Role of carbohydrate in biological functions of Friend murine leukemia virus gp71.
Purified gp71 of Friend murine leukemia virus (FLV) can interfere with virus infection, absorb neutralizing antibody, and in the presence of group-specific anti-gp71 antibody, hemagglutinate sheep erythrocytes. Interference by FLV gp71 with several murine leukemia viruses (MuLV) was tested in the XC and S + L- assay systems. Treatment of gp71 with trypsin or Pronase eliminated its interfering capacity. However, treatment with neuraminidase or a mixture of glycosidase enzymes, which left the major serological properties of gp71 intact, did not reduce the interference potential of gp71 for FLV or AKR MuLV. The capacity of gp71 to absorb type- or group-specific virus-neutralizing antibodies was similarly affected by the various enzyme treatments. In contrast, indirect hemagglutination by gp71 was abolished not only by proteases but also by treatment with glycosidase enzymes, although neuraminidase had no effect. Preliminary data indicate that infectivity of FLV or xenotropic MuLV was not affected by short treatment with glycosidase enzymes.


The type VI secretion system encoded in SPI-6 plays a role in gastrointestinal colonization and systemic spread of Salmonella enterica serovar Typhimurium in the chicken.
The role of the Salmonella Pathogenicity Islands (SPIs) in pathogenesis of Salmonella enterica Typhimurium infection in the chicken is poorly studied, while many studies have been completed in murine models. The Type VI Secretion System (T6SS) is a recently described protein secretion system in Gram-negative bacteria. The genus Salmonella contains five phylogenetically distinct T6SS encoded in differentially distributed genomic islands. S. Typhimurium harbors a T6SS encoded in SPI-6 (T6SSSPI-6), which contributes to the ability of Salmonella to colonize mice. On the other hand, serotype Gallinarum harbors a T6SS encoded in SPI-19 (T6SSSPI-19) that is required for colonization of chicks. In this work, we investigated the role of T6SSSPI-6 in infection of chicks by S. Typhimurium. Oral infection of White Leghorn chicks showed that a ΔT6SSSPI-6 mutant had reduced colonization of the gut and internal organs, compared with the wild-type strain. Transfer of the intact T6SSSPI-6 gene cluster into the T6SS mutant restored bacterial colonization. In addition, our results showed that transfer of T6SSSPI-19 from S. Gallinarum to the ΔT6SSSPI-6 mutant of S. Typhimurium not only complemented the colonization defect but also resulted in a transient increase in the colonization of the cecum and ileum of chicks at days 1 and 3 post-infection. Our data indicates that T6SSSPI-6 contributes to chicken colonization and suggests that both T6SSSPI-6 and T6SSSPI-19 perform similar functions in vivo despite belonging to different phylogenetic families.


The Impact of Positive and Negative Affect and Issue Framing on Issue Interpretation and Risk Taking.
Two studies examined the influence of transient affective states and issue framing on issue interpretation and risk taking within the context of strategic decision making. In Study 1, participants in whom transient positive or negative affective states were induced by reading a short story showed systematic differences in issue interpretation and risk taking in a strategic decision making context. Compared to negative mood participants, those in a positive mood were more likely to interpret the strategic issue as an opportunity and displayed lower levels of risk taking. Study 2 replicated and extended these results by crossing affective states with threat and opportunity frames. Results showed that framing an issue (as a threat or an opportunity) had a stronger impact on issue interpretation among negative affect participants than among positive affect participants. Affective states also moderated the impact of issue framing on risk taking: the effect of framing on risk-taking was stronger under negative rather than positive affect. These results are interpreted via information-processing and motivational effects of affect on a decision maker. Copyright 1998 Academic Press.


Binary-tree encryption strategy for optical multiple-image encryption.
In traditional optical multiple-image encryption schemes, different images typically have almost the same encryption or decryption process. Provided that an attacker manages to correctly decrypt some image, the conventional attacks upon other images are much easier to be made. In this paper, a binary-tree encryption strategy for multiple images is proposed to resist the attacks in this case. The encryption schemes produced by this strategy can not only increase the security of multiple-image encryption, but also realize an authority management with high security among the users sharing a cipher image. For a simulation test, we devise a basic binary-tree encryption scheme, whose encryption nodes are based on an asymmetric double random phase encoding in the gyrator domain. The favorable simulation results about the tested scheme can testify to the feasibility of the strategy.


Significantly increased risk of all-cause mortality among cardiac patients feeling lonely.
To explore whether living alone and loneliness 1) are associated with poor patient-reported outcomes at hospital discharge and 2) predict cardiac events and mortality 1 year after hospital discharge in women and men with ischaemic heart disease, arrhythmia, heart failure or heart valve disease. A national cross-sectional survey including patients with known cardiac disease at hospital discharge combined with national register data at baseline and 1-year follow-up. Loneliness was evaluated using one self-reported question, and information on cohabitation was available from national registers. Patient-reported outcomes were Short Form-12, Hospital Anxiety and Depression Scale and HeartQoL. Clinical outcomes were 1-year cardiac events (myocardial infarction, stroke, cardiac arrest, ventricular tachycardia/fibrillation) and all-cause mortality from national registers. A total of 13 443 patients (53%) with ischaemic heart disease, arrhythmia, heart failure or heart valve disease completed the survey. Of these, 70% were male, and mean age was 66.1 among women and 64.9 among men. Across cardiac diagnoses, loneliness was associated with significantly poorer patient-reported outcomes in men and women. Loneliness predicted all-cause mortality among women and men (HR 2.92 (95% CI 1.55 to 5.49) and HR 2.14 (95% CI 1.43 to 3.22), respectively). Living alone predicted cardiac events in men only (HR 1.39 (95% CI 1.05 to 1.85)). A strong association between loneliness and poor patient-reported outcomes and 1-year mortality was found in both men and women across cardiac diagnoses. The results suggest that loneliness should be a priority for public health initiatives, and should also be included in clinical risk assessment in cardiac patients.


Comparison of scanning laser polarimetry using variable corneal compensation and retinal nerve fiber layer photography for detection of glaucoma.
To compare retinal nerve fiber layer (RNFL) measurements obtained with scanning laser polarimetry (SLP) using variable corneal polarization compensation with standard red-free photography for detection of RNFL damage in glaucoma. This observational, cross-sectional study included 1 eye of each of 42 patients with open-angle glaucoma, 32 patients suspected of having glaucoma, and 40 healthy subjects. The RNFL measurements using SLP with variable corneal compensation were obtained within 3 months of red-free photographs. Two independent observers graded RNFL photographs using a standardized protocol. Superior and inferior hemiretinas were scored separately, and a global score was obtained by averaging scores from each hemiretina. The RNFL photography scores were compared with RNFL thickness measurements obtained with SLP. The receiver operating characteristic (ROC) curves were constructed to assess the abilities of the different methods to differentiate glaucoma patients from healthy subjects. The RNFL thickness decreased with increased RNFL damage as assessed by photographs in both hemiretinas (R(2) = 15%-47%). The area under the ROC curve for the best SLP parameter, Nerve Fiber Indicator, was significantly greater than the area under the ROC curve for the global RNFL photography score (0.91 vs 0.84, P =.03). A moderate correlation was found between RNFL thickness measurements obtained with SLP and RNFL scores from red-free photographs. Compared with semiquantitative RNFL photography scores, the best SLP parameter had a higher diagnostic accuracy to separate glaucoma patients from healthy subjects.


Actinomycin D revisited in testicular cancer. A case report.
Between 20-30% of patients with advanced germ cell tumors relapse or fail to achieve a complete response to conventional cisplatin based chemotherapy. Ifosphamide has been used very effectively in combination with cisplatin and etoposide (VIP) or in combination with cisplatin and vinblastine (VeIP). Actinomycin D with chlorambucil and methotrexate was widely used in the 1960s with complete responses in 20% of patients and long term survival of 6-10%. There exists no information on the use of actinomycin as a salvage in cisplatin refractory patients. One patient with metastatic germ cell tumor who failed chemotherapy with cisplatin and ifosphamide was successfully treated with an actinomycin D based regimen. Actinomycin D is an active agent in testicular cancer and maybe used in patients refractory to platinum.


Sector analysis and predictive modelling reveal iterative shoot-like development in fern fronds.
Plants colonized the terrestrial environment over 450 million years ago. Since then, shoot architecture has evolved in response to changing environmental conditions. Our current understanding of the innovations that altered shoot morphology is underpinned by developmental studies in a number of plant groups. However, the least is known about mechanisms that operate in ferns--a key group for understanding the evolution of plant development. Using a novel combination of sector analysis, conditional probability modelling methods and histology, we show that shoots, fronds ('leaves') and pinnae ('leaflets') of the fern Nephrolepis exaltata all develop from single apical initial cells. Shoot initials cleave on three faces to produce a pool of cells from which individual frond apical initials are sequentially specified. Frond initials then cleave in two planes to produce a series of lateral merophyte initials that each contributes a unit of three pinnae to half of the mediolateral frond axis. Notably, this iterative pattern in both shoots and fronds is similar to the developmental process that operates in shoots of other plant groups. Pinnae initials first cleave in two planes to generate lateral marginal initials. The apical and marginal initials then divide in three planes to coordinately generate the determinate pinna. These findings impact both on our understanding of fundamental plant developmental processes and on our perspective of how shoot systems evolved.


Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.
The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here. BOLERO-2 is a phase III, double-blind, randomized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo (PBO) + EXE 25 mg/day in postmenopausal women with HR(+) advanced breast cancer with prior exposure to NSAIs. The primary end point was PFS by local investigator assessment; OS was a key secondary end point. At the time of data cutoff (3 October 2013), 410 deaths had occurred and 13 patients remained on treatment. Median OS in patients receiving EVE + EXE was 31.0 months [95% confidence interval (CI) 28.0-34.6 months] compared with 26.6 months (95% CI 22.6-33.1 months) in patients receiving PBO + EXE (hazard ratio = 0.89; 95% CI 0.73-1.10; log-rank P = 0.14). Poststudy treatments were received by 84% of patients in the EVE + EXE arm versus 90% of patients in the PBO + EXE arm. Types of poststudy therapies were balanced across arms, except for chemotherapy (53% EVE + EXE versus 63% PBO + EXE). No new safety concerns were identified. In BOLERO-2, adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinically meaningful and statistically significant improvement in the primary end point, PFS (4.6-months prolongation in median PFS; P < 0.0001). Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting. NCT00863655.


cDNA library construction for next-generation sequencing to determine the transcriptional landscape of Legionella pneumophila.
The adaptation of Legionella pneumophila to the different conditions it encounters in the environment and in the host is governed by a complex regulatory system. Current knowledge of these regulatory networks and the transcriptome responses of L. pneumophila is mainly based on microarray analysis and limited to transcriptional products of annotated protein-coding genes. The application of the Next-Generation Sequencing (NGS) technology allows now genome-wide strand-specific sequencing and accurate determination of all expressed regions of the genome to reveal the complete transcriptional network and the dynamic interplay of specific regulators on a genome-wide level. NGS-based techniques promote deeper understanding of the global transcriptional organization of L. pneumophila by identifying transcription start sites (TSS), alternative TSS and operon organization, noncoding RNAs, antisense RNAs, and 5'-/3'-untranslated regions. In this chapter we describe the construction of cDNA libraries for (1) RNA deep sequencing (RNA-seq) and (2) TSS mapping using the Illumina technology.


Effects of ultra-high pressure on effective synthesis of fructooligosaccharides and fructotransferase activity using Pectinex Ultra SP-L and inulinase from Aspergillus niger.
In this study, various levels of ultra-high pressure (UHP) were combined with the enzymatic synthesis of the fructooligosaccharide (FOS) using Pectinex Ultra SP-L and inulinase. The combination enhanced the FOS yields up to 2.5- and 1.5-fold, respectively, compared to atmospheric condition (0.1 MPa). However, the enzymatic reaction was dependent on the levels of pressure, the reaction times, and the initial sucrose concentrations. The combined UHP and inulinase showed that the maximum FOS yield (71.81%) was obtained under UHP at 200 MPa for 20 min with 300 g/L of initial sucrose as a substrate, while the FOS yield (57.13%) using Pectinex Ultra SP-L was obtained under UHP at 300 MPa for 15 min with 600 g/L of initial sucrose as a substrate. The FOS composition produced by Pectinex Ultra SP-L under the UHP was 1-kestose (GF2), nystose (GF3), and 1F-fructofuranosylnystose (GF4), whereas the FOS produced by inulinase composed of only GF2 and GF3. The combined UHP is a useful tool in the industrial application for FOS production. Highlights UHP activated the activity of Pectinex Ultra SP-L yet inactivated inulinase Pressure level, time, and sucrose concentration significantly affect FOS yields under UHP UHP enhanced FOS production with time-saving benefits within 15-20 min.


Acute tetraparesis secondary to bilateral precentral gyral cerebral ischemia: a case report.
Sudden tetraparesis represents a neurological emergency and is most often caused by traumatic spinal cord injury, spinal epidural bleeding or brainstem ischemia and less frequently by medial disc herniation or spinal ischemia. Here we report the rare case of an 82-year-old Caucasian man who developed severe tetraparesis four days after radical cystoprostatectomy. An emergency diagnostic study for spinal cord affection was normal. Brain magnetic resonance imaging revealed acute bilateral ischemic strokes in the precentral gyri as the underlying cause. This case report underlines the need to also consider unusual causes of tetraparesis in an emergency situation apart from spinal cord or brain stem injury in order not to leave severe symptomatology unclear and possibly miss therapeutic options.


Bisphenol A in Reproduction: Epigenetic Effects.
Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively. This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction. BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF). The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring.


Effect of N-glycosylation on turnover and subcellular distribution of N-acetylgalactosaminyltransferase I and sialyltransferase II in neuroblastoma cells.
Gangliosides are sialylated glycosphingolipids whose biosynthesis is catalyzed by a series of endoplasmic reticulum (ER)- and Golgi-resident glycosyltransferases. Protein expression, processing, and subcellular localization of the key regulatory enzymes for ganglioside biosynthesis, sialyltransferase II (ST-II) and N-acetylgalactosaminyltransferase I (GalNAcT), were analyzed upon transient expression of the two enzymes in the neuroblastoma cell lines NG108-15 and F-11. The enzymes were endowed with a C-terminal epitope tag peptide (FLAG) for immunostaining and immunoaffinity purification using a FLAG-specific antibody. Mature ST-II-FLAG and GalNAcT-FLAG were expressed as N-glycoproteins with noncomplex oligosaccharides. ST-II-FLAG was distributed to the Golgi apparatus, whereas GalNAcT-FLAG was found in the ER and Golgi. Inhibition of early N-glycoprotein processing with castanospermine resulted in a distribution of ST-II-FLAG to the ER, whereas that of GalNAcT-FLAG remained unaltered. In contrast to GalNAcT, the activity of ST-II and the amount of immunostained enzyme were reduced concomitantly by 75% upon incubation with castanospermine. This was due to a fourfold increased turnover of ST-II-FLAG, which was not found with GalNAcT-FLAG. The ER retention and increased turnover of ST-II-FLAG were most likely due to its inability to bind to calnexin upon inhibition of early N-glycoprotein processing. Calnexin binding was not observed for GalNAcT-FLAG, indicating a differential effect of N-glycosylation on the turnover and subcellular localization of the two glycosyltransferases.


Barriers and Facilitators for Implementing a Decision Support System to Prevent and Treat Disease-Related Malnutrition in a Hospital Setting: Qualitative Study.
Disease-related malnutrition is a challenge among hospitalized patients. Despite guidelines and recommendations for prevention and treatment, the condition continues to be prevalent. The MyFood system is a recently developed decision support system to prevent and treat disease-related malnutrition. To investigate the possible implementation of the MyFood system in clinical practice, the aims of the study were (1) to identify current practice, routines, barriers, and facilitators of nutritional care; (2) to identify potential barriers and facilitators for the use of MyFood; and (3) to identify the key aspects of an implementation plan. A qualitative study was performed among nurses, physicians, registered dietitians, and middle managers in 2 departments in a university hospital in Norway. Focus group discussions and semistructured interviews were used to collect data. The Consolidated Framework for Implementation Research (CFIR) was used to create the interview guide and analyze the results. The transcripts were analyzed using a thematic analysis. A total of 27 health care professionals participated in the interviews and focus groups, including nurses (n=20), physicians (n=2), registered dietitians (n=2), and middle managers (n=3). The data were analyzed within 22 of the 39 CFIR constructs. Using the 5 CFIR domains as themes, we obtained the following results: (1) Intervention characteristics: MyFood was perceived to have a relative advantage of being more trustworthy, systematic, and motivational and providing increased awareness of nutritional treatment compared with the current practice. Its lack of communication with the existing digital systems was perceived as a potential barrier; (2) Outer settings: patients from different cultural backgrounds with language barriers and of older age were potential barriers for the use of the MyFood system; (3) Inner settings: no culture for specific routines or systems related to nutritional care existed in the departments. However, tension for change regarding screening for malnutrition risk, monitoring and nutritional treatment was highlighted in all categories of interviewees; (4) Characteristics of the individuals: positive attitudes toward MyFood were present among the majority of the interviewees, and they expressed self-efficacy toward the perceived use of MyFood; (5) Process: providing sufficient information to everyone in the department was highlighted as key to the success of the implementation. The involvement of opinion leaders, implementation leaders, and champions was also suggested for the implementation plan. This study identified several challenges in the nutritional care of hospitalized patients at risk of malnutrition and deviations from recommendations and guidelines. The MyFood system was perceived as being more precise, trustworthy, and motivational than the current practice. However, several potential barriers were identified. The assessment of the current situation and the identification of perceived barriers and facilitators will be used in planning an implementation and effect study, including the creation of an implementation plan.


A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance.
The therapeutic benefits of the neuraminidase (NA) inhibitor oseltamivir are dampened by the emergence of drug resistance mutations in influenza A virus (IAV). To investigate the mechanistic features that underlie resistance, we developed an approach to quantify the effects of all possible single-nucleotide substitutions introduced into important regions of NA. We determined the experimental fitness effects of 450 nucleotide mutations encoding positions both surrounding the active site and at more distant sites in an N1 strain of IAV in the presence and absence of oseltamivir. NA mutations previously known to confer oseltamivir resistance in N1 strains, including H275Y and N295S, were adaptive in the presence of drug, indicating that our experimental system captured salient features of real-world selection pressures acting on NA. We identified mutations, including several at position 223, that reduce the apparent affinity for oseltamivir in vitro. Position 223 of NA is located adjacent to a hydrophobic portion of oseltamivir that is chemically distinct from the substrate, making it a hotspot for substitutions that preferentially impact drug binding relative to substrate processing. Furthermore, two NA mutations, K221N and Y276F, each reduce susceptibility to oseltamivir by increasing NA activity without altering drug binding. These results indicate that competitive expansion of IAV in the face of drug pressure is mediated by a balance between inhibitor binding and substrate processing.


Comprehensive Secondary Metabolite Profiling Toward Delineating the Solid and Submerged-State Fermentation of Aspergillus oryzae KCCM 12698.
Aspergillus oryzae has been commonly used to make koji, meju, and soy sauce in traditional food fermentation industries. However, the metabolic behaviors of A. oryzae during fermentation in various culture environments are largely uncharacterized. Thus, we performed time resolved (0, 4, 8, 12, 16 day) secondary metabolite profiling for A. oryzae KCCM 12698 cultivated on malt extract agar and broth (MEA and MEB) under solid-state fermentation (SSF) and submerged fermentation (SmF) conditions using the ultrahigh performance liquid chromatography-linear trap quadrupole-ion trap-mass spectrometry (UHPLC-LTQ-IT-MS/MS) followed by multivariate analyses. We observed the relatively higher proportions of coumarins and oxylipins in SSF, whereas the terpenoids were abundant in SmF. Moreover, we investigated the antimicrobial efficacy of metabolites that were extracted from SSF and SmF. The SSF extracts showed higher antimicrobial activities as compared to SmF, with higher production rates of bioactive secondary metabolites viz., ketone-citreoisocoumarin, pentahydroxy-anthraquinone, hexylitaconic acid, oxylipins, and saturated fatty acids. The current study provides the underpinnings of a metabolomic framework regarding the growth and bioactive compound production for A. oryzae under the primarily employed industrial cultivation states. Furthermore, the study holds the potentials for rapid screening and MS-characterization of metabolites helpful in determining the consumer safety implications of fermented foods involving Koji mold.


Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers.
Xp11 translocation renal cell carcinoma (RCC) harbor various TFE3 gene fusions, and are known to underexpress epithelial immunohistochemical (IHC) markers such as cytokeratin and EMA relative to usual adult type RCC; however, their profile in reference to other IHC markers that are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers. We created 2 tissue microarrays (TMA) containing five 1.4-mm cores from each of 21 Xp11 translocation RCC (all confirmed by TFE3 IHC, 6 further confirmed by genetics), 7 clear cell RCC (CCRCC), and 6 papillary RCC (PRCC). These TMA were labeled for a panel of IHC markers. In contrast to earlier published data, Xp11 translocation RCC frequently expressed renal transcription factors PAX8 (16/21 cases) and PAX2 (14/21 cases), whereas only 1 of 21 cases focally expressed MiTF and only 5 of 21 overexpressed p21. Although experimental data suggest otherwise, Xp11 translocation RCC did not express WT-1 (0/21 cases). Although 24% of Xp11 translocation RCC expressed HIF-1alpha (like CCRCC), unlike CCRCC CA IX expression was characteristically only focal (mean 6% cell labeling) in Xp11 translocation RCC. Other markers preferentially expressed in CCRCC or PRCC, such as HIG-2, claudin 7, and EpCAM, yielded inconsistent results in Xp11 translocation RCC. Xp11 translocation RCC infrequently expressed Ksp-cadherin (3/21 cases) and c-kit (0/21 cases), markers frequently expressed in chromophobe RCC. Using an H-score that is the product of intensity and percentage labeling, Xp11 translocation RCC expressed higher levels of phosphorylated S6, a measure of mTOR pathway activation (mean H score=88), than did CCRCC (mean H score=54) or PRCC (mean H score=44). In conclusion, in contrast to prior reports, Xp11 translocation RCC usually express PAX2 and PAX8 but do not usually express MiTF. Although they may express HIF-1alpha, they only focally express the downstream target CA IX. They inconsistently express markers associated with other RCC subtypes, further highlighting the lack of specificity of the latter markers. TFE3 and Cathepsin K remain the most sensitive and specific markers of these neoplasms. Elevated expression of phosphorylated S6 in Xp11 translocation RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms.


Image formation in fluorescence coherence-gated imaging through scattering media.
Recently, we have experimentally demonstrated a new form of cross-sectional, coherence-gated fluorescence imaging referred to as SD-FCT ('spectral-domain fluorescence coherence tomography'). Imaging in SD-FCT is accomplished by spectrally detecting self-interference of the spontaneous emission of fluorophores, thereby providing depth-resolved information on the axial positions of fluorescent probes. Here, we present a theoretical investigation of the factors affecting the detected SD-FCT signal through scattering media. An imaging equation for SD-FCT is derived that includes the effects of defocusing, numerical-aperture, and the optical properties of the medium. A comparison between the optical sectioning capabilities of SD-FCT and confocal microscopy is also presented. Our results suggest that coherence gating in fluorescence imaging may provide an improved approach for depth-resolved imaging of fluorescently labeled samples; high axial resolution (a few microns) can be achieved with low numerical apertures (NA<0.09) while maintaining a large depth of field (a few hundreds of microns) in a relatively low scattering medium (6 mean free paths), whereas moderate NA's can be used to enhance depth selectivity in more highly scattering biological samples.


Biodegradation of ivory (natural apatite): possible involvement of fungal activity in biodeterioration of the Lewis Chessmen.
Fungal biodeterioration of ivory was investigated with in vitro inoculation of samples obtained from boar and walrus tusks with the fungi Aspergillus niger and Serpula himantioides, species of known geoactive abilities. A combination of light and scanning electron microscopy together with associated analytical techniques was used to characterize fungal interactions with the ivory, including changes in ivory composition, dissolution and tunnelling, and the formation of new biominerals. The research was aimed at providing further understanding of the potential roles of fungi in the colonization and deterioration of ivory in terrestrial environments, but also contributes to our knowledge regarding the possible origins of the surface damage observed on early medieval sculptures made largely from walrus tusks, referred to as 'the Lewis hoard of gaming pieces', that were presumably produced for playing chess. The experiments have shown that the possibility of damage to ivory being caused by fungi is realistic. Scanning electron microscopy revealed penetration of fungal hyphae within cracks in the walrus tusk that showed also widespread tunnelling by fungal hyphae as well as 'fungal footprints' where the surface was etched as a consequence of mycelial colonization. Similar phenomena were observed with boar tusk ivory, while production of metabolites could lead to complete dissolution of the sample. Colonization of ivory and/or exposure to fungal activity lead to extensive secondary biomineral formation, and this was identified as calcium oxalate, mainly as the monohydrate, whewellite.


Prostate-specific antigen testing and prostate biopsy: are self-reported lower urinary tract symptoms and health-related quality of life associated with the decision to undergo these investigations?
To investigate whether men's self-reported health-related quality of life and lower urinary tract symptoms (LUTS) are associated with acceptance of prostate-specific antigen (PSA) testing and subsequent prostate biopsy. In a prospective questionnaire study of men aged 50-69 years, nested within the primary-care-based Prostate testing for cancer and Treatment study in nine UK areas, the Hospital Anxiety and Depression Scale (HADS), 12-item Short Form Health Survey (SF-12) and a self-reported LUTS measure (ICSmaleSF) were completed immediately before having a PSA test or prostate biopsy, or after not responding to an invitation for a PSA test or refusing a biopsy. Analyses compared 348 men accepting or 232 not responding to invitations for PSA testing and 318 accepting or 48 refusing a prostate biopsy. Men accepting or not responding to the invitation for a PSA test had similar HADS, SF-12 and LUTS scores. Men accepting a biopsy had similar HADS and SF-12 scores to those refusing biopsy, but significantly more LUTS (P < 0.01 for hesitancy, reduced stream, intermittency, incomplete emptying, frequency during the day). Depressed or anxious mood, comorbidity and LUTS were not associated with the decision to respond to invitations for a PSA test. Men agreeing to a biopsy were more likely to have LUTS than those refusing, suggesting that men believe that LUTS are a symptom of prostate cancer. Men needing a prostate biopsy require more information about LUTS so that they can make informed choices about testing for prostate cancer.


Trabecular bone microarchitecture and characteristics in different regions of the glenoid.
Success of shoulder surgery depends on implant fixation to the glenoid trabecular bone. The purpose of this study was to evaluate the anatomic characteristics of the normal glenoid trabecular bone microarchitecture to help assist in implant design and provide data for finite element analyses. Eight cadavers without evidence of osteoarthritis were used. Glenoids were scanned with micro-computed tomography and then divided into lateral and medial, then superior, inferior, anterior, and posterior quadrants (8 total segments). Each segment was analyzed for total mineral density, bone volume fraction, structure model index, and trabecular thickness (Tb.Th), number (Tb.N), and separation. Bone volume fraction was significantly higher (P<.05) in the posterolateral (20.8%±4.5%) and posteromedial (18.6%±2.5%) regions. Both Tb.N and Tb.Th were also highest in the posterolateral (Tb.N, 1.74±0.374 mm; Tb.Th, 0.148±0.017 mm) and posteromedial (Tb.N, 1.49±0.401 mm; Tb.Th, 0.165±0.016 mm) regions. Trabecular separation was greatest in the superomedial segment (1.00±0.181 mm) and lowest in the posterolateral region (0.663±0.121 mm). For structural model index, both the posterolateral (0.314) and posteromedial (0.312) regions had lower values than the other regions. The posterior segment of the normal glenoid in both the lateral and medial regions has the highest density, which is attributed to the increased trabecular number and thickness with decreased separation. This increased density may be attributed to the posterior directed loading of the glenohumeral joint. The trabecular microarchitecture in the glenoid is plate-like, as indicated by the low structural model index.


Identification of the dynamic relationship between intrapartum uterine pressure and fetal heart rate for normal and hypoxic fetuses.
Labor and delivery are routinely monitored electronically with sensors that measure and record maternal uterine pressure (UP) and fetal heart rate (FHR), a procedure referred to as cardiotocography (CTG). Delay or failure to recognize abnormal patterns in these recordings can result in a failure to prevent fetal injury. We address the challenging problem of interpreting intrapartum CTG in a novel way by modeling the dynamic relationship between UP (as an input) and FHR (as an output). We use a nonparametric approach to estimate the dynamics in terms of an impulse response function (IRF). We apply singular value decomposition to suppress noise, IRF delay, and memory estimation to identify the temporal extent of the response and surrogate testing to assess model significance. We construct models for a database of CTG recordings labeled by outcome, and compare the models during the last 3 h of labor as well as across outcome classes. The results demonstrate that the UP-FHR dynamics can be successfully modeled as an input-output system. Models for pathological cases had stronger, more delayed, and more predictable responses than those for normal cases. In addition, the models evolved in time, reflecting a clinically plausible evolution of the fetal state due to the stress of labor.


Do your commitments match your convictions?
How many of us keep pace day to day, up-holding our obligations to our bosses, families, and the community, even as our overall satisfaction with work and quality of life decline? And yet, our common response to the situation is: "I'm too busy to do anything about it now." Unfortunately, unless a personal or professional crisis strikes, very few of us step back, take stock of our day-to-day actions, and make a change. In this article, London Business School strategy professors Donald Sull and Dominic Houlder examine the reasons why a gap often exists between the things we value most and the ways we actually spend our time, money, and attention. They also suggest a practical approach to managing the gap. The framework they propose is based on their study of organizational commitments--the investments, promises, and contracts made today that bind companies to a future course of action. Such commitments can prevent organizations from responding effectively to change. A similar logic applies to personal commitments--the day-to-day decisions we make about how we allocate our precious resources. These decisions are individually small and, therefore, easy to lose sight of. When we do, a gap can develop between our commitments and our convictions. Sull and Houlder make no value judgments about the content of personal commitments; they've devised a somewhat dispassionate tool to help you take a thorough inventory of what matters to you most. It involves listing your most important values and assigning to each a percentage of your annual salary, the hours out of your week, and the amount of energy you devote. Using this exercise, you should be able to identify big gaps--stated values that receive little or none of your scarce resources or a single value that sucks a disproportionate share of resources--and change your allocations accordingly.


[Glycemic and insulin indices of tube feeding formulas in healthy adults].
In acute illnesses, plasma glucose levels are often increased and generally parallel the severity of stress. Hyperglycemia caused by reduced insulin sensitivity and reduced insulin secretion is associated with increased susceptibility to infections. Maintaining blood glucose levels at or below 110 mg/dl reduces morbidity and mortality in critically ill patients. To measure the glucose and insulin responses of four commercially available enteral formulas compared with a standard meal reference product. The glycemic index (GI) and the insulin index (II) were determined in a randomized, cross over protocol in 38 healthy volunteers between 18 and 46 years of age. Each subject underwent five tests: three with the standard meal (bread) and two with the study products. The enteral formulas were Clinutren HPR (whole protein of high protein value), Crucial (casein peptide based formula), Peptamen, (whey peptide based formula), Glytrol (formula for diabetics with whole protein with fiber). Each study product was evaluated 10 times. The diabetic formula and the high protein energy dense formulas induced a significantly lower GI (p <0.02) compared with the standard meal. The GI response did not appear to be due to enhanced insulin secretion. The other tested formulas had lower GI than the standard meal, but in addition they exhibited increased II The whey based peptide formulation produced the highest insulin response (p <0.03). Both GI and II are related to the concentration, form and type of protein contained in the enteral formula. The whey peptide formulation produced a low GI with the highest insulin index. Based on the low GI of these enteral products, all can be useful to provide nutritional support during metabolic stress, without adding an additional challenge to blood glucose management.


Cord blood-derived hematopoietic stem/progenitor cells: current challenges in engraftment, infection, and ex vivo expansion.
Umbilical cord blood has served as an alternative to bone marrow for hematopoietic transplantation since the late 1980s. Numerous clinical studies have proven the efficacy of umbilical cord blood. Moreover, the possible immaturity of cells in umbilical cord blood gives more options to recipients with HLA mismatch and allows for the use of umbilical cord blood from unrelated donors. However, morbidity and mortality rates associated with hematopoietic malignancies still remain relatively high, even after cord blood transplantation. Infections and relapse are the major causes of death after cord blood transplantation in patients with hematopoietic diseases. Recently, new strategies have been introduced to improve these major problems. Establishing better protocols for simple isolation of primitive cells and ex vivo expansion will also be very important. In this short review, we discuss several recent promising findings related to the technical improvement of cord blood transplantation.


Rocking the MBOAT: Structural insights into the membrane bound O-acyltransferase family.
The membrane-bound O-acyltransferase (MBOAT) superfamily catalyses the transfer of acyl chains to substrates implicated in essential cellular functions. Aberrant function of MBOATs is associated with various diseases and MBOATs are promising drug targets. There has been recent progress in structural characterisation of MBOATs, advancing our understanding of their functional mechanism. Integrating information across the MBOAT family, we characterise a common MBOAT fold and provide a blueprint for substrate and inhibitor engagement. This work provides context for the diverse substrates, mechanisms, and evolutionary relationships of protein and small-molecule MBOATs. Further work should aim to characterise MBOATs, as inherently lipid-associated proteins, within their membrane environment.


Vision-based flight control in the hawkmoth Hyles lineata.
Vision is a key sensory modality for flying insects, playing an important role in guidance, navigation and control. Here, we use a virtual-reality flight simulator to measure the optomotor responses of the hawkmoth Hyles lineata, and use a published linear-time invariant model of the flight dynamics to interpret the function of the measured responses in flight stabilization and control. We recorded the forces and moments produced during oscillation of the visual field in roll, pitch and yaw, varying the temporal frequency, amplitude or spatial frequency of the stimulus. The moths' responses were strongly dependent upon contrast frequency, as expected if the optomotor system uses correlation-type motion detectors to sense self-motion. The flight dynamics model predicts that roll angle feedback is needed to stabilize the lateral dynamics, and that a combination of pitch angle and pitch rate feedback is most effective in stabilizing the longitudinal dynamics. The moths' responses to roll and pitch stimuli coincided qualitatively with these functional predictions. The moths produced coupled roll and yaw moments in response to yaw stimuli, which could help to reduce the energetic cost of correcting heading. Our results emphasize the close relationship between physics and physiology in the stabilization of insect flight.


Multispecies Epidemiologic Surveillance Study after an Outbreak of Yersiniosis at an African Green Monkey Research Facility.
After an outbreak of Yersinia enterocolitica at a NHP research facility, we performed a multispecies investigation of the prevalence of Yersinia spp. in various mammals that resided or foraged on the grounds of the facility, to better understand the epizootiology of yersiniosis. Blood samples and fecal and rectal swabs were obtained from 105 captive African green monkeys (AGM), 12 feral cats, 2 dogs, 20 mice, 12 rats, and 3 mongooses. Total DNA extracted from swab suspensions served as template for the detection of Y. enterocolitica DNA by real-time PCR. Neither Y. enterocolitica organisms nor their DNA were detected from any of these samples. However, Western blotting revealed the presence of Yersinia antibodies in plasma. The AGM samples revealed a seroprevalence of 91% for Yersinia spp. and of 61% for Y. enterocolitica specifically. The AGM that were housed in cages where at least one fatality occurred during the outbreak (clinical group) had similar seroprevalence to that of AGM housed in unaffected cages (nonclinical group). However, the nonclinical group was older than the clinical group. In addition, 25%, 100%, 33%, 10%, and 10% of the sampled local cats, dogs, mongooses, rats, and mice, respectively, were seropositive. The high seroprevalence after this outbreak suggests that Y. enterocolitica was transmitted effectively through the captive AGM population and that age was an important risk factor for disease. Knowledge regarding local environmental sources of Y. enterocolitica and the possible role of wildlife in the maintenance of yersiniosis is necessary to prevent and manage this disease.


SYMPATHETIC OPHTHALMIA: Clinicopathologic Correlation in a Consecutive Case Series.
To correlate the clinical course of sympathetic ophthalmia with the histological and immunohistochemical characteristics of the enucleated inciting eye. A consecutive case series with baseline clinical features and subsequent histopathologic findings. Evaluation of the 16 enucleated inciting eyes (blind and painful) disclosed that 9 of the 16 had typical histology, fulfilling the criteria for sympathetic ophthalmia of diffuse granulomatous inflammation. Among the 16, 11 sustained previous penetrating trauma, 4 underwent previous eye surgery, and 1 patient presented with an unknown etiology. Patients with atypical histology (7 of 7) were taking corticosteroids at the time of enucleation. Only 2 of 9 patients with typical histology were taking corticosteroids at the time of enucleation. At 6 months after enucleation of the inciting eye, 4 of the 7 patients with atypical histology had a visual acuity of ≥20/40 compared with 8 of 8 patients (100%) with typical histology. On a 4-point scale (0-3+), the choroidal infiltrate of the 9 histopathologically typical eyes showed an average of 2.5+ CD68 (macrophages), 2.5+ CD20 (B cells), and 1.5+ CD3 (T cells). Histopathologic findings had minimal correlation with the clinical course of sympathetic ophthalmia. Corticosteroid treatment before enucleation may influence the pathologic confirmation of sympathetic ophthalmia. The predominance of B lymphocytes and macrophages over T lymphocytes may represent different stages of the disease process.


Firing and cellular properties of V2a interneurons in the rodent spinal cord.
Previous studies have shown that a group of ventrally located neurons, designated V2a interneurons, play a key role in maintaining locomotor rhythmicity and in ensuring appropriate left-right alternation during locomotion (Crone et al., 2008, 2009). These V2a interneurons express the transcription factor Chx10. The aim of the present study was to characterize the locomotor-related activity of individual V2a interneurons, their cellular properties, and their detailed anatomical attributes in Chx10-GFP mice. A dorsal horn-removed preparation was developed to allow for visual whole-cell patch recordings from V2a interneurons along the entire lumbar spinal cord while at the same time leaving enough of the spinal cord intact to generate fictive locomotion. During drug-evoked locomotor-like activity, a large proportion of Chx10 cells showed rhythmic firing or membrane potential fluctuations related to either flexor or extensor activity in every lumbar segment. Chx10 cells received predominantly rhythmic excitatory input. Chx10 neurons displayed a wide variety of firing and potential rhythmogenic properties. However, none of these properties was obviously related to the observed rhythmicity during locomotor-like activity. In dual recordings, we found no evidence of Chx10 neuron interconnectivity. Intracellular fills revealed diverse projection patterns with most Chx10 interneurons being local with projections to the central pattern generator and motor neuron regions of the spinal cord and others with long ascending and/or descending branches. These data are compatible with V2a neurons having a role in regulating segmental left-right alternation and ipsilateral motor neuron firing with little effect on rhythm generation.


The role of surface proteins in cell proliferation as studied with thrombin and other proteases.
This communication explores the capacity of different proteases to stimulate DNA synthesis in resting chick embryo fibroblasts and to cause the removal of cell membrane proteins previosly postulated as important in the regulation of growth and division of cells. Thrombin, a highly specific protease and a known mitogen, was incubated with chick embryo fibroblasts, and analysis was made of the cell membrane proteins. Of particular interest were a protein of molecular weight 250,000, which is known to be readily removed by the action of trypsin and is not present in most transformed cells, and two other proteins, which are reduced in amount in transformed as compared to confluent resting cell cultures. None of these three proteins was removed by thrombin when the latter was added to confluent cells in concentrations sufficient to cause significant increase in DNA synthesis twelve hours after stimulation by the protease. The presence or absence of these proteins in the membranes of confluent resting or transformed cells of chick embryo fibroblasts does not seem to be directly related to the process of regulation of DNA synthesis and cellular division.


Effectiveness of suicide prevention gatekeeper training for university teachers in Japan.
Suicide is a leading cause of death among Japanese college and university students. Our previous study showed that the gatekeeper training (GKT) program significantly improved competence and confidence in the management of suicidal students in university administrative staff. However, we could not determine which component of the program was effective, nor if this program was effective for university teachers as well. In the current study, 81 university teachers were recruited; 63 of them received a general mental health lecture (MHL) and 18 of them received a 2.5 -h GKT program based on the Mental Health First Aid program. Competence and confidence in managing suicide intervention and behavioral intention as a gatekeeper were assessed by a self-report questionnaire before and immediately after the intervention. As a result, we found a significant improvement in competence in the management of suicidal students in the GKT group compared to the MHL group. We also found significant improvements in confidence in the management of suicidal students and behavioral intention as gatekeepers in the GKT group, although the questionnaires for these outcomes were not validated. The program satisfaction score was significantly higher in the GKT group than in the MHL group. To our knowledge, this is the first study to evaluate a GKT program for university teachers in Japan. By comparing the two groups, we explicitly confirmed that active involvement of the participants is crucial for effective suicide prevention training.


Formulating clinical strategies for angiotensin antagonism: a review of preclinical and clinical studies.
Extensive animal studies and a growing number of human clinical trials have now definitively demonstrated the central role of the renin-angiotensin-aldosterone system in the expression and modulation of cardiovascular disease. In contrast to the original hypothesis, the benefits of angiotensin antagonism do not emanate from the antihypertensive effect alone. Subsequent extensive investigations of angiotensin blockade suggest that the benefits of this approach may also result from the pharmacologic alteration of endothelial cell function and the ensuing changes in the biology of the vasculature. The more recent availability of direct antagonists of the AT(1) angiotensin receptor has introduced an element of doubt into this realm of clinical decision making. The receptor antagonists and the more widely studied converting-enzyme inhibitors share many endpoint attributes. Nevertheless, the partially overlapping mechanisms of action for the two classes of angiotensin antagonists confer distinct pharmacologic properties, including side effect profiles, mechanisms of action, and theoretic salutary effects upon the expression of cardiovascular disease. The current review will attempt to contrast the biology of angiotensin converting-enzyme inhibition with angiotensin II receptor antagonism. A discussion of the differential effects of these drug classes on endothelial cell function and on the modulation of vascular disease will be utilized to provide a theoretic framework for clinical decision making and therapeutics.


Predictors of personal, perceived and self-stigma towards anxiety and depression.
Stigma towards individuals experiencing a mental illness is associated with a range of negative psychological, social and financial outcomes. Factors associated with stigma remain unclear; the relationship between stigma and various personal factors may depend on both the type of disorder being stigmatised and what type of stigma is assessed. Different forms of stigma include personal stigma (negative attitudes towards others), perceived stigma (perceived attitudes of others) and self-stigma (self-attribution of others' negative attitudes). Three hundred and fifty university students and members of the general public completed an online survey assessing contact with and knowledge of both depression and anxiety, age, gender, current depression and anxiety symptoms, and personal, perceived and self-stigma for both depression and anxiety. Greater contact with, and knowledge of that illness predicted lower personal stigma for both anxiety and depression. Participants with greater levels of current depression symptomatology and females, reported higher perceived stigma towards depression. Males reported higher personal stigma for anxiety. For both anxiety and depression, higher current symptomatology was associated with greater levels of self-stigma towards the illness. Findings confirm the role of contact and knowledge in personal stigma for both disorders, consistent with previous findings. This finding also supports evidence that interventions addressing these factors are associated with a decline in personal stigma. However, lack of relationship between contact with, and knowledge of a mental illness and perceived and self-stigma for either depression or anxiety suggests that these factors may not play a major role in perceived or self-stigma. The identification of symptomatology as a key factor associated with self-stigma for both anxiety and depression is significant, and has implications for community-wide interventions aiming to increase help-seeking behaviour, as well as individual treatment strategies for clinicians. Further research should examine whether these relationships hold for groups with clinically diagnosed depression and anxiety disorders.


Albumin and procollagen type I gene regulation in alcohol and viral-induced human liver disease.
Common features of chronic alcoholic liver disease are progressive hypoalbuminemia and liver fibrosis. The molecular mechanisms which account for these effects are still controversial. Therefore, in the present study we evaluated albumin and collagen gene expression in livers of alcohol abusers and patients with viral-induced liver disease. Albumin and pro-alpha 1 (I) collagen mRNA levels were determined in 30 patients who underwent diagnostic liver biopsy. Of 14 alcoholics, 7 had alcoholic hepatitis alone, while the other 7 had cirrhosis plus alcoholic hepatitis. Of 16 non-alcoholic patients with chronic viral infection, 6 had chronic active hepatitis and 10 cirrhosis plus chronic active hepatitis. Total RNA was extracted from a portion of each biopsy, hybridized with a human albumin or collagen cDNA clone and compared to 2 normal surgical specimens which served as controls. The Northern hybridization studies revealed that: despite the presence of inflammation and fibrosis, the albumin mRNA levels of alcoholics were similar to normal controls; these alcoholics had significantly higher levels of albumin mRNA than did patients with similar histological stages of disease due to viral infection; and all the categories of patients had markedly increased procollagen mRNA levels when compared to controls. Given these results it is tempting to speculate that alcohol may actually increase albumin mRNA content in man as it does in animals. Furthermore, the increased procollagen mRNA levels in fibrotic livers suggest that an increase in collagen synthesis may be a significant factor in the pathogenesis of hepatic fibrosis.


Ticagrelor monotherapy beyond one month after PCI in ACS or stable CAD in elderly patients: a pre-specified analysis of the GLOBAL LEADERS trial.
Antiplatelet treatment in the elderly post percutaneous coronary interventions (PCI) remains a complex issue. Here we report the results of the pre-specified subgroup analysis of the GLOBAL LEADERS trial evaluating the long-term safety and cardiovascular efficacy of ticagrelor monotherapy among patients categorised according to the pre-specified cut-off value of 75 years of age. This was a pre-specified analysis of the randomised GLOBAL LEADERS trial (n=15,991), comparing 23-month ticagrelor monotherapy (after one month of DAPT) with the reference treatment (12-month DAPT followed by 12 months of aspirin). Among elderly patients (>75 years; n=2,565), the primary endpoint (two-year all-cause mortality or new Q-wave core lab-adjudicated myocardial infarction [MI]) occurred in 7.2% and 9.4% of patients in the ticagrelor monotherapy and the reference group, respectively (hazard ratio [HR] 0.75, 95% confidence interval [CI]: 0.58-0.99, p=0.041; pint=0.23); BARC-defined bleeding type 3/5 occurred in 5.2% and 4.1%, respectively (HR 1.29, 95% CI: 0.89-1.86; p=0.180; pint=0.06). The elderly with stable CAD had a higher rate of BARC 3/5 type bleeding (HR 2.05, 95% CI: 1.18-3.55) with ticagrelor monotherapy versus the reference treatment (pint=0.02). Elderly patients had a lower rate of definite or probable stent thrombosis (ST) with ticagrelor monotherapy (0.4% vs 1.4%, p=0.015, pint=0.01), compared with the reference group. In this pre-specified, exploratory analysis of the overall neutral trial, there was no differential treatment effect of ticagrelor monotherapy (after one-month dual therapy with aspirin) found in elderly patients undergoing PCI with respect to the rate of the primary endpoint of all-cause death or new Q-wave MI. The lower rate of ST in the elderly with ticagrelor monotherapy is hypothesis-generating. ClinicalTrials.gov identifier: NCT01813435.


Investigating Differences Between Drugs Used in the Australian Night-Time Economy: Demographics, Substance Use, and Harm.
Understanding the characteristics of drug users in the night-time economy (NTE), and whether particular drugs are associated with risky practices and experience of harm, is necessary to inform targeted policy responses in this context. To investigate the correlates of drugs used in the Australian NTE relating to demographics, alcohol use, and experience of harm. Patrons were interviewed in the NTE of five Australian cities in 2012-2013 (n = 7,028; 61.9% male, median age 22 years). A custom designed survey gathered demographic data, alcohol, and substance use on the current night, and experience of harm in/around licensed venues in the past 3 months. Multivariate logistic regression analyses examined the correlates of drug use. Ecstasy was most commonly reported (4.0%), followed by cannabis (2.9%), methamphetamine (2.6%), and cocaine (1.6%). Ecstasy users were more likely to be younger and report energy drink consumption. Cannabis users were more likely to be male, and to have been involved in intoxication-related accidents/injuries and sexual aggression in/around licensed venues in the past 3 months. Methamphetamine users were more likely to have been interviewed later, and to have engaged in pre-drinking. Cocaine users were more likely to be male, aged 21 years or more, have a blood alcohol concentration of greater than 0.10%, and to have been involved in intoxication-related accidents/injuries in the past three months. Conclusions/Importance: We identified significant differences between types of drug users and the harms they experience, underscoring the need to develop innovative harm reduction policies in the NTE rather than blanket population-based approaches.


Seroprevalence of Hepatitis B Among HIV-infected Children and Adolescents Receiving Antiretroviral Therapy in the TREAT Asia Pediatric HIV Observational Database.
Hepatitis B (HBV)-HIV coinfection is associated with liver inflammation, which can progress to liver fibrosis/cirrhosis and hepatocellular carcinoma. We determined HBV seroprevalence in children and adolescents participating in the TREAT Asia Pediatric HIV Observational Database. A multisite cross-sectional study was conducted in HIV-infected patients currently <25 years old receiving antiretroviral treatment (ART) who had HBV surface antigen (HBsAg), or HBV surface antibody (anti-HBs) or HBV core antibody (anti-HBc) tested during 2012-2013. HBV coinfection was defined as having either a positive HBsAg test or being anti-HBc positive and anti-HBs negative, reflective of past HBV infection. HBV seroprotection was defined as having a positive anti-HBs test. A total of 3380 patients from 6 countries (Vietnam, Thailand, Cambodia, Malaysia, Indonesia and India) were included. The current median (interquartile range) age was 11.2 (7.8-15.1) years. Of the 2755 patients (81.5%) with HBsAg testing, 130 (4.7%) were positive. Of 1558 (46%) with anti-HBc testing, 77 (4.9%) were positive. Thirteen of 1037 patients with all 3 tests were anti-HBc positive and HBsAg and anti-HBs negative. One child was positive for anti-HBc and negative for anti-HBs but did not have HBsAg tested. The prevalence of HBV coinfection was 144/2759 (5.2%) (95% confidence interval: 4.4-6.1). Of 1093 patients (32%) with anti-HBs testing, 257 (23.5%; confidence interval: 21.0-26.0) had positive tests representing HBV seroprotection. The estimated prevalence of HBV coinfection in this cohort of Asian HIV-infected children and adolescents on ART was 5.2%. The majority of children and adolescents tested in this cohort (76.5%) did not have protective HBV antibody. The finding supports HBV screening of HIV-infected children and adolescents to guide revaccination, the use of ART with anti-HBV activity and future monitoring.


Magnesium therapy for nephrolithiasis.
Critically evaluate the experimental evidence and clinical trial outcomes as the basis for use of magnesium (Mg) supplements as therapy for calcium oxalate nephrolithiasis. Literature search of MedLine and Web of Science through January 2005; articles cited in papers found by searches. Magnesium inhibits calcium oxalate crystallization in human urine and model systems. Magnesium also inhibits absorption of dietary oxalate from the gut lumen. Three early trials of Mg oxide (MgO) and Mg hydroxide (Mg(OH)2) reported lower rates of recurrent stone formation. However in a double-blind, randomized, placebo-controlled trial with more carefully selected patients, there was no significant difference between recurrence rates with 650 or 1300 mg MgO daily and the placebo. Another trial reported 391 mg (21 meq) Mg daily as a mixed salt, Mg potassium citrate, reduced calcium stone recurrence by 90%, similar to potassium citrate, but with better gastrointestinal tolerance. The failure of MgO and Mg(OH)2 as sole therapy may be related to poor absorption and low rates of Mg deficiency in the patient populations tested. Clinical trial evidence does not justify the use of MgO or Mg(OH)2 as a sole therapy for calcium oxalate kidney stones in a general patient population. However, the addition of magnesium to potassium citrate therapy improves outcomes. Clinical trials should focus on patients who are likely to be Mg deficient.


Irreversible thermal denaturation of bovine pancreatic ribonuclease-A. Physico-chemical characterization of initial products.
The isolation and characterization of the products formed during the irreversible thermal denaturation of enzyme RNAase-A are described. RNAase-A, when maintained in aqueous solution at pH 7.0 and 70 degrees for 2 h, gives soluble products which have been fractionated by gel filtration on Sephadex G-75 into four components. These components are designated RNAase-At1, RNAase-At2, RNAase-At3 and RNAase-At4 according to the order of their elution from Sephadex G-75. RNAase-At4 shows the same specific activity towards yeast RNA as native RNAase-A and is virtually indistinguishable from it by the physical methods employed. However, chromatography on CM-cellulose separates it into three components that show the same u.v. spectra and specific activity towards yeast RNA as native RNAase-A. RNAase-At1, RNAase-At2 and RNAase-At3 are all structurally altered derivatives of RNAase-A and they exhibit low specific activity (5-10%) towards yeast RNA. In the presence of added S-protein, all these derivatives show greatly enhanced enzymic activity. RNAase-At1 and RNAase-At2 are polymers, covalently crosslinked by intermolecular disulfide bridges; whereas RNAase-At3 is a monomer. Physical studies such as 1H-n.m.r., sedimentation analysis, u.v. absorption spectra and CD spectra reveal that RNAase-At3 is a unfolded derivative of RNAase-A. However, it is seen to possess sufficient residual structure which gives rise to a low but easily detectable enzymic activity.


Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis.
Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment. MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs. This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.


Lessons for cardiac regeneration and repair through development.
Cell-based regenerative strategies have the potential to revolutionize the way cardiovascular injury is treated, but successful therapies will require a precise understanding of the mechanisms that dictate cell fate, survival and differentiation. Recent advances in the study of cardiac development hold promise for unlocking the keys for successful therapies. Using mouse models and embryonic stem cells, researchers are uncovering cardiac progenitor cells in both embryonic and adult contexts. Furthermore, the signaling molecules and transcriptional regulators that govern these cells and their behavior are being revealed. Here, we focus on the recent advances in these areas of cardiac developmental research and their impact on the expanding field of regenerative medicine.


Regulation of hepcidin expression at high altitude.
Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores.


Survey of subjective "God encounter experiences": Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT.
Naturally occurring and psychedelic drug-occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared. In this study, five groups of individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1184 psilocybin, 1251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. The Non-Drug Group was most likely to choose "God" as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose "Ultimate Reality." Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking. Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in approximately half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience. Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.


Assembly of a tile-based multilayered DNA nanostructure.
The Watson-Crick complementarity of DNA is exploited to construct periodically patterned nanostructures, and we herein demonstrate tile-based three dimensional (3D) multilayered DNA nanostructures that incorporate two design strategies: vertical growth and horizontal layer stacking with substrate-assisted growth. To this end, we have designed a periodically holed double-double crossover (DDX) template that can be used to examine the growth of the multilayer structures in both the vertical and horizontal directions. For vertical growth, the traditional 2D double crossover (DX) DNA lattice is seeded and grown vertically from periodic holes in the DDX template. For horizontal stacking, the DDX layers are stacked by binding the connector tiles between each layer. Although both types of multilayers exhibited successful formation, the observations with an atomic force microscope indicated that the DDX layer growth achieved with the horizontal stacking approach could be considered to be slightly better relative to the vertical growth of the DX layers in terms of uniformity, layer size, and discreteness. In particular, the newly designed DDX template layer provided a parallel arrangement between each domain with substrate-assisted growth. This kind of layer arrangement suggests a possibility of using our design scheme in the construction of other periodic structures.


Outcomes after internal versus external tocodynamometry for monitoring labor.
It has been hypothesized that internal tocodynamometry, as compared with external monitoring, may provide a more accurate assessment of contractions and thus improve the ability to adjust the dose of oxytocin effectively, resulting in fewer operative deliveries and less fetal distress. However, few data are available to test this hypothesis. We performed a randomized, controlled trial in six hospitals in The Netherlands to compare internal tocodynamometry with external monitoring of uterine activity in women for whom induced or augmented labor was required. The primary outcome was the rate of operative deliveries, including both cesarean sections and instrumented vaginal deliveries. Secondary outcomes included the use of antibiotics during labor, time from randomization to delivery, and adverse neonatal outcomes (defined as any of the following: an Apgar score at 5 minutes of less than 7, umbilical-artery pH of less than 7.05, and neonatal hospital stay of longer than 48 hours). We randomly assigned 1456 women to either internal tocodynamometry (734) or external monitoring (722). The operative-delivery rate was 31.3% in the internal-tocodynamometry group and 29.6% in the external-monitoring group (relative risk with internal monitoring, 1.1; 95% confidence interval [CI], 0.91 to 1.2). Secondary outcomes did not differ significantly between the two groups. The rate of adverse neonatal outcomes was 14.3% with internal monitoring and 15.0% with external monitoring (relative risk, 0.95; 95% CI, 0.74 to 1.2). No serious adverse events associated with use of the intrauterine pressure catheter were reported. Internal tocodynamometry during induced or augmented labor, as compared with external monitoring, did not significantly reduce the rate of operative deliveries or of adverse neonatal outcomes. (Current Controlled Trials number, ISRCTN13667534; Netherlands Trial number, NTR285.)


Second cancer following cancer of the digestive system in Connecticut, 1935-82.
The risk of developing a second primary cancer was evaluated in approximately 64,000 persons diagnosed with cancer of the digestive system in Connecticut during 1935-82. Significant excesses of all second cancers combined were observed following cancer of the esophagus (58 observed vs. 33 expected), small intestine (41 vs. 24), and colon (2,268 vs. 1,714). A slight excess of multiple primaries was observed following cancer of the liver and biliary tract (47 vs. 40). The observed number of second cancers was nearly equal to the expected number for persons initially diagnosed with cancers of the stomach (251 vs. 258), rectum (952 vs. 941), and pancreas (40 vs. 40). Persons with initial cancers of the small intestine, colon, and rectum also had excess second cancers arising primarily in the colon, which suggested the influence of common etiologic factors or possibly misclassified metastases in some. Shared dietary, socioeconomic, or hormonal factors may explain the excess of uterine and ovarian cancers among patients with colon cancer and the excess of breast cancer among patients with colon and rectal cancers. Oral and respiratory cancers occurred more frequently than expected in persons with an initial esophageal cancer, which is likely due to common risk factors of cigarette smoking or alcohol intake, or both. The elevations in cancer of the prostate among males with cancers of the esophagus, small intestine, colon, rectum, liver/biliary, and pancreas are probably artifacts associated with increased medical surveillance of cancer patients. The prostate cancer excesses were limited to the first year after diagnosis of the initial cancer or decreased over time for all but cancer of the colon and small intestines. Increased medical surveillance may also contribute to the excess renal and bladder cancers seen within 5 years of diagnosis of stomach cancer. Excesses were also seen for second pancreatic cancer among small intestine and liver/biliary cancer patients and second kidney and brain cancers among those with colon cancer. The deficits of stomach and rectal cancer among persons initially diagnosed with the same tumors, respectively, were anticipated because surgical removal of the organ is the primary form of treatment. Patients with rectal cancer also had deficits of stomach and pancreatic cancers. Future research should clarify the role of diet, alcohol, metabolic and endocrine factors, and host susceptibility on the risk of second neoplasms following cancer of the digestive system.


Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM-1) kinase.
The kinase PIM-1 plays a pivotal role in cytokine signaling and is implicated in the development of a number of tumors. The three-dimensional structure of PIM-1 is characterized by an unique hinge region which lacks a second hydrogen bond donor and makes it particularly important to determine how inhibitors bind to this kinase. We determined the structures of PIM-1 in complex with bisindolylmaleimide (BIM-1) and established the structure-activity relationship (SAR) for this inhibitor class. In addition, we screened a kinase targeted library and identified a number of high affinity inhibitors of PIM-1 such as imidazo[1,2-b]pyridazines, pyrazolo[1,5-a]pyrimidines, and members of the flavonoid family. In this paper we present an initial SAR of the identified scaffolds determined on the basis of a thermostability shift assay, calorimetric binding data, and biochemical assays which may find applications for the treatment of PIM-1 dependent cancer types.


Selective inhibition of BET bromodomains.
Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.


Unplanned return to theater: A quality of care and risk management index?
Surgical quality and risk management is a major public health issue. The consequences of unplanned return to theater are social, occupational, financial and even legal. Unscheduled revision surgery is a major adverse event, resulting from serious complications - some of which are thought to be avoidable. The present study sought to assess and analyze the incidence of unplanned return to theater in an orthopedic surgery department. The study hypothesis was that some of the complications involved could be avoided. A mixed retrospective-prospective study examined a consecutive series of 10,158 patients operated on in an orthopedic and traumatologic surgery department between January 2011 and December 2013. Patients undergoing revision surgery for reasons directly related to the primary procedure were analyzed. Patients were distributed among the following subgroups: infection, implant dislocation; hemorrhagic complication, mechanical complication, problem of primary technique, stiffness, wound healing disorder. Specific indicators of dysfunction liable to have contributed to onset of the complication were applied in each subgroup, to determine the avoidable or unavoidable nature of the event. Two hundred and twenty-four patients (2.2%) underwent revision surgery for reasons directly related to the primary procedure. One hundred and eight cases (48.2%) were considered to have been avoidable: 48 infections (21.4%), 27 implant dislocations (12%), 15 hemorrhagic complications (6.7%), 66 mechanical complications (29.5%), 35 technical problems at primary surgery (15.6%), 21 cases of stiffness (9.3%), and 12 cases of delayed wound healing (5.3%). Mean time to revision surgery was 2.7 ± 2.6 months. Extending the time-window to 1 year recruited extra cases: in 31.7% of cases, onset was after the 90th postoperative day, which is the usual deadline. The rate of unplanned return to theater was higher after unscheduled (traumatic: 3.2%) than scheduled surgery (1.7%, P < 0.001). Return to surgery in orthopedic and traumatologic surgery is underestimated. Annual incidence was 2.2%, and twice as high (3.2%) following traumatologic compared to scheduled surgery (1.7%). Analysis found that almost half the cases were avoidable. They represent a relevant and easily assessed indicator of treatment quality and associated risk management. A national or even international database in the form of an anonymous registry of revision surgeries would be useful.


Optimising frontline learning and engagement between consultant-led neonatal teams in the West Midlands: a survey on the utility of an augmented simulation training technique.
In England, neonatal care is delivered in operational delivery networks, comprising a combination of the Neonatal Intensive Care (NICU), Local-Neonatal (LNU) or Special-Care Units (SCU), based on their ability to care for babies with different degrees of illness or prematurity. With the development of network care pathways, the most premature and sickest are mostly triaged for delivery in services linked to NICU. This has created anxiety for teams in LNU and SCU. Less exposure to sicker babies has resulted in limited opportunities to maintain expertise for when these babies unexpectedly deliver at their centre and thereafter require transfer for care, to NICU. Simultaneously, LNU and SCU teams develop skills in the care of the less ill and premature baby which would also be of benefit to NICU teams. A need for mutual learning through inter-unit multidirectional collaborative learning and engagement (hereafter also called neonatal networking) between teams of different designations emerged. Here, neonatal networking is defined as collaboration, shared clinical learning and developing an understanding of local systems strengths and challenges between units of different and similar designations. We describe the responses to the development of a clinical and systems focussed platform for this engagement between different teams within our neonatal ODN. An interactive 1-day programme was developed in the West Midlands, focussing on a non-hierarchical, equal partnership between neonatal teams from different unit designations. It utilised simulation around clinical scenarios, with a slant towards consultant engagement. Four groups rotating through four clinical simulation scenarios were developed. Each group participated in a clinical simulation scenario, led by a consultant and supported by nurses and doctors in training together with facilitators, with a further ~two consultants, as observers within the group. All were considered learners. Consultant candidates took turns to be participants and observers in the simulation scenarios so that at the end of the day all had led a scenario. Each simulation-clinical debrief session was lengthened by a further ~ 20 min, during which freestyle discussion with all learners occurred. This was to promote further bonding, through multidirectional sharing, and with a systems focus on understanding the strengths and challenges of practices in different units. A consultant focus was adopted to promote a long-term engagement between units around shared care. There were four time points for this neonatal networking during the course of the day. Qualitative assessment and a Likert scale were used to assess this initiative over 4 years. One hundred fifty-five individuals involved in frontline neonatal care participated. Seventy-seven were consultants, supported by neonatal trainees, staff grade doctors, clinical fellows, advanced neonatal nurse practitioners and nurses in training. All were invited to participate in the survey. The survey response rate was 80.6%. Seventy-nine percent felt that this learning strategy was highly relevant; 96% agreed that for consultants this was appropriate adult learning. Ninety-eight percent agreed that consultant training encompassed more than bedside clinical management, including forging communication links between teams. Thematic responses suggested that this was a highly useful method for multi-directional learning around shared care between neonatal units. Simulation, enhanced with systems focussed debrief, appeared to be an acceptable method of promoting multidirectional learning within neonatal teams of differing designations within the WMNODN.


Development and characterization of 20 polymorphic microsatellite markers for Epinephelus marginatus (Lowe, 1834) (Perciformes: Epinephelidae) using 454 pyrosequencing.
The dusky grouper, Epinephelus marginatus, is a well-known and widespread marine fish assessed as endangered by the International Union for the Conservation of Nature. Analyzing the genetic diversity of this species is, therefore, of utmost importance and necessary for conservation purposes. Microsatellites are molecular tools with advantages that are ideal for population analyses. This study provides the first set of species-specific microsatellite loci for E. marginatus that can be applied when assessing both intra- and interpopulation genetic variation. Twenty microsatellite loci were isolated and characterized for the dusky grouper by genotyping 20 individuals obtained from the North Eastern Atlantic Ocean (n = 4) and from the South Western Atlantic Ocean (n = 16). The number of alleles per locus varied from 2 to 11, while the observed and expected heterozygosities ranged from 0.25 to 0.94 and 0.34 to 0.89, respectively. The polymorphic information content varied from moderately to highly informative. This suite of markers provides the first specific nuclear tools for E. marginatus and, thus, allows to assess with more specificity different populations' structures.


Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction.
Chronic caloric restriction (CR) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. Despite the differences in the implementation of CR, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. In this review, we define these modifications and systematically summarize the current evidence related to CR and the epigenome. We then explain the significance of genome-wide epigenetic modifications in the context of disease development. Although substantial evidence exists for the widespread effect of CR on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellular mechanisms that lead to improved health. We provide compelling evidence that CR produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.


Roles of sodium, potassium, calcium, and natriuretic factors in hypertension.
This review first summarizes evidence from animals and humans for and against a role for dietary sodium in the genesis and treatment of hypertension. The evidence for its role is strongest in those subjects with impaired ability to excrete sodium because of organic renal disease or mineralocorticoid excess. Here, restriction of dietary sodium promptly lowers pressure. Its role in the genesis of essential hypertension is more controversial. Nevertheless, it appears that some patients with mild to moderate essential hypertension respond to moderate sodium restriction with a modest fall in pressure. This restriction also seems to reduce the amount of antihypertensive medication needed to keep pressure under control. Next, the mechanism of the pressure response to dietary sodium chloride is considered, with emphasis on potassium depletion and increased plasma levels of prohypertensive sodium pump inhibitor and antihypertensive atrial natriuretic peptide. The evidence for a primary role for dietary potassium in the genesis of hypertension then is summarized; certain subsets of subjects with a high incidence of hypertension also have a lower potassium intake. Some investigators have found that dietary potassium supplementation lowers pressure in established hypertension. This may result from natriuresis and from vasodilation subsequent to stimulation of Na+,K(+)-ATPase in vascular smooth muscle and adrenergic nerve terminals. After the role of dietary calcium is discussed, practical aspects of dietary sodium restriction and dietary potassium supplementation in the therapy for established hypertension are considered. The review concludes with comments on their possible roles in the prevention of hypertension.


Synthesis, Crystal Structure and Green Luminescence in Zero-Dimensional Tin Halide (C8H14N2)2SnBr6.
Organic-inorganic hybrid metal halides with broad-band emission are currently receiving an increasing interest for their unique light emission properties. Here we report a novel lead-free zero-dimensional (0D) tin halide, (C8H14N2)2SnBr6, in which isolated [SnBr6]4- octahedrons are cocrystallized with organic cations, 1,3-bis(aminomethyl)benzene (C8H14N22+). Upon photoexcitation, the bulk crystals exhibit broad-band green emission peaking at 507 nm with a full width at half-maximum (fwhm) of 82 nm (0.395 eV), a Stokes shift of 157 nm (1.09 eV), and a photoluminescence quantum yield (PLQY) of 36 ± 4%. Combined structural analysis and density functional theory (DFT) calculations indicate that the excited state structural distortion of [SnBr6]4- octahedral units account for the formation of this green emission. The relatively small Stokes shift and narrow fwhm of the emission are hence caused by the reduced distortion of [SnBr6]4- octahedrons and rigid molecular structure. The discovery of lead-free (C8H14N2)2SnBr6 and insight into the mechanism of green emission provide an essential platform toward unveiling the relationship between structure and property for 0D metal halide perovskites.


Effect of exogenous circulating anti-bPL antibodies on bovine placental lactogen measurements in foetal samples.
The involvement of placental lactogen (PL) in the regulation of foetal growth has been investigated in different species by in vivo immunomodulation techniques. However, when circulating antibodies are present together with the hormone, the procedure for hormonal measurement becomes considerably complex. The aim of this study was the immunoneutralization of bovine placental lactogen (bPL) concentrations in bovine foetal circulation by direct infusion of rabbit anti-bPL purified immunoglobulins (IgG) via a foetal catheter (in vivo study). The ability of a RIA based on guinea pig anti-bPL antiserum, for the measurement of bPL concentrations in samples containing exogenous rabbit anti-bPL immunoglobulins, was also analyzed in in vitro and in vivo conditions. Six bovine foetuses were chronic cannulated on the aorta via the medial tarsal artery. Infusion of rabbit anti-bPL IgG was performed during late gestation. Pooled rabbit anti-bPL antisera had a maximal neutralization capacity of 25 microg bPL/mL of immunoglobulin. Interference of rabbit anti-bPL immunoglobulin with radioimmunoassay measurement using guinea pig anti-bPL as primary antibody was first evaluated in vitro. Polyclonal anti-bPL antibodies raised in rabbit were added in foetal sera to produce 100 samples with known antibodies titers (dilutions ranging from 1:2,500 till 1:1,280,000). Assessment of the interference of rabbit anti-bPL antibody showed that bPL concentrations were significantly lower (P < 0.05) in samples added with dilutions of rabbit antiserum lower than 1:80,000 (one foetus) or 1:10,000 (four foetuses). It was also shown that the recovery of added bPL (12 ng/mL) was markedly reduced in those samples in which exogenous rabbit anti-bPL were added at dilutions lower than 1:20,000. Concentrations of foetal bPL were determined in samples from cannulated foetuses. In foetuses 1 and 6, bPL concentrations remained almost unchanged (<5 ng/mL) during the whole experimental period. In Foetus 3, bPL concentrations decreased immediately after IgG infusion and thereafter, they increased until parturition. The use of a bPL RIA using a guinea pig anti-bPL as primary antiserum allowed for the measurement of bPL concentrations in foetal plasma in presence of rabbit anti-bPL IgG into the foetal circulation. Long-term foetal catheterization allowed for the study of the influence of direct infusion of anti-bPL IgG on peripheral bPL concentrations in bovine foetuses.


Kernel fisher discriminants for outlier detection.
The problem of detecting atypical objects or outliers is one of the classical topics in (robust) statistics. Recently, it has been proposed to address this problem by means of one-class SVM classifiers. The method presented in this letter bridges the gap between kernelized one-class classification and gaussian density estimation in the induced feature space. Having established the exact relation between the two concepts, it is now possible to identify atypical objects by quantifying their deviations from the gaussian model. This model-based formalization of outliers overcomes the main conceptual shortcoming of most one-class approaches, which, in a strict sense, are unable to detect outliers, since the expected fraction of outliers has to be specified in advance. In order to overcome the inherent model selection problem of unsupervised kernel methods, a cross-validated likelihood criterion for selecting all free model parameters is applied. Experiments for detecting atypical objects in image databases effectively demonstrate the applicability of the proposed method in real-world scenarios.


What is normal vaginal flora?
To observe the composition of the vaginal flora of healthy women over time, and in relation to hormonal changes, sexual activity, and hygiene habits. A longitudinal surveillance of the vaginal flora over an eight week period. 26 female health care workers in local genitourinary medicine clinics. The participants were anonymised. They filled in diary cards daily. Blind vaginal swabs were self-taken two-seven times weekly. A smear was air-dried for later Gram staining. The swabs were also cultured for Candida spp, Gardnerella vaginalis, anaerobes, Mycoplasma hominis and Ureaplasma urealyticum. Of 26 subjects, only four had normal vaginal microbiology throughout. One woman, who was not sexually active, had bacterial vaginosis (BV) throughout and nine (35%) had intermittent BV. Candidiasis was found intermittently in eight women (31%), and eight had normal microscopy. U urealyticum was isolated intermittently in 40% of women with BV, 25% with candida, and 50% with normal microscopy. Many women were symptomatic, but symptoms correlated poorly with microbiological findings. All but two women were sexually active; however, more women with BV were exposed to semen. BV seemed to be related to frequent use of scented soap, and there appeared to be an additive effect of clothing and hygiene factors. Our study raises doubts about what should be regarded as normal vaginal flora. It calls into question the significance of finding BV or U urealyticum on a single occasion in asymptomatic women, or of finding normal flora in symptomatic women. The effect of external factors on the vaginal flora deserve further study.