Direct benefits and evolutionary transitions to complex societies.
The selective forces that drive the evolution of cooperation have been intensely debated. Evolutionary transitions to cooperative breeding, a complex form of cooperation, have been hypothesized to be linked to low degrees of promiscuity, which increases intragroup relatedness and the indirect (that is, kin selected) benefits of helping. However, ecological factors also promote cooperative breeding, and may be more important than relatedness in some contexts. Identifying the key evolutionary drivers of cooperative breeding therefore requires an integrated assessment of these hypotheses. Here we show, using a phylogenetic framework that explicitly evaluates mating behaviours and ecological factors, that evolutionary transitions to cooperative breeding in cichlid fishes were not associated with social monogamy. Instead, group living, biparental care and diet type directly favoured the evolution of cooperative breeding. Our results suggest that cichlid fishes exhibit an alternative path to the evolution of complex societies compared to other previously studied vertebrates, and these transitions are driven primarily by direct fitness benefits.


Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study.
Since 1990, the recommended adjuvant therapy for patients with surgically resected node-positive colon cancer has been 5-fluorouracil (5-FU), usually in combination with leucovorin or levamisole. The purpose of this study is to assess the distribution of adjuvant 5-FU treatment in the elderly. The Surveillance, Epidemiology and End Results-Medicare database provides population-based information on cancer patients, representing approximately 14% of the United States population, along with health care utilization data from Medicare claims files. We studied patients with node-positive colon cancer diagnosed between 1992 and 1996 who survived at least 120 days beyond diagnosis (N = 4998). About 50% of elderly patients received 5-FU within 4 months of diagnosis. The proportion of patients treated with 5-FU increased by about 10% from 1992 to 1996. In a multiple logistic regression model, 5-FU treatment was less likely to be given to older patients (compared with those aged 65-69 years, the odds ratio (OR) [95% CI] was 0.82 [0.67-1.00] for ages 70 to 74 years, 0.47 [0.39-0.57] for ages 75 to 79, 0.17 [0.13-0.20] for ages 80 to 84, and 0.04 [0.03-0.05] for ages 85 to 88 years. Non-Hispanic black patients were less likely to be treated than non-Hispanic white patients (OR 0.46 [0.36-0.59]); patients with more than three positive lymph nodes were more likely to be treated than those with three or less, and those with comorbid conditions were less likely to be treated than those without such conditions. Despite its proven efficacy in reducing colon cancer mortality, 5-FU-based chemotherapy is not widely used among apparently eligible patients over age 65. Efforts are needed to ensure that elderly and non-Hispanic black patients receive appropriate treatment.


Estimation of hepatitis C virus infections resulting from vertical transmission in Egypt.
Despite having the highest hepatitis C virus (HCV) prevalence in the world, the ongoing level of HCV incidence in Egypt and its drivers are poorly understood. Whereas HCV mother-to-child infection is a well-established transmission route, there are no estimates of HCV infections resulting from vertical transmission for any country, including Egypt. The aim of this study was to estimate the absolute number of new HCV infections resulting from vertical transmission in Egypt. We developed a conceptual framework of HCV vertical transmission, expressed in terms of a mathematical model and based on maternal HCV antibody and viremia. The mathematical model estimated the number of HCV vertical infections nationally and for six subnational areas. Applying two vertical transmission risk estimates to the 2008 Egyptian birth cohort, we estimated that between 3,080 and 5,167 HCV infections resulted from vertical transmission among children born in 2008. HCV vertical transmission may account for half of incident cases in the <5-year age group. Disproportionately higher proportions of vertical infections were estimated in Lower Rural and Upper Rural subnational areas. This geographical clustering was a result of higher-area-level HCV prevalence among women and higher fertility rates. Vertical transmission is one of the primary HCV infection routes among children<5 years in Egypt. The absolute number of vertical transmissions and the young age at infection highlight a public health concern. These findings also emphasize the need to quantify the relative contributions of other transmission routes to HCV incidence in Egypt.


A hormone and proteome approach to picturing the initial metabolic events during Plasmodiophora brassicae infection on Arabidopsis.
We report on the early response of Arabidopsis thaliana to the obligate biotrophic pathogen Plasmodiophora brassicae at the hormone and proteome level. Using a CYCB1;1::GUS construct, the re-initiation of infection-related cell division is shown from 4 days after inoculation on. Sensitivity to cytokinins and auxins as well as the endogenous hormone levels are evaluated. Both an enhanced cytokinin gene response and an accumulation of isopentenyl adenine and adenosine precede this re-initiation of cell division, whereas an enhanced auxin gene response is observed from 6 days after inoculation on. The alhl mutant, impaired in the cross talk between ethylene and auxins, is resistant to P. brassicae. A differential protein analysis of infected versus noninfected roots and hypocotyls was performed using two-dimensional gel electrophoresis and quantitative image analysis, coupled to matrix-assisted laser desorption ionization time of flight-time of flight mass spectrometry-based protein identification. Of the visualized proteins, 12% show altered abundance compared with the noninfected plants, including proteins involved in metabolism, cell defense, cell differentiation, and detoxification. Combining the hormone and proteome data, we postulate that, at the very first stages of Plasmodiophora infection, plasmodial-produced cytokinins trigger a local re-initiation of cell division in the root cortex. Consequently, a de novo meristematic area is established that acts as a sink for host-derived indole-3-acetic acid, carbohydrates, nitrogen, and energy to maintain the pathogen and to trigger gall development.


Dietary nitrate reduces skeletal muscle oxygenation response to physical exercise: a quantitative muscle functional MRI study.
Dietary inorganic nitrate supplementation (probably via conversion to nitrite) increases skeletal muscle metabolic efficiency. In addition, it may also cause hypoxia-dependent vasodilation and this has the potential to augment oxygen delivery to exercising skeletal muscle. However, direct evidence for the latter with spatial localization to exercising muscle groups does not exist. We employed quantitative functional MRI (fMRI) to characterize skeletal muscle oxygen utilization and replenishment by assessment of tissue oxygenation maximal change and recovery change, respectively. Eleven healthy subjects were enrolled, of whom 9 (age 33.3 ± 4.4 years, five males) completed the study. Each subject took part in three MRI visits, with dietary nitrate (7cl concentrated beetroot juice) consumed before the third visit. During each visit fMRIs were conducted concurrently with plantar flexion exercise at workloads of 15% and 25% maximum voluntary contraction (MVC). No significant changes were found between visits 1 and 2 in the fMRI measures. A decrease in maximal change was found at 15% MVC in soleus between visits 2 and 3 (5.12 ± 2.36 to 2.55 ± 1.42, P = 0.004) and between visits 1 and 3 (4.43 ± 2.12 to 2.55 ± 1.42, P = 0.043), but not at 25% MVC or within gastrocnemius. There was no difference in recovery change between visits. We found that dietary nitrate supplementation reduces tissue oxygenation alterations during physical exercise in skeletal muscle. This effect is more prominent in muscles with predominantly type 1 fibers and at lower workloads. This indicates that in healthy subjects dietary nitrate predominantly affects skeletal muscle energy efficiency with no change in oxygen delivery.


Understanding Care Linkage and Engagement Across 15 Adolescent Clinics: Provider Perspectives and Implications for Newly HIV-Infected Youth.
The National HIV/AIDS Strategy emphasizes rapid care linkage and engagement for HIV-infected individuals, though many adolescents are never tested, delay entering care, and frequently drop out. We conducted 183 staff interviews at 15 adolescent medicine clinics (baseline, n = 64; Year 1, n = 60; Year 2, = 59). We used a constant comparative thematic method to examine how providers approached and discussed care linkage/engagement. Qualitative analyses revealed differences in providers' conceptualizations of linkage and engagement. Providers saw linkage as mechanistic and health system driven. It was defined by number of clinic visits and involved relatively little youth agency. In contrast, providers defined engagement by youths' responsibility and participation in their own care. Linkage and engagement are related but distinct aspects of care that require different resources and levels of staff involvement. Integrating an understanding of these differences into future interventions will allow clinic staff to help youth improve long-term health outcomes.


The phosphorylation of coated membrane proteins in intact neurons.
To complement studies that have demonstrated the prominent phosphorylation of a 50-kD coated vesicle polypeptide in vitro, we have evaluated the phosphorylation of coated membrane proteins in intact cells. A co-assembly assay has been devised in which extracts of cultured rat sympathetic neurons labeled with [32P]-Pi were combined with unlabeled carrier bovine brain coat proteins and reassembled coat structures were isolated by gradient centrifugation. Two groups of phosphorylated polypeptides, of 100-110 kD (pp100-110) and 155 kD (pp155) apparent molecular mass, were incorporated into reassembled coats. The neuronal pp100-110 are structurally and functionally related to the 100-110-kD component of the bovine brain assembly protein (AP), a protein complex that also contains 50-kD and 16.5-kD components and is characterized by its ability to promote the reassembly of clathrin coat structures under physiological conditions of pH and ionic strength (Zaremba, S. and J. H. Keen, 1983, J. Cell Biol., 97:1337-1348). The neuronal pp155 detected in reassembled coat structures was readily observable in total extracts of [32P]-Pi-labeled neurons dissolved in SDS-containing buffer. A bovine brain counterpart to the neuronal pp155 was also observed when brain coated vesicles were subjected to two-dimensional gel electrophoresis. Phosphoserine was the predominant phosphoaminoacid found in both the pp100 and pp155. A structural and functional counterpart to the 50-kD brain assembly polypeptide (AP50) was also identified in these neurons. Although the brain AP50 is prominently phosphorylated by an endogenous protein kinase in isolated coated vesicle preparations, the neuronal AP50 was not detectably phosphorylated in intact cells as assessed by two-dimensional non-equilibrium pH gradient gel electrophoresis of labeled cells dissolved directly in SDS-containing buffers. These results demonstrate that the bovine brain assembly polypeptides of 50 kD and 100-110 kD that we have previously described, as well as a novel 155-kD polypeptide reported here, have structural and functional counterparts in cultured neurons. They also indicate that phosphorylation of the 100-110-kD AP may be involved in the regulation of coated membrane structure and function. The extent of phosphorylation of the AP50 in intact cells and in isolated coated vesicles is strikingly different: it has been suggested that the latter process reflects an autophosphorylation reaction (Campbell C., J. Squicciarini, M. Shia, P. F. Pilch, and R. E. Fine, 1984, Biochemistry, 23:4420-4426).(ABSTRACT TRUNCATED AT 400 WORDS)


A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts.
intra-abdominal candidiasis (IAC) may include Candida involvement of peritoneum or intra-abdominal abscess and is burdened by high morbidity and mortality rates in surgical patients. Unfortunately, international guidelines do not specifically address this particular clinical setting due to heterogeneity of definitions and scant direct evidence. In order to cover this unmet clinical need, the Italian Society of Intensive Care and the International Society of Chemotherapy endorsed a project aimed at producing practice recommendations for the management of immune-competent adult patients with IAC. A multidisciplinary expert panel of 22 members (surgeons, infectious disease and intensive care physicians) was convened and assisted by a methodologist between April 2012 and May 2013. Evidence supporting each statement was graded according to the European Society of Clinical Microbiology and Infection Diseases (ESCMID) grading system. Only a few of the numerous recommendations can be summarized in the Abstract. Direct microscopy examination for yeast detection from purulent and necrotic intra-abdominal specimens during surgery or by percutaneous aspiration is recommended in all patients with nonappendicular abdominal infections including secondary and tertiary peritonitis. Samples obtained from drainage tubes are not valuable except for evaluation of colonization. Prophylactic usage of fluconazole should be adopted in patients with recent abdominal surgery and recurrent gastrointestinal perforation or anastomotic leakage. Empirical antifungal treatment with echinocandins or lipid formulations of amphotericin B should be strongly considered in critically ill patients or those with previous exposure to azoles and suspected intra-abdominal infection with at least one specific risk factor for Candida infection. In patients with nonspecific risk factors, a positive mannan/antimannan or (1→3)-β-D-glucan (BDG) or polymerase chain reaction (PCR) test result should be present to start empirical therapy. Fluconazole can be adopted for the empirical and targeted therapy of non-critically ill patients without previous exposure to azoles unless they are known to be colonized with a Candida strain with reduced susceptibility to azoles. Treatment can be simplified by stepping down to an azole (fluconazole or voriconazole) after at least 5-7 days of treatment with echinocandins or lipid formulations of amphotericin B, if the species is susceptible and the patient has clinically improved. Specific recommendations were elaborated on IAC management based on the best direct and indirect evidence and on the expertise of a multinational panel.


A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas.
The complex events by which digestive enzyme zymogens and lysosomal hydrolases are segregated from each other and differentially transported to their respective membrane-bound intracellular organelles in the pancreas have been noted to be disturbed during the early stages of several models of experimental pancreatitis. As a result, lysosomal hydrolases such as cathepsin B are redistributed to the subcellular zymogen granule-rich fraction and lysosomal hydrolases as well as digestive enzyme zymogens are colocalized within large cytoplasmic vacuoles. The current study was designed to create an in vitro system that would reproduce this redistribution phenomenon. Our results indicate that cathepsin B redistribution occurs when rat pancreatic fragments are incubated with a supramaximally stimulating concentration of the cholecystokinin analogue caerulein along with plasma from an animal subjected to in vivo supramaximal caerulein stimulation. Neither the plasma nor a supramaximally stimulating concentration of caerulein, alone, is sufficient to induce in vitro cathepsin B redistribution. The ability of the plasma to induce in vitro cathepsin redistribution is dependent upon its content of a 10,000-30,000-D protein and is lost by exposure to protease inhibitors. In vitro cathepsin B redistribution also occurs when rat pancreatic fragments are incubated with plasma obtained from opossums with hemorrhagic necrotizing pancreatitis caused by bile/pancreatic duct ligation.


Genetic determinants of Venezuelan equine encephalitis emergence.
Following a period of inactivity from 1973-1991, Venezuelan equine encephalitis (VEE) reemerged during the past decade in South America and Mexico. Experimental studies of VEE virus (VEEV) infection of horses with virus strains isolated during these outbreaks have revealed considerable variation in the ability of equine-virulent, epizootic strains to exploit horses as efficient amplification hosts. Subtype IC strains from recent outbreaks in Venezuela and Colombia amplify efficiently in equines, with a correlation between maximum viremia titers and the extent of the outbreak from which the virus strain was isolated. Studies of enzootic VEEV strains that are believed to represent progenitors of the epizootic subtypes support the hypothesis that adaptation to efficient replication in equines is a major determinant of emergence and the ability of VEEV to spread geographically. Correlations between the ability of enzootic and epizootic VEEV strains to infect abundant, equiphilic mosquitoes, and the location and extent of these outbreaks, also suggest that specific adaptation to Ochlerotatus taeniorhynchus mosquitoes is a determinant of some but not all emergence events. Genetic studies imply that mutations in the E2 envelope glycoprotein gene are major determinants of adaptation to both equines and mosquito vectors.


ErbB2 is required for muscle spindle and myoblast cell survival.
Signaling mediated by ErbB2 is thought to play a critical role in numerous developmental processes. However, due to the embryonic lethality associated with the germ line inactivation of erbB2, its role in adult tissues remains largely obscure. Given the expression of ErbB2 at the neuromuscular junction, we have created a muscle-specific knockout to assess its role there. This resulted in viable mice with a progressive defect in proprioception due to loss of muscle spindles. Interestingly, a partial reduction of ErbB2 levels also reduced the number of muscle spindles. Although histological analysis of the muscle revealed an otherwise normal architecture, induction of muscle injury revealed a defect in muscle regeneration. Consistent with these observations, primary myoblasts lacking ErbB2 exhibit extensive apoptosis upon differentiation into myofibers. Taken together, these results illustrate a dual role for ErbB2 in both muscle spindle maintenance and survival of myoblasts.


Innate Lymphoid Cells Are Required for Endometrial Resistance to Chlamydia trachomatis Infection.
In some women, sexually transmitted Chlamydia trachomatis may ascend to infect the endometrium, leading to pelvic inflammatory disease. To identify endometrial innate immune components that interact with Chlamydia, we introduced C. trachomatis into mouse endometrium via transcervical inoculation and compared the infectious yields in mice with and without immunodeficiency. Live C. trachomatis recovered from vaginal swabs or endometrial tissues peaked on day 3 and then declined in all mice with or without deficiency in adaptive immunity, indicating a critical role for innate immunity in endometrial control of C. trachomatis infection. Additional knockout of interleukin 2 receptor common gamma chain (IL-2Rγc) from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity, demonstrating an important role for innate lymphoid cells (ILCs). Consistently, deficiency in IL-7 receptor alone, a common gamma chain-containing receptor required for ILC development, significantly reduced endometrial innate immunity. Furthermore, mice deficient in RORγt or T-bet became more susceptible to endometrial infection with C. trachomatis, suggesting a role for group 3-like ILCs in endometrial innate immunity. Furthermore, genetic deletion of gamma interferon (IFN-γ) but not IL-22 or antibody-mediated depletion of IFN-γ from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity. Finally, depletion of NK1.1+ cells from adaptive immunity-deficient mice both significantly reduced IFN-γ and increased C. trachomatis burden in the endometrial tissue, confirming that mouse ILCs contribute significantly to endometrial innate immunity via an IFN-γ-dependent effector mechanism. It will be worth investigating whether IFN-γ-producing ILCs also improve endometrial resistance to sexually transmitted C. trachomatis infection in women.


MXene Printing and Patterned Coating for Device Applications.
As a thriving member of the 2D nanomaterials family, MXenes, i.e., transition metal carbides, nitrides, and carbonitrides, exhibit outstanding electrochemical, electronic, optical, and mechanical properties. They have been exploited in many applications including energy storage, electronics, optoelectronics, biomedicine, sensors, and catalysis. Compared to other 2D materials, MXenes possess a unique set of properties such as high metallic conductivity, excellent dispersion quality, negative surface charge, and hydrophilicity, making them particularly suitable as inks for printing applications. Printing and pre/post-patterned coating methods represent a whole range of simple, economically efficient, versatile, and eco-friendly manufacturing techniques for devices based on MXenes. Moreover, printing can allow for complex 3D architectures and multifunctionality that are highly required in various applications. By means of printing and patterned coating, the performance and application range of MXenes can be dramatically increased through careful patterning in three dimensions; thus, printing/coating is not only a device fabrication tool but also an enabling tool for new applications as well as for industrialization.


Systematic review: bias in imaging studies - the effect of manipulating clinical context, recall bias and reporting intensity.
To perform a systematic review of diagnostic test accuracy studies which manipulate or investigate the context of interpretation. In particular, those which modify or conceal sample characteristics (e.g. disease prevalence or reporting intensity) or research setting ("laboratory" versus "field"). We also investigated recall bias. We searched the biomedical literature to March 2010 using 3 complementary strategies. Inclusion criteria were: imaging studies quantifying the effect on diagnosis of modifying the context of observers' interpretations, varying disease prevalence, concealing sample characteristics, reporting intensity and recall bias. 11247 abstracts were reviewed, 201 full texts examined and 12 ultimately included. There were 5 to 9520 patients and 2 to 129 observers per study. Nine studies investigated clinical review bias of sample level information. Only 3 studies investigated prevalence, 2 of which investigated maximum enrichment well below the levels often used by researchers. We identified no research specifically directed at concealing disease prevalence. Available research found no evidence of recall bias or "washout" on study results. Several sources of bias central to the design of diagnostic test accuracy studies are poorly researched; the implications for evidence-based-practice remain uncertain. Research is suggested to guide methodological design, particularly in the context of screening. Imaging research studies often ignore the possible effect of disease prevalence It is unclear how the expectation of disease influences radiological interpretation The potential effect of observer recall bias is poorly researched Such factors might introduce bias into radiological research methodology This systematic review attempts to illustrate these points.


Statin use and risk of depression: a Swedish national cohort study.
Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990). National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression. Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81). The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.


Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease.
Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.


Thermotropic phase boundaries in classic ferroelectrics.
High-performance piezoelectrics are lead-based solid solutions that exhibit a so-called morphotropic phase boundary, which separates two competing phases as a function of chemical composition; as a consequence, an intermediate low-symmetry phase with a strong piezoelectric effect arises. In search for environmentally sustainable lead-free alternatives that exhibit analogous characteristics, we use a network of competing domains to create similar conditions across thermal inter-ferroelectric transitions in simple, lead-free ferroelectrics such as BaTiO3 and KNbO3. Here we report the experimental observation of thermotropic phase boundaries in these classic ferroelectrics, through direct imaging of low-symmetry intermediate phases that exhibit large enhancements in the existing nonlinear optical and piezoelectric property coefficients. Furthermore, the symmetry lowering in these phases allows for new property coefficients that exceed all the existing coefficients in both parent phases. Discovering the thermotropic nature of thermal phase transitions in simple ferroelectrics thus presents unique opportunities for the design of 'green' high-performance materials.


Femtosecond pulse shaping using the geometric phase.
We demonstrate a femtosecond pulse shaper that utilizes polarization gratings to manipulate the geometric phase of an optical pulse. This unique approach enables circular polarization-dependent shaping of femtosecond pulses. As a result, it is possible to create coherent pulse pairs with orthogonal polarizations in a 4f pulse shaper setup, something until now that, to our knowledge, was only achieved via much more complex configurations. This approach could be used to greatly simplify and enhance the functionality of multidimensional spectroscopy and coherent control experiments, in which multiple coherent pulses are used to manipulate quantum states in materials of interest.


Primary structure and biochemical properties of an M2 muscarinic receptor.
A partial amino acid sequence obtained for porcine atrial muscarinic acetylcholine receptor was used to isolate complementary DNA clones containing the complete receptor coding region. The deduced 466-amino acid polypeptide exhibits extensive structural and sequence homology with other receptors coupled to guanine nucleotide binding (G) proteins (for example, the beta-adrenergic receptor and rhodopsins); this similarity predicts a structure of seven membrane-spanning regions distinguished by the disposition of a large cytoplasmic domain. Stable transfection of the Chinese hamster ovary cell line with the atrial receptor complementary DNA leads to the binding of muscarinic antagonists in these cells with affinities characteristic of the M2 receptor subtype. The atrial muscarinic receptor is encoded by a unique gene consisting of a single coding exon and multiple, alternatively spliced 5' noncoding regions. The atrial receptor is distinct from the cerebral muscarinic receptor gene product, sharing only 38% overall amino acid homology and possessing a completely nonhomologous large cytoplasmic domain, suggesting a role for the latter region in differential effector coupling.


Communicating the deadly consequences of global warming for human heat stress.
In December of 2015, the international community pledged to limit global warming to below 2 °C above preindustrial (PI) to prevent dangerous climate change. However, to what extent, and for whom, is danger avoided if this ambitious target is realized? We address these questions by scrutinizing heat stress, because the frequency of extremely hot weather is expected to continue to rise in the approach to the 2 °C limit. We use analogs and the extreme South Asian heat of 2015 as a focusing event to help interpret the increasing frequency of deadly heat under specified amounts of global warming. Using a large ensemble of climate models, our results confirm that global mean air temperature is nonlinearly related to heat stress, meaning that the same future warming as realized to date could trigger larger increases in societal impacts than historically experienced. This nonlinearity is higher for heat stress metrics that integrate the effect of rising humidity. We show that, even in a climate held to 2 °C above PI, Karachi (Pakistan) and Kolkata (India) could expect conditions equivalent to their deadly 2015 heatwaves every year. With only 1.5 °C of global warming, twice as many megacities (such as Lagos, Nigeria, and Shanghai, China) could become heat stressed, exposing more than 350 million more people to deadly heat by 2050 under a midrange population growth scenario. The results underscore that, even if the Paris targets are realized, there could still be a significant adaptation imperative for vulnerable urban populations.


Serious infections due to methicillin-resistant Staphylococcus aureus: an evolving challenge for physicians.
Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized major cause of nosocomial infection worldwide. During the past decade, however, the epidemiology of staphylococcal infections has partially changed, with an increase in the number of patients who acquire infections in the community. The changing epidemiology is a cause for concern among physicians, leading to an increase in the number of patients with infections due to MRSA diagnosed at hospital admission and in the emergency department. The aims of this article are to review the current state of knowledge regarding MRSA infections, to identify those factors which may help physicians to recognize the patients at high risk, and to manage these infections appropriately.


Controlling cost escalation of healthcare: making universal health coverage sustainable in China.
An increasingly number of low- and middle-income countries have developed and implemented a national policy towards universal coverage of healthcare for their citizens over the past decade. Among them is China which has expanded its population coverage by health insurance from around 29.7% in 2003 to over 90% at the end of 2010. While both central and local governments in China have significantly increased financial inputs into the two newly established health insurance schemes: new cooperative medical scheme (NCMS) for the rural population, and urban resident basic health insurance (URBMI), the cost of healthcare in China has also been rising rapidly at the annual rate of 17.0%% over the period of the past two decades years. The total health expenditure increased from 74.7 billion Chinese yuan in 1990 to 1998 billion Chinese yuan in 2010, while average health expenditure per capital reached the level of 1490.1 Chinese yuan per person in 2010, rising from 65.4 Chinese yuan per person in 1990. The repaid increased population coverage by government supported health insurance schemes has stimulated a rising use of healthcare, and thus given rise to more pressure on cost control in China.There are many effective measures of supply-side and demand-side cost control in healthcare available. Over the past three decades China had introduced many measures to control demand for health care, via a series of co-payment mechanisms. The paper introduces and discusses new initiatives and measures employed to control cost escalation of healthcare in China, including alternative provider payment methods, reforming drug procurement systems, and strengthening the application of standard clinical paths in treating patients at hospitals, and analyses the impacts of these initiatives and measures. The paper finally proposes ways forward to make universal health coverage in China more sustainable.


Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis.
Translocation-associated gene fusions are well recognized in acute myeloid leukemia. Other molecular genetic changes are less well known. The novel cDNA technology has opened the avenue to large-scale gene expression analysis. Our aim was to perform cDNA microarray analysis of acute myeloid leukemia (AML). We performed cDNA microarray analysis using the Clontech hematology filter (containing 406 genes) on 15 patients to study gene expression profiling in AML. As reference, we used whole bone marrow from 5 healthy donors. Our results revealed 50 differentially expressed genes in at least 3 out of 15 patients. Twenty-two genes were upregulated (ratio > or =4), whereas 28 genes were downregulated (ratio < or =0.25). All but one of the 13 genes tested by real-time polymerase chain reaction (PCR) showed the same expression profiles. Among the overexpressed genes, several were those earlier associated with chromosomal translocations and gene fusions. These genes were FGFR1, MYC, NPM1, DEC, and BCL2. The expression of two upregulated genes, HOXA4 and CSF1R, was significantly higher in patients with a white blood cell count higher than 30 x 10(9)/L cells. In patients whose white blood cell count was higher than 100 x 10(9)/L cells, both CLC and GRN were significantly underexpressed, whereas HOXA4 and DAPK1 were overexpressed. FGFR1 and CAMLG were more frequently significantly overexpressed in patients with CD56 immunophenoytpe. Clinical and prognostic significance of differential gene expression should be studied with a larger series of patients by using other techniques, such as quantitative real-time PCR.


Effects of sphingosine, staurosporine, and phorbol ester on neurites of rat sympathetic neurons growing in compartmented cultures.
Local application of sphingosine (1-10 microM), an inhibitor of protein kinase C, to NGF-supplied, distal neurites of rat sympathetic neurons in compartmented cultures caused their retraction and/or degeneration within 24 hr. This effect was specific for distal neurites because sphingosine (even at 100 microM) applied to cell bodies and/or proximal neurites did not destroy these regions of the cells, and their distal neurites continued to elongate. However, effects of other agents suggest that the retraction/degeneration observed in distal neurites directly exposed to sphingosine is not mediated by inhibition of protein kinase C: application of staurosporine, another inhibitor of protein kinase C, to distal neurites did not cause retraction or degeneration; treatment of neurons for 24 or more hours with 2 microM phorbol 12-myristate 13-acetate (PMA), used to downregulate protein kinase C activity, slowed neurite extension about 50%, but did not cause degeneration; and neurons pretreated with PMA still displayed retraction/degeneration of neurites when they were subsequently exposed to sphingosine. Also, replacement of NGF supplied to distal neurites with anti-NGF IgG did not cause retraction/degeneration of neurites within 1 d, suggesting that the effect of sphingosine did not arise by interference with the action of NGF. The specificity of the sphingosine-induced retraction/degeneration for distal neurites suggests that this effect operates via specific mechanisms in distal neurites that can trigger their retraction/degeneration. Such mechanisms could play important roles in nerve growth inhibition, nerve fiber retraction, and degeneration that occur normally in the nervous system and in response to injury and disease. Also, the ability of neurites to grow in the presence of PMA suggests that neurite growth is not dependent upon the activity of protein kinase C. However, the reduced rate of neurite extension in the presence of PMA suggests that chronic PMA treatment may affect mechanism(s) that can modulate neurite growth.


Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage.
The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Cellular responses to the environment include elevating defense systems, such as the antioxidant defense system. Hypoxia-evoked reactive oxygen species (ROS)-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC) death that leads to blinding disorders. The protein peroxiredoxin 6 (PRDX6) plays a pleiotropic role in negatively regulating death signaling in response to stressors, and thereby stabilizes cellular homeostasis. We have shown that RGCs exposed to hypoxia (1%) or hypoxia mimetic cobalt chloride display reduced expression of PRDX6 with higher ROS expression and activation of NF-κB. These cells undergo apoptosis, while cells with over-expression of PRDX6 demonstrate resistance against hypoxia-driven RGC death. The RGCs exposed to hypoxia either with 1% oxygen or cobalt chloride (0-400 μM), revealed ~30%-70% apoptotic cell death after 48 and 72 h of exposure. Western analysis and real-time PCR showed elevated expression of PRDX6 during hypoxia at 24 h, while PRDX6 protein and mRNA expression declined from 48 h onwards following hypoxia exposure. Concomitant with this, RGCs showed increased ROS expression and activation of NF-κB with IkB phosphorylation/degradation, as examined with H2DCF-DA and transactivation assays. These hypoxia-induced adverse reactions could be reversed by over-expression of PRDX6. Because an abundance of PRDX6 in cells was able to attenuate hypoxia-induced RGC death, the protein could possibly be developed as a novel therapeutic agent acting to postpone RGC injury and delay the progression of glaucoma and other disorders caused by the increased-ROS-generated death signaling related to hypoxia.


Gastrointestinal symptoms predictors of health-related quality of life in pediatric patients with functional gastrointestinal disorders.
To investigate the patient-reported multidimensional gastrointestinal symptoms predictors of generic health-related quality of life (HRQOL) in pediatric patients with functional gastrointestinal disorders (FGIDs). The Pediatric Quality of Life Inventory™ (PedsQL™) Gastrointestinal Symptoms Scales and PedsQL™ 4.0 Generic Core Scales were completed in a 9-site study by 259 pediatric patients with functional constipation, functional abdominal pain (FAP), or irritable bowel syndrome (IBS). Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were identified as clinically important symptom differentiators from healthy controls based on prior findings, and subsequently tested for bivariate and multivariate linear associations with overall HRQOL. Gastrointestinal symptoms were differentially associated with decreased HRQOL in bivariate analyses for the three FGIDs. In predictive models utilizing hierarchical multiple regression analyses controlling for age, gender, and race/ethnicity, gastrointestinal symptoms differentially accounted for an additional 47, 40, and 60 % of the variance in patient-reported HRQOL for functional constipation, FAP, and IBS, respectively, reflecting large effect sizes. Significant individual gastrointestinal symptoms predictors were identified after controlling for the other gastrointestinal symptoms in the FGID-specific predictive models. Gastrointestinal symptoms represent potentially modifiable predictors of generic HRQOL in pediatric patients with FGIDs. Identifying the condition-specific gastrointestinal symptoms that are the most important predictors from the patient perspective facilitates a patient-centered approach to targeted interventions designed to ameliorate impaired overall HRQOL.


Immunohistochemical analysis of SOX6 expression in human brain tumors.
We previously demonstrated that the developmentally regulated gene, SOX6, is strongly expressed in glioma cells and in the fetal brain, but only faintly in the normal adult brain. Recent studies have indicated that brain tumor cells may share antigens, signaling systems, and behavior with neural stem/progenitor cells. To test the validity of this proposition, we analyzed the expression of SOX6 in various human central nervous system (CNS) tumors. Immunohistochemical analysis revealed that astrocytic and oligodendroglial tumors expressed SOX6; neuronal-glial cell tumors (central neurocytoma) and embryonal tumors (medulloblastoma), which arise from multipotential stem cell precursors, also showed a high intensity of SOX6 staining. In contrast, ependymal tumors (ependymoma and subependymoma), meningioma, and schwannoma, which are all well differentiated tumors, showed either no staining or only faint staining for SOX6. These results suggest that SOX6 may be expressed in bipotential or multipotential cells capable of neuronal and glial differentiation, but not in fully differentiated cells. SOX6 may be a useful marker for the diagnosis of tumors arising from immature bipotential cells that may differentiate into neuronal and glial cells.


Laparoscopic resection of gastric stromal tumor: a tailored approach.
Many different laparoscopic approaches to resection of gastric stromal tumor have been described in the literature. We reviewed our experience of laparoscopic approaches to surgical resection of gastric stromal tumors seven in six consecutive patients. The tumor locations were the gastric cardia (n = 2), gastroesophageal junction (n = 1), gastric fundus (n = 2), and gastric antrum (n = 2). Laparoscopic localization of endoluminal tumors included intraoperative endoscopy, laparoscopic ultrasound, and laparoscopic palpation. There were five males with a mean age of 57 years. Laparoscopic approaches to resection were laparoscopic wedge resection (n = 4) for tumors in the gastric fundus and antrum, laparoscopic enucleation (n = 2) for tumors in the gastric cardia, and transgastric endoluminal resection (n = 1) for a tumor located at the gastroesophageal junction. There was no conversion to laparotomy. The mean operative time was 143 +/- 54 minutes and mean blood loss was 57 +/- 27 mL. None of the patients required intensive care stay. The mean length of hospital stay was 3 days. There were no major or minor complications and no mortality. Surgical pathology demonstrated gastric stromal tumor with less than 2/50 mitosis per high power field in all seven specimens. Tumor size ranged from 2.8 cm to 7.1 cm in greatest diameter. There has been no tumor recurrence with a mean follow-up of 9 months. Laparoscopic resection of benign gastric stromal tumor is safe and feasible. The laparoscopic approaches to surgical resection should be tailored based on the location and characteristics of the tumor.


Genome-wide DNA methylation changes in skeletal muscle between young and middle-aged pigs.
Age-related physiological, biochemical and functional changes in mammalian skeletal muscle have been shown to begin at the mid-point of the lifespan. However, the underlying changes in DNA methylation that occur during this turning point of the muscle aging process have not been clarified. To explore age-related genomic methylation changes in skeletal muscle, we employed young (0.5 years old) and middle-aged (7 years old) pigs as models to survey genome-wide DNA methylation in the longissimus dorsi muscle using a methylated DNA immunoprecipitation sequencing approach. We observed a tendency toward a global loss of DNA methylation in the gene-body region of the skeletal muscle of the middle-aged pigs compared with the young group. We determined the genome-wide gene expression pattern in the longissimus dorsi muscle using microarray analysis and performed a correlation analysis using DMR (differentially methylated region)-mRNA pairs, and we found a significant negative correlation between the changes in methylation levels within gene bodies and gene expression. Furthermore, we identified numerous genes that show age-related methylation changes that are potentially involved in the aging process. The methylation status of these genes was confirmed using bisulfite sequencing PCR. The genes that exhibited a hypomethylated gene body in middle-aged pigs were over-represented in various proteolysis and protein catabolic processes, suggesting an important role for these genes in age-related muscle atrophy. In addition, genes associated with tumorigenesis exhibited aged-related differences in methylation and expression levels, suggesting an increased risk of disease associated with increased age. This study provides a comprehensive analysis of genome-wide DNA methylation patterns in aging pig skeletal muscle. Our findings will serve as a valuable resource in aging studies, promoting the pig as a model organism for human aging research and accelerating the development of comparative animal models in aging research.


Effect of stress on diagnosis of hypertension.
Blood pressure assessment by a physician elicits an alerting reaction and a pressor response in the patient. The magnitude and time course of this response are described for a large number of hypertensive subjects in whom the assessments were performed during ambulatory intra-arterial blood pressure monitoring. In nearly all of the subjects, the physician's visit was accompanied by blood pressure and heart rate increases that peaked within 4 minutes and then declined. The response was characterized by a relatively high average value; a large between-subject variability; no relation with patient age, baseline hemodynamic values, and responses to laboratory stressors; and no attenuation with multiple repetition of the physician's visit. On the other hand, the increase in blood pressure was considerably less when blood pressure assessment was made by a nurse than when it was made by a physician; in both instances, a 10-minute wait was associated with marked reduction of the initial response. Thus, the stress inherent in usual blood pressure-measuring procedures is responsible for considerable overestimations of patients' blood pressures. There are means by which this can be minimized, although a residual error is likely to remain in most subjects. Whether the stress-devoid blood pressure is a better prognostic index than the stress-related one remains unknown.


Conical wave propagation and diffraction in two-dimensional hexagonally packed granular lattices.
Linear and nonlinear mechanisms for conical wave propagation in two-dimensional lattices are explored in the realm of phononic crystals. As a prototypical example, a statically compressed granular lattice of spherical particles arranged in a hexagonal packing configuration is analyzed. Upon identifying the dispersion relation of the underlying linear problem, the resulting diffraction properties are considered. Analysis both via a heuristic argument for the linear propagation of a wave packet and via asymptotic analysis leading to the derivation of a Dirac system suggests the occurrence of conical diffraction. This analysis is valid for strong precompression, i.e., near the linear regime. For weak precompression, conical wave propagation is still possible, but the resulting expanding circular wave front is of a nonoscillatory nature, resulting from the complex interplay among the discreteness, nonlinearity, and geometry of the packing. The transition between these two types of propagation is explored.


Temperature influences histone methylation and mRNA expression of the Jmj-C histone-demethylase orthologues during the early development of the oyster Crassostrea gigas.
In many groups, epigenetic mechanisms influence developmental gene regulation under environmental inputs. The Pacific oyster Crassostrea gigas belongs to lophotrochozoans and its larval development is highly dependent on temperature, but the role of epigenetic mechanisms in this context is unknown despite high levels of the recently characterized Jumonji histone demethylase (JHDM) orthologues (Cg_Jumonji) suggesting a physiological relevance of histone methylation in the oyster development. Because in other species alterations of the histone methylation pattern have deleterious outcomes, we investigated the influence of temperature during the oyster larval life on histone methylation and JHDM expression. To shed light on this point, oyster embryonic and early larval development experiments were carried out at different temperatures (18 °C, 25 °C and 32 °C). Histone methylation levels were investigated using fluorescent ELISA at 6 and 24h post-fertilization. When compared to the 25 °C group, at 18 °C H3K4, H3K9 and H3K27 residues were hypomethylated at 6h post fertilization (hpf) and hypermethylated at 24 hpf. In contrast, at 32 °C, 6hpf animals present a dramatic hypermethylation (ca. 4-fold) of all examined residues, which is minored but sustained at 24 hpf. RT-qPCR investigations of the mRNA expression of the nine oyster JHDMs, showed gene- and stage-specific temperature sensitivities throughout the early life of oysters. This study provides evidence of the biological significance of histone methylation during development in a lophotrochozoan species. Our results also indicate that temperature influences histone methylation, possibly through the expression level of putative actors of its regulation, which might participate in developmental control. To our knowledge, this is the first report indicating a direct relationship between an epigenetic mark and an environmental parameter in marine molluscs. Such investigations could help better understand the molecular mechanisms of development and adaptation in lophotrochozoans.


Orthotopic transplantation of histologically intact clinical specimens of stomach cancer to nude mice: correlation of metastatic sites in mouse and individual patient donors.
Fresh surgical specimens derived from 36 patients with advanced stomach cancer were orthotopically transplanted in nude mice using histologically intact tissue. Twenty of 36 patient tumors gave rise to locally growing tumors in the mice. All 20 patients whose stomach tumors resulted in local growth in the nude mice had clinical lymph-node involvement, whereas 8 of the other 16 patients whose tumors were rejected had lymph-node involvement. There was a statistical correlation (p < 0.01) between local tumor growth in nude mice and clinical lymph-node involvement. Of the 20 cases resulting in local growth in the nude mice, 5 had clinical liver metastases and all 5 cases resulted in liver metastases in the nude mice. Of the 20 cases, 6 had clinical peritoneal involvement of their tumor, and of these 5 resulted in peritoneal metastasis in the nude mice. There were statistical correlations (p < 0.01) for both liver metastases and peritoneal involvement between patients and mice. These results indicate that, after orthotopic transplantation of histologically intact stomach cancers from patients to nude mice, the subsequent metastatic behavior of the tumors in the mice closely correlated with the course of the tumors in the patients.


Epithelial to mesenchymal transition of a primary prostate cell line with switches of cell adhesion modules but without malignant transformation.
Epithelial to mesenchymal transition (EMT) has been connected with cancer progression in vivo and the generation of more aggressive cancer cell lines in vitro. EMT has been induced in prostate cancer cell lines, but has previously not been shown in primary prostate cells. The role of EMT in malignant transformation has not been clarified. In a transformation experiment when selecting for cells with loss of contact inhibition, the immortalized prostate primary epithelial cell line, EP156T, was observed to undergo EMT accompanied by loss of contact inhibition after about 12 weeks in continuous culture. The changed new cells were named EPT1. EMT of EPT1 was characterized by striking morphological changes and increased invasion and migration compared with the original EP156T cells. Gene expression profiling showed extensively decreased epithelial markers and increased mesenchymal markers in EPT1 cells, as well as pronounced switches of gene expression modules involved in cell adhesion and attachment. Transformation assays showed that EPT1 cells were sensitive to serum or growth factor withdrawal. Most importantly, EPT1 cells were not able to grow in an anchorage-independent way in soft agar, which is considered a critical feature of malignant transformation. This work for the first time established an EMT model from primary prostate cells. The results show that EMT can be activated as a coordinated gene expression program in association with early steps of transformation. The model allows a clearer identification of the molecular mechanisms of EMT and its potential role in malignant transformation.


Socioeconomic status and substance use among young adults: a comparison across constructs and drugs.
Little consensus exists regarding the relationship between socioeconomic status (SES) and substance use. This study examined the associations of three indicators of family SES during childhood--income, wealth, and parental education--with smoking, alcohol use, and marijuana use during young adulthood. Data were obtained from the national Panel Study of Income Dynamics, a survey of U.S. families that incorporates data from parents and their children. In 2005 and 2007, the Panel Study of Income Dynamics was supplemented with two waves of Transition into Adulthood data drawn from a national sample of young adults, 18-23 years old. Data from the young adults (N = 1,203; 66.1% White; 51.5% female) on their current use of alcohol, cigarettes, and marijuana were used as outcome variables in logistic regressions. Socioeconomic background was calculated from parental reports of education, wealth, and income during the respondent's childhood (birth through age 17 years). Smoking in young adulthood was associated with lower childhood family SES, although the association was explained by demographic and social role covariates. Alcohol use and marijuana use in young adulthood were associated with higher childhood family SES, even after controlling for covariates. Findings based on three indicators of family background SES--income, wealth, and parental education--converged in describing unique patterns for smoking and for alcohol and marijuana use among young adults, although functional relationships across SES measures varied. Young adults with the highest family background SES were most prone to alcohol and marijuana use.


Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force.
Prostate cancer is the most common nonskin cancer in men in the United States, and prostate cancer screening has increased in recent years. In 2002, the U.S. Preventive Services Task Force concluded that evidence was insufficient to recommend for or against screening for prostate cancer with prostate-specific antigen (PSA) testing. To examine new evidence on benefits and harms of screening asymptomatic men for prostate cancer with PSA. English-language articles identified in PubMed and the Cochrane Library (search dates, January 2002 to July 2007), reference lists of retrieved articles, and expert suggestions. Randomized, controlled trials and meta-analyses of PSA screening and cross-sectional and cohort studies of screening harms and of the natural history of screening-detected cancer were selected to answer the following questions: Does screening for prostate cancer with PSA, as a single-threshold test or as a function of multiple tests over time, decrease morbidity or mortality? What are the magnitude and nature of harms associated with prostate cancer screening, other than overtreatment? What is the natural history of PSA-detected, nonpalpable, localized prostate cancer? Studies were reviewed, abstracted, and rated for quality by using predefined U.S. Preventive Services Task Force criteria. No good-quality randomized, controlled trials of screening for prostate cancer have been completed. In 1 cross-sectional and 2 prospective cohort studies of fair to good quality, false-positive PSA screening results caused psychological adverse effects for up to 1 year after the test. The natural history of PSA-detected prostate cancer is poorly understood. Few eligible studies were identified. Long-term adverse effects of false-positive PSA screening test results are unknown. Prostate-specific antigen screening is associated with psychological harms, and its potential benefits remain uncertain.


One-year evaluation of a neonatal screening program for cystic fibrosis in Switzerland.
From January 2011 onward, the Swiss newborn screening (NBS) program has included a test for cystic fibrosis (CF). In this study, we evaluate the first year of implementation of the CF-NBS program. The CF-NBS program consists of testing in two steps: a heel prick sample is drawn (= Guthrie test) for measurement of immunoreactive trypsinogen (IRT) and for DNA screening. All children with a positive screening test are referred to a CF center for further diagnostic testing (sweat test and genetic analysis). After assessment in the CF center, the parents are given a questionnaire. All the results of the screening process and the parent questionnaires were centrally collected and evaluated. In 2011, 83 198 neonates were screened, 84 of whom (0.1%) had a positive screening result and were referred to a CF center. 30 of these 84 infants were finally diagnosed with CF (positive predictive value: 35.7%). There was an additional infant with CF and meconium ileus whose IRT value was normal. The 31 diagnosed children with CF correspond to an incidence of 1 : 2683. The average time from birth to genetically confirmed diagnosis was 34 days (range: 13-135). 91% of the parents were satisfied that their child had undergone screening. All infants receiving a diagnosis of CF went on to receive further professional care in a CF center. The suggested procedure for CF-NBS has been found effective in practice; there were no major problems with its implementation. It reached high acceptance among physicians and parents.


Fimbria-dependent activation of cell adhesion molecule expression in Porphyromonas gingivalis-infected endothelial cells.
Porphyromonas gingivalis is an oral pathogen that has recently been associated with chronic inflammatory diseases such as atherosclerosis. The strength of the epidemiological associations of P. gingivalis with atherosclerosis can be increased by the demonstration that P. gingivalis can initiate and sustain growth in human vascular cells. We previously established that P. gingivalis can invade aortic, heart, and human umbilical vein endothelial cells (HUVEC), that fimbriae are required for invasion of endothelial cells, and that fimbrillin peptides can induce the expression of the chemokines interleukin 8 and monocyte chemotactic protein. In this study, we examined the expression of surface-associated cell adhesion molecules on endothelial cells in response to P. gingivalis infection by fluorescence-activated cell sorting FACS analysis and confocal microscopy. Coculture of HUVEC with P. gingivalis strain 381 or A7436 resulted in the induction in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P- and E-selectins, which was maximal at 48 h postinfection. In contrast, we did not observe induction of ICAM-1, VCAM-1, or P- or E-selectin expression in HUVEC cultured with the noninvasive P. gingivalis fimA mutant DPG3 or when P. gingivalis was incubated with fimbrillin peptide-specific anti-sera prior to the addition to HUVEC. Furthermore, the addition of a peptide corresponding to the N-terminal domain of fimbrillin to HUVEC resulted in an increase in ICAM-1, VCAM-1, and P- and E-selectins, which was maximal at 48 h and similar to that observed for live P. gingivalis. Treatment of P. gingivalis-infected HUVEC with cytochalsin D, which prevented P. gingivalis invasion, also resulted in the inhibition of ICAM-1, VCAM-1, or P- and E-selectin expression. Taken together, these results indicate that active P. gingivalis invasion of HUVEC mediated via the major fimbriae stimulates surface-associated cell adhesion molecule expression. Stimulation of adhesion molecules involved in the recruitment of leukocytes to sites of inflammation by P. gingivalis may play a role in the pathogenesis of systemic inflammatory diseases associated with this microorganism, including atherosclerosis.


Increased long-term mortality in patients with cardiovascular implantable electronic device infections.
Device infection is associated with increased mortality in patients receiving cardiovascular implantable electronic device (CIED) therapy. However, long-term mortality associated with CIED infections has not been systematically analyzed in larger studies. This study sought to determine the long-term mortality associated with CIED infection in a large cohort of Medicare beneficiaries. We used a retrospective study design to analyze 3-year mortality in 200,219 Medicare fee-for-service patients admitted for CIED generator implantation, replacement, or revision between January 1, 2007 and December 31, 2007. Multivariate analysis adjusting for age, sex, race, and 28 comorbidities was performed to determine the relative risk (RR) of death in the 12 quarters following CIED infection. Patients with CIED infection, compared to device recipients without infection, had increased mortality that persisted for at least 3 years after the admission quarter for all device types: pacemakers (PMs: 53.8% vs 33%; P < 0.001), implantable cardioverter defibrillator (ICD: 47.7% vs 31.6%; P < 0.001), and cardiac resynchronization therapy-defibrillator (CRT-D: 50.8% vs 36.5%; P < 0.001). After adjusting for patient demographics and comorbidities, significantly increased RR of death following CIED infection persisted for at least 3 years following PM infection, and for at least 2 years with single- and dual-chamber ICD infection. CIED recipients who develop device infection have increased, device-dependent, long-term mortality even after successful treatment of infection. The etiology of this persistent increased risk of death associated with CIED infection is unknown and merits further investigation.


The development of service user-led recommendations for health and social care services on leaving hospital with memory loss or dementia - the SHARED study.
Health and social care services are under strain providing care in the community particularly at hospital discharge. Patient and carer experiences can inform and shape services. To develop service user-led recommendations enabling smooth transition for people living with memory loss from acute hospital to community. Lead and co-researchers conducted semi-structured interviews with 15 pairs of carers and patients with memory loss at discharge, 6 and 12 weeks post-discharge and one semi-structured interview with health and social care professionals and Admiral Nurses. Framework analysis was guided by co-researchers. Two focus groups of study participants, facilitated by co-researchers, met to shape and finalize recommendations. Recruitment took place in acute hospitals in two National Health Service (NHS) Trusts in England. Patients were aged 65 and over, with memory loss, an in-patient for at least 1 week returning to the community, who had a carer consenting to be in the study. Poor delivery of services caused considerable stress to some study families living with memory loss. Three key recommendations included a need for a written, mutually agreed discharge plan, a named coordinator of services, and improved domiciliary care services. Vulnerable patients with memory loss find coming out of hospital after an extended period a stressful experience. The SHARED study contributes to understanding the hospital discharge process through the eyes of the patient and carer living with memory loss and has the potential to contribute to more efficient use of resources and to improving health outcomes in communities.


Supercharged jejunum flap for total esophageal reconstruction: single-surgeon 3-year experience and outcomes analysis.
Esophageal reconstruction after total esophagectomy remains a formidable task irrespective of the conduit chosen. Historically, the gastric pull-up and colonic interposition have served as primary choices for such defects. However, where the stomach and colon are unavailable or unsuitable, the jejunum serves as a reliable alternative for the reconstruction of total esophageal defects. The authors performed an outcomes analysis of a single surgeon's surgical technique and experience. Patients who received supercharged pedicled jejunum flaps for reconstruction of total esophageal defects over a 3-year period were included in this study. Data were collected prospectively evaluating operative technique, length of hospital stay, operative time, complications, postoperative diet, and quality-of-life outcomes analysis. Five patients underwent supercharged pedicled jejunal flap surgery during this study period. All flaps had complete viability and no microvascular complications. One patient had a radiographic anastomotic leak detected by barium swallow that was reexplored and closed primarily and reinforced with a pectoralis advancement flap with subsequent resolution. All patients are currently tolerating a regular diet and there are no symptoms of reflux or dumping. No conduit strictures or redundancy has been found to date, and there has been no need for reoperation in the long term. The supercharged jejunum flap is a reliable alternative to the gastric pull-up and colonic interposition for total esophageal reconstruction. In our experience, the key maneuver in this technique is a substernal tunnel for the jejunal conduit and exposure of recipient vessels and the esophageal stump by means of a manubriectomy, clavicle resection, partial first rib resection and, occasionally, a second rib resection.


Patterns of muscle strength loss with age in the general population and patients with a chronic inflammatory state.
There is growing recognition of the serious consequences of sarcopenia on the functionality and autonomy in old age. Recently, the age-related changes in several inflammatory mediators have been implicated in the pathogenesis of sarcopenia. The purposes of this systematic review were two-fold: (1) to describe the patterns of muscle strength loss with age in the general population, and (2) to quantify the loss of muscle strength in rheumatoid arthritis as representative for an underlying inflammatory state. Handgrip strength was used as a proxy for overall muscle strength. Results from 114 studies (involving 90,520 subjects) and 71 studies (involving 10,529 subjects) were combined in a meta-analysis for the general and rheumatoid arthritis population respectively and standardized at an equal sex distribution. For the general population we showed that between the ages of 25 years and 95 years mean handgrip strength declined from 45.5 kg to 23.2 kg for males and from 27.1 kg to 12.8 kg for females. We noted a steeper handgrip strength decline after 50 years of age (rate of 0.37 kg/year). In the rheumatoid arthritis population handgrip strength was not associated with chronological age between the ages of 35 years and 65 years and was as low as 20.2 kg in male and 15.1 in female. Rheumatoid arthritis disease duration was inversely associated with handgrip strength. This meta-analysis shows distinct patterns of age-related decrease of handgrip strength in the general population. Handgrip strength is strongly associated with the presence and duration of an inflammatory state as rheumatoid arthritis. The putative link between age-related inflammation and sarcopenia mandates further study as it represents a potential target for intervention to maintain functional independence in old age.


How can controlled human infection models accelerate clinical development and policy pathways for vaccines against Shigella?
Controlled Human Infection Models (CHIMs) now exist for several infectious diseases. CHIMs offer significant insight into disease pathogenesis, as well the potential to rapidly test clinical proof-of-concept of vaccine candidates. The application of CHIMs to identify a correlate of protection that may reduce the sample size of, or obviate the need for clinical efficacy studies to achieve licensure is of considerable interest to vaccine developers and public health stakeholders. This topic was the subject of a workshop at the 2018 Vaccines Against Shigella and ETEC (VASE) conference, in the context of O-antigen-based Shigella vaccines.


Localised outbreak of Falciparum malaria in Singapore.
Malaria is primarily an imported disease in Singapore. Local outbreaks are uncommon. We describe a localised outbreak of three patients with Falciparum malaria, which we believe to be locally acquired. There was one fatality due to severe disease and late presentation. Malaria should be considered as a cause of febrile illness as the likelihood of cure depends on early detection and treatment.


Physician profiling: can Medicare paint an accurate picture?
Physician profiling, that is, the comparison of the health care services used by a physician's patients to average service use or another benchmark, has been proposed as a way to improve Medicare. It has been used by private health plans and physician groups to identify both efficient practice patterns and the physicians who practice efficiently. The Medicare Payment Advisory Commission (MedPAC) and the Government Accountability Office (GAO) have recommended that Medicare adopt physician profiling to slow spending growth and improve efficiency. Recent legislation would mandate that Medicare employ profiling. This issue brief reviews MedPAC and GAO's analyses of profiling, concerns about using this type of information, and the obstacles in incorporating profiling in the Medicare program.


Assessing the impact of the threatened crucian carp (Carassius carassius) on pond invertebrate diversity: A comparison of conventional and molecular tools.
Fishes stocked for recreation and angling can damage freshwater habitats and negatively impact biodiversity. The pond-associated crucian carp (Carassius carassius) is rare across Europe and is stocked for conservation management in England, but its impacts on pond biota are understudied. Freshwater invertebrates contribute substantially to aquatic biodiversity, encompassing many rare and endemic species, but their small size and high abundance complicate their assessment. Practitioners have employed sweep-netting and kick-sampling with microscopy (morphotaxonomy), but specimen size/quality and experience can bias identification. DNA and environmental DNA (eDNA) metabarcoding offer alternative means of invertebrate assessment. We compared invertebrate diversity in ponds (N = 18) with and without crucian carp using morphotaxonomic identification, DNA metabarcoding and eDNA metabarcoding. Five 2 L water samples and 3 min sweep-net samples were collected at each pond. Inventories produced by morphotaxonomic identification of netted samples, DNA metabarcoding of bulk tissue samples and eDNA metabarcoding of water samples were compared. Alpha diversity was greatest with DNA or eDNA metabarcoding, depending on whether standard or unbiased methods were considered. DNA metabarcoding reflected morphotaxonomic identification, whereas eDNA metabarcoding produced markedly different communities. These complementary tools should be combined for comprehensive invertebrate assessment. Crucian carp presence minimally reduced alpha diversity in ponds, but positively influenced beta diversity through taxon turnover (i.e., ponds with crucian carp contained different invertebrates to fishless ponds). Crucian carp presence contributes to landscape-scale invertebrate diversity, supporting continued conservation management in England. Our results show that molecular tools can enhance freshwater invertebrate assessment and facilitate development of more accurate and ecologically effective pond management strategies.


Peptides, polypeptides and peptide-polymer hybrids as nucleic acid carriers.
Cell penetrating peptides (CPPs), and protein transduction domains (PTDs) of viruses and other natural proteins serve as a template for the development of efficient peptide based gene delivery vectors. PTDs are sequences of acidic or basic amphipathic amino acids, with superior membrane trespassing efficacies. Gene delivery vectors derived from these natural, cationic and cationic amphipathic peptides, however, offer little flexibility in tailoring the physicochemical properties of single chain peptide based systems. Owing to significant advances in the field of peptide chemistry, synthetic mimics of natural peptides are often prepared and have been evaluated for their gene expression, as a function of amino acid functionalities, architecture and net cationic content of peptide chains. Moreover, chimeric single polypeptide chains are prepared by a combination of multiple small natural or synthetic peptides, which imparts distinct physiological properties to peptide based gene delivery therapeutics. In order to obtain multivalency and improve the gene delivery efficacies of low molecular weight cationic peptides, bioactive peptides are often incorporated into a polymeric architecture to obtain novel 'polymer-peptide hybrids' with improved gene delivery efficacies. Peptide modified polymers prepared by physical or chemical modifications exhibit enhanced endosomal escape, stimuli responsive degradation and targeting efficacies, as a function of physicochemical and biological activities of peptides attached onto a polymeric scaffold. The focus of this review is to provide comprehensive and step-wise progress in major natural and synthetic peptides, chimeric polypeptides, and peptide-polymer hybrids for nucleic acid delivery applications.


ADHD Endophenotypes in Caribbean Families.
Objective: The aim of this study is to contrast the genetics of neuropsychological tasks in individuals from nuclear families clustering ADHD in a Caribbean community. Method: We recruited and clinically characterized 408 individuals using an extensive battery of neuropsychological tasks. The genetic variance underpinning these tasks was estimated by heritability. A predictive framework for ADHD diagnosis was derived using these tasks. Results: We found that individuals with ADHD differed from controls in tasks of mental control, visuospatial ability, visuoverbal memory, phonological and verbal fluency, verbal and semantic fluency, cognitive flexibility, and cognitive ability. Among them, tasks of mental control, visuoverbal memory, phonological fluency, semantic verbal fluency, and intelligence had a significant heritability. A predictive model of ADHD diagnosis using these endophenotypes yields remarkable classification rate, sensitivity, specificity, and precision values (above 80%). Conclusion: We have dissected new cognitive endophenotypes in ADHD that can be suitable to assess the neurobiological and genetic basis of ADHD.


Synthesis and structure-activity relationships of amide and hydrazide analogues of the cannabinoid CB(1) receptor antagonist N-(piperidinyl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716).
Analogues of the biaryl pyrazole N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) were synthesized to investigate the structure-activity relationship (SAR) of the aminopiperidine region. The structural modifications include the substitution of alkyl hydrazines, amines, and hydroxyalkylamines of varying lengths for the aminopiperidinyl moiety. Proximity and steric requirements at the aminopiperidine region were probed by the synthesis of analogues that substitute alkyl hydrazines of increasing chain length and branching. The corresponding amide analogues were compared to the hydrazides to determine the effect of the second nitrogen on receptor binding affinity. The N-cyclohexyl amide 14 represents a direct methine for nitrogen substitution for 5, reducing the potential for heteroatom interaction, while the morpholino analogue 15 adds the potential for an additional heteroatom interaction. The series of hydroxyalkyl amides of increasing chain length was synthesized to investigate the existence of additional receptor hydrogen binding sites. In displacement assays using the cannabinoid agonist [(3)H](1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl) cyclohexan-1-ol (CP 55 940; 2) or the antagonist [(3)H]5, 14 exhibited the highest CB(1) affinity. In general, increasing the length and bulk of the substituent was associated with increased receptor affinity and efficacy (as measured in a guanosine 5'-triphosphate-gamma-[(35)S] assay). However, in most instances, receptor affinity and efficacy increases were no longer observed after a certain chain length was reached. A quantitative SAR study was carried out to characterize the pharmacophoric requirements of the aminopiperidine region. This model indicates that ligands that exceed 3 A in length would have reduced potency and affinity with respect to 5 and that substituents with a positive charge density in the aminopiperidine region would be predicted to possess increased pharmacological activity.


Sixteen going on sixty-six: A longitudinal study of personality stability and change across 50 years.
How much do people's personalities change or remain stable from high school to retirement? To address these questions, we used a large U.S. sample (N = 1,795) that assessed people's personality traits in adolescence and 50 years later. We also used 2 independent samples, 1 cross-sectional and 1 short-term longitudinal (N = 3,934 and N = 38, respectively), to validate the personality scales and estimate measurement error. This was the first study to test personality stability/change over a 50-year time span in which the same data source was tapped (i.e., self-report). This allowed us to use 4 different methods (rank-order stability, mean-level change, individual-level change, and profile stability) answering different developmental questions. We also systematically tested gender differences. We found that the average rank-order stability was .31 (corrected for measurement error) and .23 (uncorrected). The average mean-level change was half of a standard deviation across personality traits, and the pattern of change showed maturation. Individual-level change also supported maturation, with 20% to 60% of the people showing reliable change within each trait. We tested 3 aspects of personality profile stability, and found that overall personality profile stability was .37, distinctive profile stability was .17, and profile normativeness was .51 at baseline and .62 at the follow-up. Gender played little role in personality development across the life span. Our findings suggest that personality has a stable component across the life span, both at the trait level and at the profile level, and that personality is also malleable and people mature as they age. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The Optimization of Transcostal Phased Array Refocusing Using the Semidefinite Relaxation Method.
Tumors in organs partially obscured by the rib cage represent a challenge for high-intensity focused ultrasound (HIFU) therapy. The ribs distort the HIFU beams in a manner that reduces the focusing gain at the target, which could result in treatment-limiting collateral damage. In fact, skin burns are a common complication during the ablation of hepatic tumors. This problem can be addressed by employing optimal refocusing algorithms that are designed to achieve a specified focusing gain at the target while controlling the exposure to the ribs in the path of the HIFU beam. However, previously proposed optimal refocusing algorithms did not allow for the controlled transmission through the ribs. In this article, we introduce a new approach for refocusing that can more efficiently steer power toward the target while limiting the power deposition on the ribs. The approach utilizes the semidefinite relaxation (SDR) technique to approximate the original (nonconvex) optimization problem. An important advantage of the SDR-based method over previously proposed optimization methods is the control of the side lobes in the focal plane. The method also allows for specifying an acceptable level of exposure to the ribs. Simulation results using a 1-MHz spherical concave phased array focused on an inhomogeneous medium are presented to demonstrate the performance of the SDR refocusing approach. A finite-difference time-domain propagation model was used to model the propagation in the inhomogeneous tissues, including the ribs. Temperature simulations based on the inhomogeneous transient bioheat transfer equation (tBHTE) demonstrate the significance of the improvements in the focusing gain when using the limited power deposition (LPD) method. The results also demonstrate that the LPD method yields well-behaved array excitation vectors, realizable by currently existing drivers.


Passive data collection and use in healthcare: A systematic review of ethical issues.
Passive data refers to data generated without the active participation of the subject. This includes data from global positioning systems and accelerometers or metadata on phone call and text activity. Although the potential healthcare applications are far-reaching, passive data raises numerous ethical challenges. We performed a systematic review to identify all ethical concerns, normative standpoints, and underlying arguments related to the use of passive data in healthcare. Among the various challenges discussed in the ethical literature, informational privacy, informed consent, and data security were the primary focus of the current debate. Other topics of discussion were the evaluation and regulation of products, equity in access, vulnerable patient groups, ownership, and secondary use. No clear ethical framework has been established that stimulates passive data-driven innovation while protecting patient integrity. The consensus in the ethical literature, as well as the parallels with similar concerns and solutions in other fields, can lay a foundation for the construction of an ethical framework. The future debate should focus on conflicts between two or more ethical, technical, or clinical values to ensure a safe and effective implementation of passive data in healthcare.


Structural evolution in a hydrothermal reaction between Nb2O5 and NaOH solution: from Nb2O5 grains to microporous Na2Nb2O6.2/3H2O fibers and NaNbO3 cubes.
Niobium pentoxide reacts actively with concentrate NaOH solution under hydrothermal conditions at as low as 120 degrees C. The reaction ruptures the corner-sharing of NbO(7) decahedra and NbO(6) octahedra in the reactant Nb(2)O(5), yielding various niobates, and the structure and composition of the niobates depend on the reaction temperature and time. The morphological evolution of the solid products in the reaction at 180 degrees C is monitored via SEM: the fine Nb(2)O(5) powder aggregates first to irregular bars, and then niobate fibers with an aspect ratio of hundreds form. The fibers are microporous molecular sieve with a monoclinic lattice, Na(2)Nb(2)O(6).(2)/(3)H(2)O. The fibers are a metastable intermediate of this reaction, and they completely convert to the final product NaNbO(3) cubes in the prolonged reaction of 1 h. This study demonstrates that by carefully optimizing the reaction condition, we can selectively fabricate niobate structures of high purity, including the delicate microporous fibers, through a direct reaction between concentrated NaOH solution and Nb(2)O(5). This synthesis route is simple and suitable for the large-scale production of the fibers. The reaction first yields poorly crystallized niobates consisting of edge-sharing NbO(6) octahedra, and then the microporous fibers crystallize and grow by assembling NbO(6) octahedra or clusters of NbO(6) octahedra and NaO(6) units. Thus, the selection of the fibril or cubic product is achieved by control of reaction kinetics. Finally, niobates with different structures exhibit remarkable differences in light absorption and photoluminescence properties. Therefore, this study is of importance for developing new functional materials by the wet-chemistry process.


User testing of an adaptation of fishbone diagrams to depict results of systematic reviews.
Summary of findings tables in systematic reviews are highly informative but require epidemiological training to be interpreted correctly. The usage of fishbone diagrams as graphical displays could offer researchers an effective approach to simplify content for readers with limited epidemiological training. In this paper we demonstrate how fishbone diagrams can be applied to systematic reviews and present the results of an initial user testing. Findings from two systematic reviews were graphically depicted in the form of the fishbone diagram. To test the utility of fishbone diagrams compared with summary of findings tables, we developed and pilot-tested an online survey using Qualtrics. Respondents were randomized to the fishbone diagram or a summary of findings table presenting the same body of evidence. They answered questions in both open-ended and closed-answer formats; all responses were anonymous. Measures of interest focused on first and second impressions, the ability to find and interpret critical information, as well as user experience with both displays. We asked respondents about the perceived utility of fishbone diagrams compared to summary of findings tables. We analyzed quantitative data by conducting t-tests and comparing descriptive statistics. Based on real world systematic reviews, we provide two different fishbone diagrams to show how they might be used to display complex information in a clear and succinct manner. User testing on 77 students with basic epidemiological training revealed that participants preferred summary of findings tables over fishbone diagrams. Significantly more participants liked the summary of findings table than the fishbone diagram (71.8% vs. 44.8%; p < .01); significantly more participants found the fishbone diagram confusing (63.2% vs. 35.9%, p < .05) or indicated that it was difficult to find information (65.8% vs. 45%; p < .01). However, more than half of the participants in both groups were unable to find critical information and answer three respective questions correctly (52.6% in the fishbone group; 51.3% in the summary of findings group). Fishbone diagrams are compact visualizations that, theoretically, may prove useful for summarizing the findings of systematic reviews. Initial user testing, however, did not support the utility of such graphical displays.


Measuring Patient-Reported Outcomes Adaptively: Multidimensionality Matters!
As there is currently a marked increase in the use of both unidimensional (UCAT) and multidimensional computerized adaptive testing (MCAT) in psychological and health measurement, the main aim of the present study is to assess the incremental value of using MCAT rather than separate UCATs for each dimension. Simulations are based on empirical data that could be considered typical for health measurement: a large number of dimensions (4), strong correlations among dimensions (.77-.87), and polytomously scored response data. Both variable- (SE < .316, SE < .387) and fixed-length conditions (total test length of 12, 20, or 32 items) are studied. The item parameters and variance-covariance matrix Φ are estimated with the multidimensional graded response model (GRM). Outcome variables include computerized adaptive test (CAT) length, root mean square error (RMSE), and bias. Both simulated and empirical latent trait distributions are used to sample vectors of true scores. MCATs were generally more efficient (in terms of test length) and more accurate (in terms of RMSE) than their UCAT counterparts. Absolute average bias was highest for variable-length UCATs with termination rule SE < .387. Test length of variable-length MCATs was on average 20% to 25% shorter than test length across separate UCATs. This study showed that there are clear advantages of using MCAT rather than UCAT in a setting typical for health measurement.


Biophysical Characterization of Supported Lipid Bilayers Using Parallel Dual-Wavelength Surface Plasmon Resonance and Quartz Crystal Microbalance Measurements.
Supported lipid bilayers (SLBs) have been used extensively as an effective model of biological membranes, in the context of in vitro biophysics research, and the membranes of liposomes, in the context of the development of nanoscale drug delivery devices. Despite numerous surface-sensitive techniques having been applied to their study, the comprehensive optical characterization of SLBs using surface plasmon resonance (SPR) has not been conducted. In this study, Fresnel multilayer analysis is utilized to effectively calculate layer parameters (thickness and refractive indices) with the aid of dual-wavelength and dispersion coefficient analysis, in which the linear change in the refractive index as a function of wavelength is assumed. Using complementary information from impedance-based quartz crystal microbalance experiments, biophysical properties, for example, area-per-lipid-molecule and the quantity of lipid-associated water molecules, are calculated for different lipid types and mixtures, one of which is representative of a raft-forming lipid mixture. It is proposed that the hydration layer beneath the bilayer is, in fact, an integral part of the measured optical signal. Also, the traditional Jung model analysis and the ratio of SPR responses are investigated in terms of assessing the structure of the lipid layer that is formed.


Voxel effects within digital images of trabecular bone and their consequences on chord-length distribution measurements.
Chord-length distributions through the trabecular regions of the skeleton have been investigated since the early 1960s. These distributions have become important features for bone marrow dosimetry; as such, current models rely on the accuracy of their measurements. Recent techniques utilize nuclear magnetic resonance (NMR) microscopy to acquire 3D images of trabecular bone that are then used to measure 3D chord-length distributions by Monte Carlo methods. Previous studies have shown that two voxel effects largely affect the acquisition of these distributions within digital images. One is particularly pertinent as it dramatically changes the shape of the distribution and reduces its mean. An attempt was made to reduce this undesirable effect and good results were obtained for a single-sphere model using minimum acceptable chord (MAC) methods (Jokisch et al 2001 Med. Phys. 28 1493-504). The goal of the present work is to extend the study of these methods to more general models in order to better quantify their consequences. First, a mathematical model of a trabecular bone sample was used to test the usefulness of the MAC methods. The results showed that these methods were not efficient for this simulated bone model. These methods were further tested on a single voxelized sphere over a large range of voxel sizes. The results showed that the MAC methods are voxel-size dependent and overestimate the mean chord length for typical resolutions used with NMR microscopy. The study further suggests that bone and marrow chord-length distributions currently utilized in skeletal dosimetry models are most likely affected by voxel effects that yield values of mean chord length lower than their true values.


METHEMOGLOBIN FORMATION BY STERILE CULTURE FILTRATES OF PNEUMOCOCCUS.
1. Sterile filtrates of aerobic cultures of pneumococcus which contain hydrogen peroxide are capable of converting catalase-free solutions of crystalline oxyhemoglobin into methemoglobin. This action is dependent upon the hydrogen peroxide in the filtrates and occurs only in the absence of blood catalase. 2. In catalase-containing solutions of hemoglobin from laked corpuscles, the actual methemoglobin-forming system of Pneumococcus involves a labile constituent of the bacterial cell. This intracellular substance is itself susceptible to oxidizing agents and may be rendered inactive, if exposed to peroxide or similar substances previous to its introduction into oxyhemoglobin solutions. The activity of this function in the case of sterile filtrates of pneumococcus cultures depends, therefore, upon the liberation of cell constituents into the medium and upon the protection of these cellular substances from the oxidizing agents which are formed when pneumococcus cultures are freely exposed to air. When these cultural conditions are fulfilled sterile culture filtrates of Pneumococcus convert oxyhemoglobin into methemoglobin independent of the presence of blood catalase.


[IrCl{N(CHCHPtBu2)2}]-: a versatile source of the Ir(I)(PNP) pincer platform.
The iridium(II) complex [IrCl{N(CHCHPtBu2)2}] is reduced by KC8 to give the anionic iridium(I) pincer complex [IrCl{N(CHCHPtBu2)2}](-) which was isolated and fully characterized upon stabilization of the counter cation with crown ether as [K(15-cr-5)2][IrCl{N(CHCHPtBu2)2}]. This unprecedented anionic iridium(I) pincer complex completes the unusual, structurally characterized Ir(I)/Ir(II)/Ir(III) redox series [IrCl{N(CHCHPtBu2)2}](-/0/+), all in a square-planar coordination geometry, emphasizing the versatility of this PNP pincer ligand in stabilizing a broad range of oxidation states. The anionic chloro complex is a versatile source of the Ir(PNP) platform. Its reactivity was examined towards chloride ligand substitution against CO and N2, and oxidative addition of C-electrophiles, C-H bonds and dioxygen, allowing for the isolation of iridium(I) and iridium(III) (PNP) carbonyl, hydrocarbyl and peroxo complexes which were spectroscopically and crystallographically characterized.


Follow-Up Data Improve the Estimation of the Prevalence of Heavy Alcohol Consumption.
We aim to adjust for potential non-participation bias in the prevalence of heavy alcohol consumption. Population survey data from Finnish health examination surveys conducted in 1987-2007 were linked to the administrative registers for mortality and morbidity follow-up until end of 2014. Utilising these data, available for both participants and non-participants, we model the association between heavy alcohol consumption and alcohol-related disease diagnoses. Our results show that the estimated prevalence of heavy alcohol consumption is on average of 1.5 times higher for men and 1.8 times higher for women than what was obtained from participants only (complete case analysis). The magnitude of the difference in the mean estimates by year varies from 0 to 9 percentage points for men and from 0 to 2 percentage points for women. The proposed approach improves the prevalence estimation but requires follow-up data on non-participants and Bayesian modelling.