Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide.
Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified FRC as strong source of nitric oxide (NO) thereby directly dampening T cell expansion as well as reducing the T cell priming capacity of DC. The expression of inducible nitric oxide synthase (iNOS) was up-regulated in a subset of FRC by both DC-signals as well as interferon-γ produced by primed CD8+ T cells. Importantly, iNOS expression was induced during viral infection in vivo in both LN FRC and DC. As a consequence, the primary T cell response was found to be exaggerated in Inos(-/-) mice. Our findings highlight that in addition to their established positive roles in T cell responses FRC and DC cooperate in a negative feedback loop to attenuate T cell expansion during acute inflammation.


Essential Oil Composition and Antibacterial Studies of Vitex negundo Linn. Extracts.
Essential oils from fresh leaves, flowers and dried fruits of Vitex negundo were obtained by hydrodistillation. Using Soxhlet extractor five successive extracts from dried and powdered leaves were also taken. The chemical constituents of essential oil of leaves, flowers and dried fruits were analyzed by GC-FID and GC/MS techniques. Main constituents identified in leaves oil were delta-guaiene, carryophyllene epoxide and ethyl-hexadecenoate; in flowers oil - alpha-selinene, germacren-4-ol, carryophyllene epoxide and (E)-nerolidol while fruit oil showed beta-selinene, alpha-cedrene, germacrene D and hexadecanoic acid as the main constituents. beta-Caryophyllene was only the constituent identified as common to all three oils. alpha-Guaiene and guaia-3,7-diene were identified as common constituents in leaf and dried fruit oil while leaf and flower oils showed p -cymene, valencene, caryophyllene epoxide and (E)-nerolidol as common constituent. All the essential oils and successive extracts were evaluated for antibacterial potential against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa bacterial strains. Each of the essential oils and extracts were found to give promising results against B. subtilis and E. coli. Ethyl acetate and ethanol extracts showed prominent antibacterial activity against all the tested strains. Fruits and leaves oil were found to be most active against E. coli and S. aureus, respectively. Only flowers oil was found to be active against P. aeruginosa.


Recognizing peripheral ecosystems in marine protected areas: A case study of golden jellyfish lakes in Raja Ampat, Indonesia.
Peripheral marine ecosystems can harbor endemic diversity and attract tourism attention, yet are generally not included in conservation management plans due to their remoteness or inland positioning. A case study in Raja Ampat of seven landlocked marine lakes containing golden jellyfish (Mastigias spp.) was conducted to address the lack of fundamental insights into evolutionary, ecological and social contexts of these ecosystems. An interdisciplinary approach was taken towards identifying the jellyfish lakes as distinct management units in order to incorporate them into existing Marine Protected Areas. Mastigias papua populations showed strong genetic (ϕST: 0.30-0.86) and morphological (F = 28.62, p-value = 0.001) structure among lakes, with putative new subspecies. Risks arising from rapid increase in tourism to Raja Ampat (30-fold since 2007) warrant restrictions on jellyfish lake use. Recommendations are provided for adaptive management and science-based conservation policies for jellyfish lakes across Indonesia.


Impact of sedimentation on wetland carbon sequestration in an agricultural watershed.
Landscape redistribution of soil C is common within agricultural ecosystems. Little is known about the effects of upland sediment deposition on C dynamics within riparian wetlands. To assess sedimentation impact, we obtained profile samples of wetland soil and used the combination of (137)Cs, (210)Pb, and (14)C chronological markers to determine rates of C sequestration and mineral deposition over the history of a wetland within a first-order catchment under agricultural management in the coastal plains of the United States. Substantial post settlement deposition in the wetland soil was evidenced in places by a 20- to 40-cm layer of mineral soil that buried the original histosol. Soil profiles contained a minimum in C content within the top 35 cm of the profile which originated from a rapid deposition from low C upland soils. Radiocarbon and radioisotope dating showed that increases in C above this minimum were the result of C sequestered in the past approximately 50 yr. Modeling the kinetics of modern C dynamics using the (137)Cs and (210)Pb markers within these surface profiles provides strong evidence for accelerated C sequestration associated with mineral sediment deposition in the ecosystem. These findings indicate that at the landscape scale, dilution of ecosystem C by import of low C upland sediment into wetlands stimulates C sequestration by pulling soil C content below some pedogenic equilibrium value for the ecosystem. They also indicate that over the history of the wetland, rates of C accretion may be linked to mineral soil deposition.


Interstitial fluid pressure and alkaline gastric secretion.
The interstitial fluid pressure of the submucosa of the gastric fundus was monitored by means of Guyton's capsules in dogs anesthetized with pentobarbital. The intracapsular pressure (ICP) was measured during secretion produced by: a) hypertonic solutions placed inside the stomach; b) arterial hypertension (200 mmHg) applied during intra-arterial infusion of histamine, and c) intra-arterial infusion of acetylcholine. The first procedure did not modify the ICP. On the other hand, whenever interstitial fluid appeared in the gastric lumen during hypertension plus histamine, the mean ICP increased, mostly due to augmented capillary filtration. The hydraulic coefficient measured in these experiments was at least 4 orders of magnitude larger than the respective osmotic coefficient. The action of acetylcholine was complex: large doses enlarged the net capillary filtration, but small doses increased the mean ICP by muscle stimulation only. Contraction of the muscularis mucosae might be the most important mechanism underlying bulk flow of interstitial fluid in physiological conditions. It is concluded that hydraulic gradients across the epithelium might account for the "secretion" of "alkaline" juice.


Global evidence directing regional preventive strategies in Southeast Asia for fighting TB/HIV.
Tuberculosis (TB) and human immunodeficiency virus (HIV) co-epidemics form a huge burden of disease in the Southeast Asia region. Five out of eleven nations in this region are high TB/HIV burden countries: Myanmar, Thailand, India, Indonesia and Nepal. The trends of TB incidence in these countries have been rising in recent years, in contrast to a falling global trend. Experts in the field of TB control and health service providers have been perplexed by the association of TB and HIV infections which causes a mosaic clinical presentation, a unique course with poor treatment outcomes including death. We conducted a review of contemporary evidence relating to TB/HIV control with the aims of assisting integrated health system responses in Southeast Asia and demystifying current evidence to facilitate translating it into practice.


Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function.
Epithelial cells, once dissociated and placed in two-dimensional (2D) cultures, rapidly lose tissue-specific functions. We showed previously that in addition to prolactin, signaling by laminin-111 was necessary to restore functional differentiation of mammary epithelia. Here, we elucidate two additional aspects of laminin-111 action. We show that in 2D cultures, the prolactin receptor is basolaterally localized and physically segregated from its apically placed ligand. Detachment of the cells exposes the receptor to ligation by prolactin leading to signal transducers and activators of transcription protein 5 (STAT5) activation, but only transiently and not sufficiently for induction of milk protein expression. We show that laminin-111 reorganizes mammary cells into polarized acini, allowing both the exposure of the prolactin receptor and sustained activation of STAT5. The use of constitutively active STAT5 constructs showed that the latter is necessary and sufficient for chromatin reorganization and beta-casein transcription. These results underscore the crucial role of continuous laminin signaling and polarized tissue architecture in maintenance of transcription factor activation, chromatin organization, and tissue-specific gene expression.


Auditory Time-Frequency Masking for Spectrally and Temporally Maximally-Compact Stimuli.
Many audio applications perform perception-based time-frequency (TF) analysis by decomposing sounds into a set of functions with good TF localization (i.e. with a small essential support in the TF domain) using TF transforms and applying psychoacoustic models of auditory masking to the transform coefficients. To accurately predict masking interactions between coefficients, the TF properties of the model should match those of the transform. This involves having masking data for stimuli with good TF localization. However, little is known about TF masking for mathematically well-localized signals. Most existing masking studies used stimuli that are broad in time and/or frequency and few studies involved TF conditions. Consequently, the present study had two goals. The first was to collect TF masking data for well-localized stimuli in humans. Masker and target were 10-ms Gaussian-shaped sinusoids with a bandwidth of approximately one critical band. The overall pattern of results is qualitatively similar to existing data for long maskers. To facilitate implementation in audio processing algorithms, a dataset provides the measured TF masking function. The second goal was to assess the potential effect of auditory efferents on TF masking using a modeling approach. The temporal window model of masking was used to predict present and existing data in two configurations: (1) with standard model parameters (i.e. without efferents), (2) with cochlear gain reduction to simulate the activation of efferents. The ability of the model to predict the present data was quite good with the standard configuration but highly degraded with gain reduction. Conversely, the ability of the model to predict existing data for long maskers was better with than without gain reduction. Overall, the model predictions suggest that TF masking can be affected by efferent (or other) effects that reduce cochlear gain. Such effects were avoided in the experiment of this study by using maximally-compact stimuli.


Peripheral and gastrointestinal immune systems of healthy cattle raised outdoors at pasture or indoors on a concentrate-based ration.
Despite an increasing preference of consumers for beef produced from more extensive pasture-based production systems and potential human health benefits from the consumption of such beef, data regarding the health status of animals raised on pasture are limited. The objective of this study was to characterise specific aspects of the bovine peripheral and the gastrointestinal muscosal immune systems of cattle raised on an outdoor pasture system in comparison to animals raised on a conventional intensive indoor concentrate-based system. A number of in vitro functional tests of immune cells suggested subtle differences between the animals on the outdoor versus indoor production systems. There was a decrease in the number of neutrophils and monocytes engaged in phagocytosis in outdoor cattle (P < 0.01 and P < 0.05, respectively) in comparison to those indoors. Following mitogen stimulation, a lower level of interferon-gamma was produced in leukocytes from the outdoor animals (P < 0.05). There was evidence of a gastrointestinal nematode infection in the outdoor animals with elevated levels of serum pepsinogen (P < 0.001), a higher number of eosinophils (P < 0.05) and a higher level of interleukin-4 and stem cell factor mRNA expression (P < 0.05) in the outdoor animals in comparison to the indoor animals. Lower levels of copper and iodine were measured in the outdoor animals in comparison to indoor animals (P < 0.001). Despite distinctly contrasting production systems, only subtle differences were identified in the peripheral immune parameters measured between cattle raised at pasture in comparison to animals raised on a conventional intensive indoor concentrate-based production system.


A New Chicken Genome Assembly Provides Insight into Avian Genome Structure.
The importance of the Gallus gallus (chicken) as a model organism and agricultural animal merits a continuation of sequence assembly improvement efforts. We present a new version of the chicken genome assembly (Gallus_gallus-5.0; GCA_000002315.3), built from combined long single molecule sequencing technology, finished BACs, and improved physical maps. In overall assembled bases, we see a gain of 183 Mb, including 16.4 Mb in placed chromosomes with a corresponding gain in the percentage of intact repeat elements characterized. Of the 1.21 Gb genome, we include three previously missing autosomes, GGA30, 31, and 33, and improve sequence contig length 10-fold over the previous Gallus_gallus-4.0. Despite the significant base representation improvements made, 138 Mb of sequence is not yet located to chromosomes. When annotated for gene content, Gallus_gallus-5.0 shows an increase of 4679 annotated genes (2768 noncoding and 1911 protein-coding) over those in Gallus_gallus-4.0. We also revisited the question of what genes are missing in the avian lineage, as assessed by the highest quality avian genome assembly to date, and found that a large fraction of the original set of missing genes are still absent in sequenced bird species. Finally, our new data support a detailed map of MHC-B, encompassing two segments: one with a highly stable gene copy number and another in which the gene copy number is highly variable. The chicken model has been a critical resource for many other fields of study, and this new reference assembly will substantially further these efforts.


Hematopoietic stem cell mobilization with agents other than G-CSF.
Hematopoietic stem and progenitor mobilization has revolutionized the field of hematopoietic transplantation. Currently, hematopoietic grafts acquired from the peripheral blood of patients or donors treated with granulocyte-colony stimulating factor (G-CSF) are the preferred source for transplantation. G-CSF mobilization regimens, however, are associated with known morbidities and a significant number of normal donors and patient populations fail to mobilize sufficient numbers of hematopoietic stem and progenitor cells for transplantation, necessitating the need for non-G-CSF mobilization strategies. Mechanistic studies evaluating hematopoietic bone marrow niche interactions have uncovered novel agents with the capacity for hematopoietic mobilization. This chapter provides a comprehensive overview of mobilizing agents, other than G-CSF, and experimental procedures and technical aspects important to evaluate and define their hematopoietic mobilizing activities alone and in combination.


New tools for antigen delivery to the MHC class I pathway.
At the beginning of this new millennium, pathogens and cancer remain the leading causes of death worldwide. The development of vaccines to prevent diseases for which no vaccine currently exists, such as AIDS or malaria, or to treat chronic infections or cancers, as well as the improvement of efficacy and safety of existing vaccines, remains a high priority. In most cases, the development of such vaccines requires strategies capable of stimulating CD8(+) cytotoxic T lymphocytes (CTLs) and thus, to deliver antigen to MHC class I molecules. There exists several different pathways for loading antigenic peptides onto MHC class I molecules, either based on the endogenous cytosolic MHC I pathway or on cross-presentation. The understanding of the relevance of each of these mechanisms in CTL activation will help vaccine design to progress more rationally.


Toxicology of mycotoxins.
Humans are exposed to mycotoxins via ingestion, contact and inhalation. This must have occurred throughout human history and led to severe outbreaks. Potential diseases range from akakabio-byo to stachybotryotoxicosis and cancer. The known molecular bases of toxicology run the gamut of 23 compounds, from aflatoxins (AFs) to zearalenone, ochratoxin A and deoxynivalenol. Ergotism is one of the oldest recognized mycotoxicosis, although mycotoxin science only commenced in the 1960s with the discovery of AFs in turkey feed. AFs are carcinogenic. Some others are suspected carcinogens. The effects of mycotoxins are acute or chronic in nature. Mycotoxins are well known in the scientific community, although they have a low profile in the general population. An incongruous situation occurs in United States where mycotoxins from "moldy homes" are considered to be a significant problem, although there is a general debate about seriousness. This contrasts with the thousands of deaths from mycotoxins that occur, even now, in the technologically less developed countries (e.g., Indonesia, China, and Africa). Mycotoxins are more toxic than pesticides. Studies are moving from whole animal work to investigating the biochemical mechanisms in isolated cells, and the mechanisms of toxicity at the molecular level are being elucidated. The stereochemical nature of AFs has been shown to be important. In addition, the effect of multiple mycotoxins is being increasingly investigated, which will more accurately represent the situation in nature. It is anticipated that more fungal metabolites will be recognized as dangerous toxins and permitted statutory levels will decrease in the future.


Development and validation of a prototype 16S rRNA-based taxonomic microarray for Alphaproteobacteria.
The microarray approach has been proposed for high throughput analysis of the microbial community by providing snapshots of the microbial diversity under different environmental conditions. For this purpose, a prototype of a 16S rRNA-based taxonomic microarray was developed and evaluated for assessing bacterial community diversity. The prototype microarray is composed of 122 probes that target bacteria at various taxonomic levels from phyla to species (mostly Alphaproteobacteria). The prototype microarray was first validated using bacteria in pure culture. Differences in the sequences of probes and potential target DNAs were quantified as weighted mismatches (WMM) in order to evaluate hybridization reliability. As a general feature, probes having a WMM > 2 with target DNA displayed only 2.8% false positives. The prototype microarray was subsequently tested with an environmental sample, which consisted of an Agrobacterium-related polymerase chain reaction amplicon from a maize rhizosphere bacterial community. Microarray results were compared to results obtained by cloning-sequencing with the same DNA. Microarray analysis enabled the detection of all 16S rRNA gene sequences found by cloning-sequencing. Sequences representing only 1.7% of the clone library were detected. In conclusion, this prototype 16S rRNA-based taxonomic microarray appears to be a promising tool for the analysis of Alphaproteobacteria in complex ecosystems.


Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): Age is a key contributor to presentation.
The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set. The objective of this study is to describe the Novartis-Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes. We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients' baseline age, using phase III study data (≈8000 patients). NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%-75%) in older, disabled or progressive MS patients. Young patients benefit most from treatment. NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.


Human polyomavirus JC (JCV) infection of human B lymphocytes: a possible mechanism for JCV transmigration across the blood-brain barrier.
It has been suggested that JC virus (JCV) might travel to the central nervous system in infected B cells. Moreover, recent data suggest the presence of JCV in bone marrow plasma cells. However, the evidence for infection and replication of JCV in B cells is unclear. To address this question, we infected Epstein-Barr virus-transformed B cells with JCV and found that the viral genome decreased >1000-fold from days 0 to 20 after infection, which concurred with the absence of viral early and late messenger RNA transcripts and proteins. However, immunofluorescent images of B cells infected with fluorescein isothiocyanate-conjugated JCV demonstrated that JCV enters the B cells, and DNase protection assay confirmed the presence of intact JCV virions inside the B cells. Moreover, JCV-infected B cells were able to transmit infection to naive glial cells. These data confirm that JCV nonproductively infects B cells and possibly uses them as a vehicle for transmigration across the blood-brain barrier.


How the Nurse Anesthetist Decides to Manage Perioperative Fluid Status.
To determine the factors that affect how nurse anesthetists in a county in Sweden decide how to manage perioperative fluid status. A cross-sectional qualitative study was conducted at two surgical wards in a county hospital. Sixteen nurse anesthetists were interviewed to explore how nurse anesthetists assess patients' intraoperative fluid requirements and the subsequent measures adopted. Three categories emerged through content analysis: clinical criteria and the thought process that drives decision making, interdependence in decision making, and uncertainty in decision making. This study revealed differences with regard to fluid management among nurse anesthetists in a county in Sweden. For the assessments and subsequent measures that are carried out to ensure optimal fluid therapy, more research is needed to provide evidence, and evidence-based guidelines need to be developed in Sweden.


Mutagenicity of furan in female Big Blue B6C3F1 mice.
Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII transgene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell proliferation triggers cancer development in furan-exposed rodents.


Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.


Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica, on aceclofenac-induced acute enteritis.
DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4+ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6 , IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1β, GMCSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ+ Th1 cells, IL-4+ Th2 cells, IL-9+ Th9 cells, IL-17+ Th17 cells, and Foxp3+ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.


Cardiac catabolic factors: the degradation of heart valve intercellular matrix.
Cultures of porcine heart valves and aorta secrete a factor that stimulates the degradation of cartilage matrix in a fashion similar to that displayed by synovial catabolin. The heart valve factor also induces the release of chondroitin sulfate and hydroxyproline from isolated heart valve cultures. The present observations support the hypothesis that tissues producing catabolic factors (catabolins) may well be responsive to them and that these messengers may play a role in the cellular regulation of the degradation of intercellular macromolecules.


norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.


The Aspergillus Genome Database (AspGD): recent developments in comprehensive multispecies curation, comparative genomics and community resources.
The Aspergillus Genome Database (AspGD; http://www.aspgd.org) is a freely available, web-based resource for researchers studying fungi of the genus Aspergillus, which includes organisms of clinical, agricultural and industrial importance. AspGD curators have now completed comprehensive review of the entire published literature about Aspergillus nidulans and Aspergillus fumigatus, and this annotation is provided with streamlined, ortholog-based navigation of the multispecies information. AspGD facilitates comparative genomics by providing a full-featured genomics viewer, as well as matched and standardized sets of genomic information for the sequenced aspergilli. AspGD also provides resources to foster interaction and dissemination of community information and resources. We welcome and encourage feedback at email@example.com.


Detection of radon emission at the edges of lunar maria with the apollo alpha-particle spectrometer.
The distribution of radioactive polonium-210, a decay product of radon-222, shows enhanced concentrations at the edges of lunar maria. Enhancements are seen at the edges of Mare Fecunditatis, Mare Crisium, Mare Smythii. Mare Tranquillitatis, Mare Nubium, Mare Cognitum, and Oceanus Procellarum. The observation is indicative of the transient emission of radon gas from the perimeters of lunar maria.


Comparative assessment of in-hospital trauma mortality at a South African trauma center and matched patients treated in the United States.
The unacceptably high rate of death and disability due to injury in Sub-Saharan Africa is alarming. The objective of this work was to compare mortality rates between severely injured trauma patients at a high-volume trauma center in South Africa with matched patients in the United States. Clinical databases from the Groote Schuur Hospital for patients treated in Cape Town, South Africa and the American College of Surgeon's National Trauma Databank for patients treated at large academic trauma centers in the United States were used. Coarsened exact matching identified the most comparable patient populations based on sex, age, intent, injury type, injury mechanism, Injury Severity Score, Glasgow Coma Score, and systolic blood pressure. Conditional logistic regression generated odds ratios for mortality among the entire sample and clinically relevant subgroups. Coarsened exact matching matched 97.9% of the Groote Schuur Hospital patient sample, resulting in 3,206 matched-pairs between the Groote Schuur Hospital and National Trauma Databank cohorts. Conditional logistic regression revealed an odds ratio of mortality of 1.67 (95% confidence interval, 1.10-2.52) for patients at Groote Schuur Hospital compared with matched patients from the National Trauma Databank. Subset analyses revealed significantly increased odds of mortality among patients with blunt injuries (odds ratio 3.40, 95% confidence interval, 1.68-6.88) and patients with a Glasgow Coma Score of 8 or lower (odds ratio 4.33, 95% confidence interval, 2.10-8.95). No statistically significant difference was identified among patients with penetrating injuries or with a Glasgow Coma Score >8 (P value .90 and .39, respectively). International comparisons of interhospital variation in risk-adjusted outcomes following trauma can identify opportunities for quality improvement and have the potential to measure the impact of any corrective strategy implemented.


Quantitative automated circumpapillary microvascular density measurements: a new angioOCT-based methodology.
To develop a new methodology to detect glaucoma damage based on circumpapillary microvascular density (cpmVD) as measured by optical coherence tomography angiography (angioOCT). AngioOCT scans from a random eye of 40 healthy subjects (aged 63 ± 14 years) and 82 glaucoma patients (aged 66 ± 9 years with an average visual field loss of -7.8 ± 6.5 dB) were used to develop a new angioOCT evaluation methodology. Optic disc-centred 3 × 3 mm images were collected (Angioplex®, Zeiss Cirrus 5000 HD-OCT). An annular area with an inner radius of 1.16 mm and outer radius of 1.44 mm was chosen as the region of interest (ROI), with cpmVD calculated through lower envelope modulation avoiding the influence of the major retinal vessels. Additionally, the cpmVD and the microvascular density (mVD), stratified by sectors, were compared with the respective retinal nerve fibre layer (RNFL) thickness. A significantly lower cpmVD was observed in the glaucoma group, for all visual field sectors (p < 0.001), when comparing to the healthy group. The inferior and superior mVD sectors showed the largest differences between groups. Moreover, glaucoma was linked to a reduction of cpmVD variation when compared to the healthy group. Lastly, a comparison between two healthy subgroups showed that the method is not biased by the presence of slight movement artefacts, optic disc dimensions and vessel crowding (p > 0.05). The presented open-source methodology provides a robust quantitative analysis of the 360˚ mVD. It shows that cpmVD, and mVD sectors measured by angioOCT, can be used in everyday glaucoma practice.


Multimodal Imaging of Orthotopic Mouse Model of Endometrial Carcinoma.
Orthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics in vivo, with potential relevance for monitoring response to therapy. After orthotopic injection with luc-expressing endometrial cancer cells, eleven mice developed disease detected by weekly bioluminescence imaging (BLI). In parallel the same mice underwent positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) employing 18F-fluorodeoxyglocose (18F-FDG) or 18F- fluorothymidine (18F-FLT) and contrast reagent, respectively. The mice were sacrificed when moribund, and post-mortem examination included macroscopic and microscopic examination for validation of growth of primary uterine tumours and metastases. PET-CT was also performed on a patient derived model (PDX) generated from a patient with grade 3 endometrioid endometrial cancer. Increased BLI signal during tumour growth was accompanied by increasing metabolic tumour volume (MTV) and increasing MTV x mean standard uptake value of the tumour (SUVmean) in 18F-FDG and 18F-FLT PET-CT, and MRI conspicuously depicted the uterine tumour. At necropsy 82% (9/11) of the mice developed metastases detected by the applied imaging methods. 18F-FDG PET proved to be a good imaging method for detection of patient derived tumour tissue. We demonstrate that all imaging modalities enable monitoring of tumour growth and metastatic spread in an orthotopic mouse model of endometrial carcinoma. Both PET tracers, 18F-FDG and 18F-FLT, appear to be equally feasible for detecting tumour development and represent, together with MRI, promising imaging tools for monitoring of patient-derived xenograft (PDX) cancer models.


Noradrenaline and the kidney: friends or foes?
Septic shock, systemic inflammation and pharmacological vasodilatation are often complicated by systemic hypotension, despite aggressive fluid resuscitation and an increased cardiac output. If the physician wishes to restore arterial pressure (>80-85 mmHg), with the aim of sustaining organ perfusion pressure, the administration of systemic vasopressor agents, such as noradrenaline, becomes necessary. Because noradrenaline induces vasoconstriction in many vascular beds (visibly in the skin), however, it may decrease renal and visceral blood flow, impairing visceral organ function. This unproven fear has stopped clinicians from using noradrenaline more widely. In vasodilated states, unlike in normal circulatory conditions, however, noradrenaline may actually improve visceral organ blood flow. Animal studies show that the increased organ perfusion pressures achieved with noradrenaline improve the glomerular filtration rate and renal blood flow. There are no controlled human data to define the effects of noradrenaline on the kidney, but many patient series show a positive effect on glomerular filtration rate and urine output. There is no reason to fear the use of noradrenaline. If it is used to support a vasodilated circulation with a normal or increased cardiac output, it is likely to be the kidney's friend not its foe.


The effects of multi-domain versus single-domain cognitive training in non-demented older people: a randomized controlled trial.
Whether healthy older people can benefit from cognitive training (CogTr) remains controversial. This study explored the benefits of CogTr in community dwelling, healthy, older adults and compared the effects of single-domain with multi-domain CogTr interventions. A randomized, controlled, 3-month trial of CogTr with double-blind assessments at baseline and immediate, 6-month and 12-month follow-up after training completion was conducted. A total of 270 healthy Chinese older people, 65 to 75 years old, were recruited from the Ganquan-area community in Shanghai. Participants were randomly assigned to three groups: multi-domain CogTr, single-domain CogTr, and a wait-list control group. Twenty-four sessions of CogTr were administrated to the intervention groups over a three-month period. Six months later, three booster training sessions were offered to 60% of the initial training participants. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A), the Color Word Stroop test (CWST), the Visual Reasoning test and the Trail Making test (TMT) were used to assess cognitive function. Multi-domain CogTr produced statistically significant training effects on RBANS, visual reasoning, and immediate and delayed memory, while single-domain CogTr showed training effects on RBANS, visual reasoning, word interference, and visuospatial/constructional score (all P < 0.05). At the 12-month posttest, the multi-domain CogTr showed training effects on RBANS, delayed memory and visual reasoning, while single-domain CogTr only showed effects on word interference. Booster training resulted in effects on RBANS, visual reasoning, time of trail making test, and visuospatial/constructional index score. Cognitive training can improve memory, visual reasoning, visuospatial construction, attention and neuropsychological status in community-living older people and can help maintain their functioning over time. Multi-domain CogTr enhanced memory proficiency, while single-domain CogTr augmented visuospatial/constructional and attention abilities. Multi-domain CogTr had more advantages in training effect maintenance. Chinese Clinical Trial Registry. ChiCTR-TRC-09000732.


Processing capacity defined by relational complexity: implications for comparative, developmental, and cognitive psychology.
Working memory limits are best defined in terms of the complexity of the relations that can be processed in parallel. Complexity is defined as the number of related dimensions or sources of variation. A binary relation has one argument and one source of variation; its argument can be instantiated in only one way at a time. A binary relation has two arguments, two sources of variation, and two instantiations, and so on. Dimensionality is related to the number of chunks, because both attributes on dimensions and chunks are independent units of information of arbitrary size. Studies of working memory limits suggest that there is a soft limit corresponding to the parallel processing of one quaternary relation. More complex concepts are processed by "segmentation" or "conceptual chunking." In segmentation, tasks are broken into components that do not exceed processing capacity and can be processed serially. In conceptual chunking, representations are "collapsed" to reduce their dimensionality and hence their processing load, but at the cost of making some relational information inaccessible. Neural net models of relational representations show that relations with more arguments have a higher computational cost that coincides with experimental findings on higher processing loads in humans. Relational complexity is related to processing load in reasoning and sentence comprehension and can distinguish between the capacities of higher species. The complexity of relations processed by children increases with age. Implications for neural net models and theories of cognition and cognitive development are discussed.


Effect of simulated space radiation on selected optical materials.
The effect of simulated Nimbus spacecraft orbital (1100 km, circular, and polar) radiation on wide-band-pass glass filters, narrow-bandpass thin-film interference filters, and several fused silicas was determined by transmittance measurements over the 200-3400-nm wavelength region. No changes were observed in the filters, which were shielded with fused silica during irradiation, after exposure to a 1-yr equivalent orbital dose of electrons, nor were changes observed in the fused silicas after the same electron exposure plus a 1-yr equivalent dose of protons. Exposure to a (1/2)-yr equivalent dose of solar uv radiation, however, caused a significant degradation in the transmittance of two uv-transmitting interference filters but had no effect on two colored glass filters that transmitted in the visible and near-ir regions. As a result of the uv exposure, the fused silicas exhibited losses of several percent over the 200-300-nm wavelength region.


Clinical and Echocardiographic Characteristics and Cardiovascular Outcomes According to Diabetes Status in Patients With Heart Failure and Preserved Ejection Fraction: A Report From the I-Preserve Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction).
In patients with heart failure and preserved ejection fraction, little is known about the characteristics of, and outcomes in, those with and without diabetes mellitus. We examined clinical and echocardiographic characteristics and outcomes in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction) according to history of diabetes mellitus. Cox regression models were used to estimate hazard ratios for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Overall, 1134 of 4128 patients (27%) had diabetes mellitus. Compared with those without diabetes mellitus, they were more likely to have a history of myocardial infarction (28% versus 22%), higher body mass index (31 versus 29 kg/m2), worse Minnesota Living With Heart Failure score (48 versus 40), higher median N-terminal pro-B-type natriuretic peptide concentration (403 versus 320 pg/mL; all P<0.01), more signs of congestion, but no significant difference in left ventricular ejection fraction. Patients with diabetes mellitus had a greater left ventricular mass and left atrial area than patients without diabetes mellitus. Doppler E-wave velocity (86 versus 76 cm/s; P<0.0001) and the E/e' ratio (11.7 versus 10.4; P=0.010) were higher in patients with diabetes mellitus. Over a median follow-up of 4.1 years, cardiovascular death or heart failure hospitalization occurred in 34% of patients with diabetes mellitus versus 22% of those without diabetes mellitus (adjusted hazard ratio, 1.75; 95% confidence interval, 1.49-2.05), and 28% versus 19% of patients with and without diabetes mellitus died (adjusted hazard ratio, 1.59; confidence interval, 1.33-1.91). In heart failure with preserved ejection fraction, patients with diabetes mellitus have more signs of congestion, worse quality of life, higher N-terminal pro-B-type natriuretic peptide levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes mellitus on outcomes in heart failure with preserved ejection fraction and whether they are modifiable. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.


Effects of past copper contamination and soil structure on copper leaching from soil.
Copper contamination affects biological, chemical, and physical soil properties and associated ecological functions. Changes in soil pore organization as a result of Cu contamination can dramatically affect flow and contaminant transport in polluted soils. This study assessed the influence of soil structure on the movement of water and Cu in a long-term polluted soil. Undisturbed soil cores collected along a Cu gradient (from about 20 to about 3800 mg Cu kg soil) were scanned using X-ray computed tomography (CT). Leaching experiments were performed to analyze tracer transport, colloid leaching, and dissolved organic carbon (DOC) and Cu losses. The 5% arrival time () and apparent dispersivity (λ) for tracer breakthrough were calculated by fitting the experimental data to a nonparametric, double-lognormal probability density function. Soil bulk density, which did not follow the Cu gradient, was the main driver of preferential flow, while macroporosity determined by X-ray CT (for pores >180 μm) proved the best predictor of solute transport. Higher preferential flow due to the presence of well-aligned pores and small cracks controlled water movement in compacted soil. Transport of Cu was rapid during the first flush (≈1 pore volume) in association with the movement of colloid particles, followed by slower transport in association with the movement of DOC in the soil solution. The relative amount of Cu released was strongly correlated with macroporosity as determined by X-ray CT, indicating the promising potential of this visualization technique for predicting contaminant transport through soil.


HIV and homosexuality in Pakistan.
In Pakistan, seven times more men are reported to be infected with HIV than women. Among the Pakistani population, modes of HIV transmission include infection through sexual contact, contaminated blood and blood products, injecting drug use, and mother-to-child transmission. Although most sexual transmission of HIV results from unsafe heterosexual contact, homosexual and bisexual contact also represent important modes of transmission. According to unpublished reports, the prevalence of HIV among homosexual and bisexual Pakistani men is reaching alarming proportions. We describe the Pakistani homosexual and bisexual culture, review statistics regarding HIV prevalence and risk behaviour, and identify areas of improvement in the HIV policy with specific focus on men who have sex with men.


Saturation factor of nitroxide radicals in liquid DNP by pulsed ELDOR experiments.
We propose the use of the pulse electron double resonance (ELDOR) method to determine the effective saturation factor of nitroxide radicals for dynamic nuclear polarization (DNP) experiments in liquids. The obtained values for the nitroxide radical TEMPONE-D,(15)N at different concentrations are rationalized in terms of spin relaxation and are shown to fulfil the Overhauser theory.


Aging and HIV/AIDS: pathogenetic role of therapeutic side effects.
The intersection of aging and HIV/AIDS is a looming 'epidemic within an epidemic.' This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active antiretroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies.


Determination of flavanols by liquid chromatography with fluorescence detection. Application to the characterization of cranberry-based pharmaceuticals through profiling and fingerprinting approaches.
In this work, a new method based on reversed-phase high-performance liquid chromatography (HPLC) with fluorescence detection (FLD) was established for the determination of catechins and related oligomeric proanthocyanidins (PACs) in cranberry-based pharmaceuticals. Compounds were recovered by liquid extraction using methanol/water/hydrochloric acid (60:39:1, v:v:v) as the extraction solvent. The chromatographic separation was carried out using a core-shell C18 column under an elution program based on 0.1% formic acid in water and methanol as the components of the mobile phase. The flow rate was 0.4 mL min-1 and the injection volume was 5 μL. Chromatograms were acquired at 280 nm by UV-vis absorption and at λex 280 nm and λem 347 nm by fluorescence spectroscopy. Compared to UV detection, FLD demonstrated both increased sensitivity and selectivity to avoid interfering signals from other phenolic compounds present in the samples. Data resulting from the analysis of cranberry-based products was exploited to tackle an exploratory characterization and classification using principal component analysis. Samples were clustered according to their compositions and those enriched with PACs with antibacterial activity were clearly distinguished from the others.


Symbiotic ants as an alternative defense against giraffe herbivory in spinescent Acacia drepanolobium.
We explore here the occurrence of aggressive ants in an apparently symbiotic relationship with the savanna tree Acacia drepanolobium and their effects on giraffe herbivory on the Athi-Kapiti Plains, Kenya. Trees taller than 1.3 m were more likely to be occupied by aggressive ants in the genus Crematogaster than were shorter trees. Ants wereconcentrated on shoot tips, the plant parts preferred by giraffes. Trees with relatively more foliage had more swarming ants than did trees with less foliage. The feeding behavior of individual freeranging giraffes on Acacia drepanolobium was studied. Giraffe calves exhibited a strong sensitivity to Crematogaster ants inhabiting A. drepanolobium, feeding for significantly shorter periods on trees with a greater number of aggressive ants. Older giraffes were apparently less sensitive to ants, and did not feed for shorter periods on trees with fuller foliage, despite significantly greater ant activity on these plants. The thorns of A. drepanolobium are significantly shorter than are the thorns of A. seyal, a species without symbiotic ants, a pattern that may indicate a trade-off between ants and thorns as defenses.


Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis.
Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gαs-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.


The role of a cathepsin D-like activity in the release of Gal beta 1-4GlcNAc alpha 2-6-sialyltransferase from rat liver Golgi membranes during the acute-phase response.
Golgi-membrane-bound Gal beta 1-4GlcNAc alpha 2-6-sialyltransferase (CMP-N-acetylneuraminate:beta-galactoside alpha 2-6-sialyltransferase, EC 22.214.171.124) behaves as an acute-phase reactant increasing about 5-fold in serum in rats suffering from inflammation. The mechanism of release from the Golgi membrane is not understood. In the present study it was found that sialyltransferase could be released from the membrane by treatment with ultrasonic vibration (sonication) followed by incubation at reduced pH. Maximum release occurred at pH 5.6, and membranes from inflamed rats released more enzyme than did membranes from controls. Galactosyltransferase (UDP-galactose:N-acetylglucosamine galactosyltransferase; EC 126.96.36.199), another Golgi-located enzyme, which does not behave as an acute-phase reactant, remained bound to the membranes under the same conditions. Release of the alpha 2-6-sialyltransferase from Golgi membranes was substantially inhibited by pepstatin A, a potent inhibitor of cathepsin D-like proteinases. Inhibition of release of the sialyltransferase also occurred after preincubation of sonicated Golgi membranes with antiserum raised against rat liver lysosomal cathepsin D. Addition of bovine spleen cathepsin D to incubation mixtures of sonicated Golgi membranes caused enhanced release of the sialyltransferase. Intact Golgi membranes were incubated at lowered pH in presence of pepstatin A to inhibit any proteinase activity at the cytosolic face; subsequent sonication showed that the sialyltransferase had been released, suggesting that the proteinase was active at the luminal face of the Golgi. Golgi membranes contained a low level of cathepsin D activity (EC 220.127.116.11); the enzyme was mainly membrane-bound, since it could only be released by extraction with Triton X-100 or incubation of sonicated Golgi membranes with 5 mM-mannose 6-phosphate. Immunoblot analysis showed that the transferase released from sonicated Golgi membranes at lowered pH had an apparent Mr of about 42,000 compared with one of about 49,000 for the membrane-bound enzyme. Values of Km for the bound and released enzyme activities were comparable and were similar to values reported previously for liver and serum enzymes. The work suggests that a major portion of sialyltransferase containing the catalytic site is released from a membrane anchor by a cathepsin D-like proteinase located at the luminal face of the Golgi and that this explains the acute-phase behaviour of this enzyme.


[A prospective cohort study of premature death and influencing factors in adults aged 56-69 years from 10 regions of China].
Objective: To describe and analyze the epidemiological characteristics of premature death (death before age of 70 years) and related risk factors in approximate 100 000 adults recruited from 10 regions of China during a 10-year follow-up. Methods: Data, including demographic characteristics, lifestyle and physical indicators as well as health outcomes as of December 31, 2017, were obtained from baseline survey and long-term follow-up of the China Kadoorie Biobank (CKB) study. All-cause and cause-specific premature death in different areas, in men and women and in people with different lifestyles were analyzed. Cox proportional risk model was used to analyze the associations between baseline factors and premature death. Results: A total of 99 993 participants aged 56-69 years were included in the study. During 10 years of follow-up, 7 530 premature deaths were recorded and the premature death rate was 7.15 per 1 000 person-years. The main causes of premature death were cancer and cardiovascular and cerebrovascular diseases. The premature mortality rate was higher in rural areas, in northern region and in men, and decreased with age (P<0.05). Premature death was more likely to occur in smokers, and a dose-response relationship was observed. Compared with non-drinkers, the risk for premature death was higher in ex-drinkers (HR: 1.25 [95%CI:1.16-1.36]) and heavy drinkers (average alcohol consumption ≥60 g/d) (HR: 1.20 [95%CI:1.08-1.34]). The risk for premature death decreased with the increase of physical activity. Low body weight and central obesity were independently associated with increased risk for premature death (HR: 1.67 [95%CI:1.55-1.81] and 1.13 [95%CI:1.05-1.21], respectively). Conclusions: The main causes of premature death in adults aged 56-69 years in China during 10-year follow-up were cancer and cardiovascular and cerebrovascular diseases. The premature mortality rate varied with socioeconomic and demographic characteristics. The risk for premature death was influenced by multi factors, such as lifestyle and physical conditions.


Typhoid Fever: Tracking the Trend in Nigeria.
Typhoid fever continues to pose a serious health challenge in developing countries. A reliable database on positive blood cultures is essential for prompt interventions. To generate reliable data on Salmonella enterica serovar Typhi (S. Typhi)-positive blood culture trends in typhoidal Salmonella in Nigeria alongside changing contextual factors and antimicrobial resistance patterns, a retrospective cohort study was conducted in two hospitals in Lagos between 1993 and 2015. Medical records of typhoid patients were reviewed for positive culture and antibiogram, using standard procedures and analyzed. Additional data were retrieved from a previous study in seven facilities in Abuja and three hospitals in Kano from 2008 to 2017 and 2013 to 2017, respectively. A declining trend in percent positivity of S. Typhi was observed in Abuja with more erratic trends in Lagos and Kano. In Lagos, more than 80% of the isolates from the entire study period exhibited multiple drug resistance with a generally increasing trend. Of the chosen contextual factors, improvements were recorded in female literacy, access to improved water supply, diarrheal mortality in children younger than 5 years, gross domestic product, and poverty while access to improved sanitation facilities decreased over time nationally. Typhoid fever still poses a serious health challenge in Nigeria and in antibiotic resistance, and is a major health security issue. A combined approach that includes the use of typhoid vaccines, improvements in sanitation, and safe water supply is essential.


Dairy cattle in a temperate climate: the effects of weather on milk yield and composition depend on management.
A better understanding of how livestock respond to weather is essential to enable farming to adapt to a changing climate. Climate change is mainly expected to impact dairy cattle through heat stress and an increase in the frequency of extreme weather events. We investigated the effects of weather on milk yield and composition (fat and protein content) in an experimental dairy herd in Scotland over 21 years. Holstein Friesian cows were either housed indoors in winter and grazed over the summer or were continuously housed. Milk yield was measured daily, resulting in 762 786 test day records from 1369 individuals, and fat and protein percentage were sampled once a week, giving 89 331 records from 1220 cows/trait. The relative influence of 11 weather elements, measured from local outdoor weather stations, and two indices of temperature and humidity (THI), indicators of heat stress, were compared using separate maximum likelihood models for each element or index. Models containing a direct measure of temperature (dry bulb, wet bulb, grass or soil temperature) or a THI provided the best fits to milk yield and fat data; wind speed and the number of hours of sunshine were most important in explaining protein content. Weather elements summarised across a week's timescale from the test day usually explained milk yield and fat content better than shorter-scale (3 day, test day, test day -1) metrics. Then, examining a subset of key weather variables using restricted maximum likelihood, we found that THI, wind speed and the number of hours of sunshine influenced milk yield and composition. The shape and magnitude of these effects depended on whether animals were inside or outside on the test day. The milk yield of cows outdoors was lower at the extremes of THI than at average values, and the highest yields were obtained when THI, recorded at 0900 h, was 55 units. Cows indoors decreased milk yield as THI increased. Fat content was lower at higher THIs than at intermediate THIs in both environments. Protein content decreased as THI increased in animals kept indoors and outdoors, and the rate of decrease was greater when animals were outside than when they were inside. Moderate wind speeds appeared to alleviate heat stress. These results show that milk yield and composition are impacted at the upper extreme of THI under conditions currently experienced in Scotland, where animals have so far experienced little pressure to adapt to heat stress.


TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors.
Aggrecanases are considered to play a key role in the destruction of articular cartilage during the progression of arthritis. Here we report that the N-terminal inhibitory domain of tissue inhibitor of metalloproteinases 3 (N-TIMP-3), but not TIMP-1 or TIMP-2, inhibits glycosaminoglycan release from bovine nasal and porcine articular cartilage explants stimulated with interleukin-1alpha or retinoic acid in a dose-dependent manner. This inhibition is due to the blocking of aggrecanase activity induced by the catabolic factors. Little apoptosis of primary porcine chondrocytes is observed at an effective concentration of N-TIMP-3. These results suggest that TIMP-3 may be a candidate agent for use against cartilage degradation.


The Opiliones tree of life: shedding light on harvestmen relationships through transcriptomics.
Opiliones are iconic arachnids with a Palaeozoic origin and a diversity that reflects ancient biogeographic patterns dating back at least to the times of Pangea. Owing to interest in harvestman diversity, evolution and biogeography, their relationships have been thoroughly studied using morphology and PCR-based Sanger approaches to infer their systematic relationships. More recently, two studies utilized transcriptomics-based phylogenomics to explore their basal relationships and diversification, but sampling was limiting for understanding deep evolutionary patterns, as they lacked good taxon representation at the family level. Here, we analysed a set of the 14 existing transcriptomes with 40 additional ones generated for this study, representing approximately 80% of the extant familial diversity in Opiliones. Our phylogenetic analyses, including a set of data matrices with different gene occupancy and evolutionary rates, and using a multitude of methods correcting for a diversity of factors affecting phylogenomic data matrices, provide a robust and stable Opiliones tree of life, where most families and higher taxa are precisely placed. Our dating analyses using alternative calibration points, methods and analytical parameters provide well-resolved old divergences, consistent with ancient regionalization in Pangea in some groups, and Pangean vicariance in others. The integration of state-of-the-art molecular techniques and analyses, together with the broadest taxonomic sampling to date presented in a phylogenomic study of harvestmen, provide new insights into harvestmen interrelationships, as well as an overview of the general biogeographic patterns of this ancient arthropod group.


Decomposition rate and stabilization across six tundra vegetation types exposed to >20 years of warming.
Litter decomposition is an important driver of soil carbon and nutrient cycling in nutrient-limited Arctic ecosystems. However, climate change is expected to induce changes that directly or indirectly affect decomposition. We examined the direct effects of long-term warming relative to differences in soil abiotic properties associated with vegetation type on litter decomposition across six subarctic vegetation types. In six vegetation types, rooibos and green tea bags were buried for 70-75 days at 8 cm depth inside warmed (by open-top chambers) and control plots that had been in place for 20-25 years. Standardized initial decomposition rate and stabilization of the labile material fraction of tea (into less decomposable material) were calculated from tea mass losses. Soil moisture and temperature were measured bi-weekly during summer and plant-available nutrients were measured with resin probes. Initial decomposition rate was decreased by the warming treatment. Stabilization was less affected by warming and determined by vegetation type and soil moisture. Soil metal concentrations impeded both initial decomposition rate and stabilization. While a warmer Arctic climate will likely have direct effects on initial litter decomposition rates in tundra, stabilization of organic matter was more affected by vegetation type and soil parameters and less prone to be affected by direct effects of warming.


Korean mothers' morality in the wake of COVID-19 contact-tracing surveillance.
The Korean government collects and releases sociodemographic information about people infected with COVID-19, their travel histories, and whether or not the patients wore masks. Korean mothers then upload this information on the boards of online groups called "mom cafes." Based upon a digital ethnography of 15 "mom cafes," we examine how Korean mothers understand the travel histories of virus patients and explore the relationships between morality and materiality in the context of infectious disease surveillance. The main findings reveal that mom cafe mothers form moral personhood based on information gathered about artifacts, places, and the mobility of patients. They tie patients' travel histories inextricably to moral identities. Non-maleficence is central to Korean mothers' morality. This morality appears through the material discourses of artifacts, places, and mobility. A face mask becomes one such hallmark of morality. It is a requisite for moral persons. Those who visit crowded places, such as churches, clubs, and room salons, become immoral because they can be easily infected and spread the virus to their families and communities. To mom cafe mothers, mobile patients, such as clubbers, appear less moral than those who self-quarantine due to the high infection rate of COVID-19. We conclude that morality in this context involves the materiality of artifacts, a sense of place, and the spatial mobility of people.


MUC18 Regulates Lung Rhinovirus Infection and Inflammation.
MUC18 is upregulated in the lungs of asthma and COPD patients. It has been shown to have pro-inflammatory functions in cultured human airway epithelial cells during viral infections and in mice during lung bacterial infections. However, the in vivo role of MUC18 in the context of viral infections remains poorly understood. The goal of this study is to define the in vivo function of MUC18 during respiratory rhinovirus infection. Muc18 wild-type (WT) and knockout (KO) mice were infected with human rhinovirus 1B (HRV-1B) and sacrificed after 1 day to determine the inflammatory and antiviral responses. To examine the direct effects of Muc18 on viral infection, tracheal epithelial cells isolated from WT and KO mice were grown under air-liquid interface and infected with HRV-1B. Finally, siRNA mediated knockdown of MUC18 was performed in human airway epithelial cells (AECs) to define the impact of MUC18 on human airway response to HRV-1B. Both viral load and neutrophilic inflammation were significantly decreased in Muc18 KO mice compared to WT mice. In the in vitro setting, viral load was significantly lower and antiviral gene expression was higher in airway epithelial cells of Muc18 KO mice than the WT mice. Furthermore, in MUC18 knockdown human AECs, viral load was decreased and antiviral gene expression was increased compared to controls. Our study is the first to demonstrate MUC18's pro-inflammatory and pro-viral function in an in vivo mouse model of rhinovirus infection.


Growth and folding of the mammalian cerebral cortex: from molecules to malformations.
The size and extent of folding of the mammalian cerebral cortex are important factors that influence a species' cognitive abilities and sensorimotor skills. Studies in various animal models and in humans have provided insight into the mechanisms that regulate cortical growth and folding. Both protein-coding genes and microRNAs control cortical size, and recent progress in characterizing basal progenitor cells and the genes that regulate their proliferation has contributed to our understanding of cortical folding. Neurological disorders linked to disruptions in cortical growth and folding have been associated with novel neurogenetic mechanisms and aberrant signalling pathways, and these findings have changed concepts of brain evolution and may lead to new medical treatments for certain disorders.


Differential effects of glutamate-286 mutations in the aa(3)-type cytochrome c oxidase from Rhodobacter sphaeroides and the cytochrome bo(3) ubiquinol oxidase from Escherichia coli.
Both the aa(3)-type cytochrome c oxidase from Rhodobacter sphaeroides (RsCcO(aa3)) and the closely related bo(3)-type ubiquinol oxidase from Escherichia coli (EcQO(bo3)) possess a proton-conducting D-channel that terminates at a glutamic acid, E286, which is critical for controlling proton transfer to the active site for oxygen chemistry and to a proton loading site for proton pumping. E286 mutations in each enzyme block proton flux and, therefore, inhibit oxidase function. In the current work, resonance Raman spectroscopy was used to show that the E286A and E286C mutations in RsCcO(aa3) result in long range conformational changes that influence the protein interactions with both heme a and heme a(3). Therefore, the severe reduction of the steady-state activity of the E286 mutants in RsCcO(aa3) to ~0.05% is not simply a result of the direct blockage of the D-channel, but it is also a consequence of the conformational changes induced by the mutations to heme a and to the heme a(3)-Cu(B) active site. In contrast, the E286C mutation of EcQO(bo3) exhibits no evidence of conformational changes at the two heme sites, indicating that its reduced activity (3%) is exclusively a result of the inhibition of proton transfer from the D-channel. We propose that in RsCcO(aa3), the E286 mutations severely perturb the active site through a close interaction with F282, which lies between E286 and the heme-copper active site. The local structure around E286 in EcQO(bo3) is different, providing a rationale for the very different effects of E286 mutations in the two enzymes. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins.


How the Internet is changing gambling: findings from an Australian Prevalence Survey.
Interactive gambling as a regulated activity, coupled with easy accessibility to offshore providers represents a new mode and format of gambling superimposed on traditional land-based opportunities. This paper aimed to investigate the prevalence of gambling among Australian adults and the relationship between various gambling activities and interactive modes of access. A second aim was to compare interactive and non-interactive gamblers in terms of socio-demographic characteristics, attitudes and beliefs about gambling and gambling participation. In a nationally representative telephone survey, 15,006 Australian adults completed measures assessing past 12-month gambling participation and a sub-sample completed questions about interactive gambling and beliefs. The majority of participants (64.3 %) reported gambling at least once, with 8.1 % having gambled online. Interactive gamblers gambled on a greater number of activities overall and more frequently. Interactive gamblers were more likely to be male, younger, have home Internet access, participate in more forms of gambling and have higher gambling expenditure. Almost half of the interactive gamblers preferred land-based gambling although a small proportion also noted a number of disadvantages of interactive gambling. This study shows that the nature of gambling participation is shifting with interactive gambling having a significant and growing impact on overall gambling involvement.


Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness.
The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time. We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002). After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors, the decline in the size-specific case fatality rate suggests that improved treatment was responsible for at least two thirds of the reduction in breast cancer mortality. Although the rate of detection of large tumors fell after the introduction of screening mammography, the more favorable size distribution was primarily the result of the additional detection of small tumors. Women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a tumor that was destined to become large. The reduction in breast cancer mortality after the implementation of screening mammography was predominantly the result of improved systemic therapy.


Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer.
Human papillomavirus (HPV) causes oropharyngeal squamous cell carcinoma (OPSCC), although strongly divergent results have been reported regarding the prevalence of HPV16 in different countries, whether this represents important differences in etiology remains unclear. Applying rigorous protocols for sample processing, we centrally evaluated 1,420 head and neck tumors (533 oropharynx, 395 oral cavity and 482 larynx) from studies conducted in the US, Europe and Brazil for mucosal HPV DNA and p16INK4a expression to evaluate regional heterogeneity in the proportion of HPV16-associated OPSCC and other head and neck cancer, and to assess covariates associated with the risk of HPV16-positive OPSCC. While majority of OPSCC in the US (60%) were HPV16-positive, this proportion was 31% in Europe and only 4% in Brazil (p < 0.01). Similar differences were observed for other head and neck tumors, ranging from 7% in the US and 5% in Europe, to 0% in South America. The odds of HPV16-positive OPSCC declined with increasing pack years of smoking (OR: 0.75; 95% CI: 0.64-0.87) and drink years of alcohol use (OR: 0.64; 95% CI: 0.54-0.76). These results suggest that while the contribution of HPV16 is substantial for the oropharynx, it remains limited for oral cavity and laryngeal cancers.


Predictors of response for elagolix with add-back therapy in women with heavy menstrual bleeding associated with uterine fibroids.
Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids. This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment. Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored. The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population. Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume.


Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer.
Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.


The dark figure of sexual recidivism.
Empirical studies of sexual offender recidivism have proliferated in recent decades. Virtually all of the studies define recidivism as a new legal charge or conviction for a sexual crime, and these studies tend to find recidivism rates of the order of 5-15% after 5 years and 10-25% after 10+ years. It is uncontroversial that such a definition of recidivism underestimates the true rate of sexual recidivism because most sexual crime is not reported to legal authorities, a principle known as the "dark figure of crime." To estimate the magnitude of the dark figure of sexual recidivism, this paper uses a probabilistic simulation approach in conjunction with the following: (i) victim self-report survey data about the rate of reporting sexual crime to legal authorities; (ii) offender self-report data about the number of victims per offender; and (iii) different assumptions about the chances of being convicted of a new sexual offense given that it is reported. Under any configuration of assumptions, the dark figure is substantial, and as a consequence the disparity between recidivism defined as a new legal charge or conviction for a sex crime and recidivism defined as actually committing a new sexual crime is large. These findings call into question the utility of recidivism studies that rely exclusively on official crime statistics to define sexual recidivism, and highlight the need for additional, long-term studies that use a variety of different measures to assess whether or not sexual recidivism has occurred.


Leptospirosis in humans.
Leptospirosis is a widespread and potentially fatal zoonosis that is endemic in many tropical regions and causes large epidemics after heavy rainfall and flooding. Infection results from direct or indirect exposure to infected reservoir host animals that carry the pathogen in their renal tubules and shed pathogenic leptospires in their urine. Although many wild and domestic animals can serve as reservoir hosts, the brown rat (Rattus norvegicus) is the most important source of human infections. Individuals living in urban slum environments characterized by inadequate sanitation and poor housing are at high risk of rat exposure and leptospirosis. The global burden of leptospirosis is expected to rise with demographic shifts that favor increases in the number of urban poor in tropical regions subject to worsening storms and urban flooding due to climate change. Data emerging from prospective surveillance studies suggest that most human leptospiral infections in endemic areas are mild or asymptomatic. Development of more severe outcomes likely depends on three factors: epidemiological conditions, host susceptibility, and pathogen virulence (Fig. 1). Mortality increases with age, particularly in patients older than 60 years of age. High levels of bacteremia are associated with poor clinical outcomes and, based on animal model and in vitro studies, are related in part to poor recognition of leptospiral LPS by human TLR4. Patients with severe leptospirosis experience a cytokine storm characterized by high levels of IL-6, TNF-alpha, and IL-10. Patients with the HLA DQ6 allele are at higher risk of disease, suggesting a role for lymphocyte stimulation by a leptospiral superantigen. Leptospirosis typically presents as a nonspecific, acute febrile illness characterized by fever, myalgia, and headache and may be confused with other entities such as influenza and dengue fever. Newer diagnostic methods facilitate early diagnosis and antibiotic treatment. Patients progressing to multisystem organ failure have widespread hematogenous dissemination of pathogens. Nonoliguric (high output) renal dysfunction should be supported with fluids and electrolytes. When oliguric renal failure occurs, prompt initiation of dialysis can be life saving. Elevated bilirubin levels are due to hepatocellular damage and disruption of intercellular junctions between hepatocytes, resulting in leaking of bilirubin out of bile caniliculi. Hemorrhagic complications are common and are associated with coagulation abnormalities. Severe pulmonary hemorrhage syndrome due to extensive alveolar hemorrhage has a fatality rate of >50 %. Readers are referred to earlier, excellent summaries related to this subject (Adler and de la Peña-Moctezuma 2010; Bharti et al. 2003; Hartskeerl et al. 2011; Ko et al. 2009; Levett 2001; McBride et al. 2005).


Economic analysis of Heart and Stroke Foundation of Ontario's Hypertension Management Initiative.
Hypertension is suboptimally treated in primary care settings. We evaluated the cost-effectiveness of the Heart and Stroke Foundation of Ontario's Hypertension Management Initiative (HMI), an interdisciplinary, evidence-informed chronic disease management model for primary care that focuses on improving blood pressure management and control by primary care providers and patients according to clinical best practice guidelines. The perspective of our analysis was that of the Ontario Ministry of Health and Long-Term Care with a lifetime horizon and 5% annual discount rate. Using data from a prospective cohort study from the HMI, we created two matched groups: pre-HMI (standard care), and post-HMI (n = 1720). For each patient, we estimated the 10-year risk of cardiovascular disease (CVD) using the Framingham risk equation and life expectancy from life tables. Long-term health care costs incurred with physician visits, acute and chronic care hospitalizations, emergency department visits, same-day surgeries, and medication use were determined through linkage to administrative databases, using a bottom-up approach. The HMI intervention was associated with significant reductions in systolic blood pressure (126 mmHg vs 134 mmHg with standard care; P-value < 0.001). These improvements were associated with a reduction in the 10-year risk of CVD (9.5% risk vs 10.7% in standard care; P-value < 0.001) and a statistically significant improvement in discounted life expectancy (9.536 years vs 9.516 in standard care; P-value < 0.001). The HMI cohort had a discounted mean lifetime cost of $22,884 CAD vs $22,786 CAD for standard care, with an incremental cost-effectiveness ratio of $4939 CAD per life-year gained. We found that the HMI is a cost-effective means of providing evidence-informed, chronic disease management in primary care to patients with hypertension.


The ontogeny of inhibition and excitation in the gerbil lateral superior olive.
While the development of excitatory responses has been the focus of considerable research, the ontogeny of inhibitory connections has received relatively little attention. The lateral superior olive (LSO), an auditory nucleus in the ventral brain stem, is a favorable system in which to compare the maturation of an inhibitory and an excitatory input. Neurons in the LSO are excited by stimuli delivered to the ipsilateral ear and inhibited by similar stimuli to the contralateral ear. Single-neuron recordings were made to characterize tone-evoked responses at the onset of hearing and in adult Mongolian gerbils. The results indicated that frequency selectivity was significantly poorer in young than adult animals. In several cases, neurons within the same animal were found to have disparate tuning properties, such that one of the units had "adult-like" tuning, while the other was much more broadly tuned. No difference existed between excitatory and inhibitory tuning within any age group. The degree to which the excitatory and inhibitory characteristic frequencies of an LSO neuron were correlated was used as a measure of tonotopic map alignment. A significant improvement of matching was seen with increasing age. A comparison of excitatory and inhibitory thresholds indicated that the inhibitory system was relatively more efficacious in young than adult animals. The ability of LSO neurons to respond to interaural intensity differences, the binaural parameter to which they are sensitive, indicated 3 differences between adult and young animals: the dynamic range was smaller, the slope was shallower, and the sample of neurons encoded a constrained range of interaural intensity difference values. We conclude that the maturation of the inhibitory and excitatory systems are nearly identical.


Sources of health insurance and characteristics of the uninsured: analysis of the March 2011 current population survey.
LATEST CENSUS DATA: This Issue Brief provides historical data through 2010 on the number and percentage of nonelderly individuals with and without health insurance. Based on EBRI estimates from the U.S. Census Bureau's March 2011 Current Population Survey (CPS), it reflects 2010 data. It also discusses trends in coverage for the 1994-2010 period and highlights characteristics that typically indicate whether an individual is insured. HEALTH COVERAGE RATE CONTINUES TO DECREASE, UNINSURED INCREASE: The percentage of the nonelderly population (under age 65) with health insurance coverage decreased to 81.5 percent in 2010. Increases in health insurance coverage have been recorded in only three years since 1994, when 36.5 million nonelderly individuals were uninsured. The percentage of nonelderly individuals without health insurance coverage was 18.5 percent in 2010, up from 18.3 percent in 2009, and its highest level during the 1994-2010 period. EMPLOYMENT-BASED COVERAGE REMAINS DOMINANT SOURCE OF HEALTH COVERAGE, BUT CONTINUES TO ERODE: Employment-based health benefits remain the most common form of health coverage in the United States. In 2010, 58.7 percent of the nonelderly population had employment-based health benefits, down from 69.3 percent in 2000. SHIFTING COMPOSITION OF EMPLOYMENT-BASED COVERAGE: Between 2007 and 2010, the percentage of individuals under age 65 with employment-based coverage in their own name has dropped. In 2007, 54.2 percent had coverage in their own name. By 2010, it was down to 51.5 percent. Dependent coverage during this time period fell slightly from 17.5 percent to 17.1 percent, and increased slightly from 16.8 percent to 17.1 percent between 2009 and 2010. PUBLIC PROGRAM COVERAGE IS GROWING: Public program health coverage expanded as a percentage of the population in 2010, accounting for 21.6 percent of the nonelderly population. Enrollment in Medicaid and the State Children's Health Insurance Program increased, reaching a combined 45 million in 2010, and covering 16.9 percent of the nonelderly population, significantly above the 10.2 percent level of 1999. INDIVIDUAL COVERAGE STABLE: Individually purchased health coverage was unchanged in 2010 and has basically hovered in the 6-7 percent range since 1994. WHAT TO EXPECT IN 2011: 2010 is the most recent year for data on sources of health coverage. Unemployment in 2011 has been about 9 percent since the beginning of the year. While down from the 2010 average of 9.6 percent, it remains high and there is a continued threat of a double-dip recession increasing it even further. As a result, the nation is likely to see continued erosion of employment-based health benefits when the data for 2011 are released in 2012. Fewer working individuals translates into fewer individuals with access to health benefits in the work place, especially after COBRA subsidies have been exhausted.