paper reports the isoflavone contents of roasted coffee beans and brews, as influenced by coffee species, roast degree, and brewing procedure. Total isoflavone level is 6-fold higher in robusta coffees than in arabica ones, mainly due to formononetin. During roasting, the content of isoflavones decreases, whereas their extractability increases (especially for formononetin). Total isoflavones in espresso coffee (30 mL) varied from approximately 40 microg (100% arabica) to approximately 285 microg (100% robusta), with long espressos (70 mL) attaining more than double isoflavones of short ones (20 mL). Espressos (30 mL) prepared from commercial blends contained average amounts of 6, 17, and 78 microg of genistein, daidzein, and formononetin, respectively. Comparison of different brewing methods revealed that espresso contained more isoflavones ( approximately 170 microg/30 mL) than a cup of press-pot coffee ( approximately 130 microg/60 mL), less than a mocha coffee ( approximately 360 microg/60 mL), and amounts similar to those of a filtered coffee cup ( approximately 180 microg/120 mL).


Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression.
Several studies linking alterations in differential placental methylation with pregnancy disorders have implicated (de)regulation of the placental epigenome with fetal programming and later-in-life disease. We have previously demonstrated that maternal tobacco use is associated with alterations in promoter methylation of placental CYP1A1 and that these changes are correlated with CYP1A1 gene expression and fetal growth restriction. In this study we sought to expand our analysis of promoter methylation by correlating it to gene expression on a genome-wide scale. Employing side-by-side IlluminaHG-12 gene transcription with Infinium27K methylation arrays, we interrogated correlative changes in placental gene expression and DNA methylation associated with maternal tobacco smoke exposure at an epigenome-wide level and in consideration of signature gene pathways. We observed that the expression of 623 genes and the methylation of 1024 CpG dinucleotides are significantly altered among smokers, with only 38 CpGs showing significant differential methylation (differing by a methylation level of ≥10%). We identified a significant Pearson correlation (≥0.7 or ≤-0.7) between placental transcriptional regulation and differential CpG methylation in only 25 genes among non-smokers but in 438 genes among smokers (18-fold increase, p < 0.0001), with a dominant effect among oxidative stress pathways. Differential methylation at as few as 6 sites was attributed to maternal smoking-mediated birth weight reduction in linear regression models with Bonferroni correction (p < 1.8 × 10(-6)). These studies suggest that a common perinatal exposure (such as maternal smoking) deregulates placental methylation in a CpG site-specific manner that correlates with meaningful alterations in gene expression along signature pathways.


Impact of early intervention on psychopathology, crime, and well-being at age 25.
This randomized controlled trial tested the efficacy of early intervention to prevent adult psychopathology and improve well-being in early-starting conduct-problem children. Kindergarteners (N=9,594) in three cohorts (1991-1993) at 55 schools in four communities were screened for conduct problems, yielding 979 early starters. A total of 891 (91%) consented (51% African American, 47% European American; 69% boys). Children were randomly assigned by school cluster to a 10-year intervention or control. The intervention goal was to develop social competencies in children that would carry them throughout life, through social skills training, parent behavior-management training with home visiting, peer coaching, reading tutoring, and classroom social-emotional curricula. Manualization and supervision ensured program fidelity. Ninety-eight percent participated during grade 1, and 80% continued through grade 10. At age 25, arrest records were reviewed (N=817, 92%), and condition-blinded adults psychiatrically interviewed participants (N=702; 81% of living participants) and a peer (N=535) knowledgeable about the participant. Intent-to-treat logistic regression analyses indicated that 69% of participants in the control arm displayed at least one externalizing, internalizing, or substance abuse psychiatric problem (based on self- or peer interview) at age 25, in contrast with 59% of those assigned to intervention (odds ratio=0.59, CI=0.43-0.81; number needed to treat=8). This pattern also held for self-interviews, peer interviews, scores using an "and" rule for self- and peer reports, and separate tests for externalizing problems, internalizing problems, and substance abuse problems, as well as for each of three cohorts, four sites, male participants, female participants, African Americans, European Americans, moderate-risk, and high-risk subgroups. Intervention participants also received lower severity-weighted violent (standardized estimate=-0.37) and drug (standardized estimate=-0.43) crime conviction scores, lower risky sexual behavior scores (standardized estimate=-0.24), and higher well-being scores (standardized estimate=0.19). This study provides evidence for the efficacy of early intervention in preventing adult psychopathology among high-risk early-starting conduct-problem children.