Processes of excitation in the dendrites and in the soma of single isolated sensory nerve cells of the lobster and crayfish.
The stretch receptor organs of Alexandrowicz in lobster and crayfish possess sensory neurons which have their cell bodies in the periphery. The cell bodies send dendrites into a fine nearby muscle strand and at the opposite pole they give rise to an axon running to the central nervous system. Mechanisms of excitation between dendrites, cell soma, and axon have been studied in completely isolated receptor structures with the cell components under visual observation. Two sensory neuron types were investigated, those which adapt rapidly to stretch, the fast cells, and those which adapt slowly, the slow cells. 1. Potentials recorded from the cell body of the neurons with intracellular leads gave resting potentials of 70 to 80 mv. and action potentials which in fresh preparations exceeded the resting potentials by about 10 to 20 mv. In some experiments chymotrypsin or trypsin was used to make cell impalement easier. They did not appreciably alter resting or action potentials. 2. It has been shown that normally excitation starts in the distal portion of dendrites which are depolarized by stretch deformation. The changed potential within the dendritic terminals can persist for the duration of stretch and is called the generator potential. Secondarily, by electrotonic spread, the generator potential reduces the resting potential of the nearby cell soma. This excitation spread between dendrites and soma is seen best during subthreshold excitation by relatively small stretches of normal cells. It is also seen during the whole range of receptor stretch in neurons in which nerve conduction has been blocked by an anesthetic. The electrotonic changes in the cells are graded, reflecting the magnitude and rate of rise of stretch, and presumably the changing levels of the generator potential. Thus in the present neurons the resting potential and the excitability level of the cell soma can be set and controlled over a wide range by local events within the dendrites. 3. Whenever stretch reduces the resting membrane potential, measured in the relaxed state in the cell body, by 8 to 12 mv. in slow cells and by 17 to 22 mv. in fast cells, conducted impulses are initiated. It is thought that in slow cells conducted impulses are initiated in the dendrites while in fast cells they arise in the cell body or near to it. In fresh preparations the speed of stretch does not appreciably influence the membrane threshold for discharges, while during developing fatigue the firing level is higher when extension is gradual. 4. Some of the specific neuron characteristics are: Fast receptor cells have a relatively high threshold to stretch. During prolonged stretch the depolarization of the cell soma is not well maintained, presumably due to a decline in the generator potential, resulting in cessation of discharges in less than a minute. This appears to be the basis of the relatively rapid adaptation. A residual subthreshold depolarization can persist for many minutes of stretch. Slow cells which resemble the sensory fibers of vertebrate spindles are excited by weak stretch. Their discharge rate remains remarkably constant for long periods. It is concluded that, once threshold excitation is reached, the generator potential within slow cell dendrites is well maintained for the duration of stretch. Possible reasons for differences in discharge properties between fast and slow cells are discussed. 5. If stretch of receptor cells is gradually continued above threshold, the discharge frequency first increases over a considerable range without an appreciable change in the firing level for discharges. Beyond that range the membrane threshold for conducted responses of the cell soma rises, the impulses become smaller, and partial conduction in the soma-axon boundary region occurs. At a critical depolarization level which may be maintained for many minutes, all conduction ceases. These overstretch phenomena are reversible and resemble cathodal block. 6. The following general scheme of excitation is proposed: stretch deformation of dendritic terminals --> generator potential --> electrotonic spread toward the cell soma (prepotential) --> dendrite-soma impulse --> axon impulse. 7. Following release of stretch a transient hyperpolarization of slow receptor cells was seen. This off effect is influenced by the speed of relaxation. 8. Membrane potential changes recorded in the cell bodies serve as very sensitive detectors of activity within the receptor muscle bundles, indicating the extent and time course of contractile events.


Photoacoustic Imaging for Assessing Tissue Oxygenation Changes in Rat Hepatic Fibrosis.
Chronic liver inflammation progressively evokes fibrosis and cirrhosis resulting in compromised liver function, and often leading to cancer. Early diagnosis and staging of fibrosis is crucial because the five-year survival rate of early-stage liver cancer is high. This study investigates the progression of hepatic fibrosis induced in rats following ingestion of diethylnitrosamine (DEN). Changes in oxygen saturation and hemoglobin concentration resulting from chronic inflammation were assayed longitudinally during DEN ingestion by photoacoustic imaging (PAI). Accompanying liver tissue changes were monitored simultaneously by B-mode sonographic imaging. Oxygen saturation and hemoglobin levels in the liver increased over 5 weeks and peaked at 10 weeks before decreasing at 13 weeks of DEN ingestion. The oxygenation changes were accompanied by an increase in hepatic echogenicity and coarseness in the ultrasound image. Histology at 13 weeks confirmed the development of severe fibrosis and cirrhosis. The observed increase in PA signal representing enhanced blood oxygenation is likely an inflammatory physiological response to the dietary DEN insult that increases blood flow by the development of neovasculature to supply oxygen to a fibrotic liver during the progression of hepatic fibrosis. Assessment of oxygenation by PAI may play an important role in the future assessment of hepatic fibrosis.


Motoneurons secrete angiogenin to induce RNA cleavage in astroglia.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.


Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases.
Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups-probands with SAID, their unaffected twins, and matched, unrelated healthy controls-using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID.


The structure and reliability of health belief indices.
A wealth of research using the Health Belief Model provides empirical evidence of the model's utility in predicting health, illness, and sick role behaviors. Until recently, however, little attention has been paid to the important issues of the validity and reliability of measures used to assess various health belief dimensions. Using factor analysis, our study demonstrates that moderately reliable indices covering a wide spectrum of distinct health beliefs can be constructed and then replicated across independent samples. The factor analysis approach revealed that condition-specific measures of perception of susceptibility and severity and situation-specific measures of perceived barriers are empirically distinct from general measures of these beliefs. We therefore recommend caution in mixing general and specific questionnaire items within the same index when measuring these beliefs. A factor representing perceptions of health threat emerged, but its composition require further clarification. The degree of similarity between the factor structures in the two independent samples provides support for the existence of independent health belief dimensions.


Neonatal novelty exposure modulates hippocampal volumetric asymmetry in the rat.
Early life environmental manipulations have been shown to affect hippocampal-dependent learning, hippocampal volume and cerebral lateralization. In this study, we investigated the effects of neonatal stimulation on hippocampal volumetric asymmetry. Long-Evans hooded rats were exposed to a novel non-home environment 3 min daily for the first 3 weeks of life. Histological measures of the left and right hippocampus were made at 8 months of age. We found that neonatal novelty exposure resulted in a long-lasting change in hippocampal volumetric asymmetry. Specifically, this brief and transient early life stimulation increased the right hippocampal volumetric dominance at mid-adulthood.


A Comparative Study of G-Quadruplex Unfolding and DNA Reeling Activities of Human RECQ5 Helicase.
RECQ5 is one of five members of the RecQ family of helicases in humans, which include RECQ1, Bloom (BLM), Werner (WRN), RECQ4, and RECQ5. Both WRN and BLM have been shown to resolve G-quadruplex (GQ) structures. Deficiencies in unfolding GQ are known to result in DNA breaks and genomic instability, which are prominent in Werner and Bloom syndromes. RECQ5 is significant in suppressing sister chromatid exchanges during homologous recombination but its GQ unfolding activity are not known. We performed single-molecule studies under different salt (50-150 mM KCl or NaCl) and ATP concentrations on different GQ constructs including human telomeric GQ (with different overhangs and polarities) and GQ formed by thrombin-binding aptamer to investigate this activity. These studies demonstrated a RECQ5-mediated GQ unfolding activity that was an order of magnitude weaker than BLM and WRN. On the other hand, BLM and RECQ5 demonstrated similar single-stranded DNA (ssDNA) reeling activities that were not coupled to GQ unfolding. These results demonstrate overlap in function between these RecQ helicases; however, the relatively weak GQ destabilization activity of RECQ5 compared to BLM and WRN suggests that RECQ5 is not primarily associated with GQ destabilization, but could substitute for the more efficient helicases under conditions where their activity is compromised. In addition, these results implicate a more general role for helicase-promoted ssDNA reeling activity such as removal of proteins at the replication fork, whereas the association of ssDNA reeling with GQ destabilization is more helicase-specific.


Entropy-based generating Markov partitions for complex systems.
Finding the correct encoding for a generic dynamical system's trajectory is a complicated task: the symbolic sequence needs to preserve the invariant properties from the system's trajectory. In theory, the solution to this problem is found when a Generating Markov Partition (GMP) is obtained, which is only defined once the unstable and stable manifolds are known with infinite precision and for all times. However, these manifolds usually form highly convoluted Euclidean sets, are a priori unknown, and, as it happens in any real-world experiment, measurements are made with finite resolution and over a finite time-span. The task gets even more complicated if the system is a network composed of interacting dynamical units, namely, a high-dimensional complex system. Here, we tackle this task and solve it by defining a method to approximately construct GMPs for any complex system's finite-resolution and finite-time trajectory. We critically test our method on networks of coupled maps, encoding their trajectories into symbolic sequences. We show that these sequences are optimal because they minimise the information loss and also any spurious information added. Consequently, our method allows us to approximately calculate the invariant probability measures of complex systems from the observed data. Thus, we can efficiently define complexity measures that are applicable to a wide range of complex phenomena, such as the characterisation of brain activity from electroencephalogram signals measured at different brain regions or the characterisation of climate variability from temperature anomalies measured at different Earth regions.


RosettaAntibodyDesign (RAbD): A general framework for computational antibody design.
A structural-bioinformatics-based computational methodology and framework have been developed for the design of antibodies to targets of interest. RosettaAntibodyDesign (RAbD) samples the diverse sequence, structure, and binding space of an antibody to an antigen in highly customizable protocols for the design of antibodies in a broad range of applications. The program samples antibody sequences and structures by grafting structures from a widely accepted set of the canonical clusters of CDRs (North et al., J. Mol. Biol., 406:228-256, 2011). It then performs sequence design according to amino acid sequence profiles of each cluster, and samples CDR backbones using a flexible-backbone design protocol incorporating cluster-based CDR constraints. Starting from an existing experimental or computationally modeled antigen-antibody structure, RAbD can be used to redesign a single CDR or multiple CDRs with loops of different length, conformation, and sequence. We rigorously benchmarked RAbD on a set of 60 diverse antibody-antigen complexes, using two design strategies-optimizing total Rosetta energy and optimizing interface energy alone. We utilized two novel metrics for measuring success in computational protein design. The design risk ratio (DRR) is equal to the frequency of recovery of native CDR lengths and clusters divided by the frequency of sampling of those features during the Monte Carlo design procedure. Ratios greater than 1.0 indicate that the design process is picking out the native more frequently than expected from their sampled rate. We achieved DRRs for the non-H3 CDRs of between 2.4 and 4.0. The antigen risk ratio (ARR) is the ratio of frequencies of the native amino acid types, CDR lengths, and clusters in the output decoys for simulations performed in the presence and absence of the antigen. For CDRs, we achieved cluster ARRs as high as 2.5 for L1 and 1.5 for H2. For sequence design simulations without CDR grafting, the overall recovery for the native amino acid types for residues that contact the antigen in the native structures was 72% in simulations performed in the presence of the antigen and 48% in simulations performed without the antigen, for an ARR of 1.5. For the non-contacting residues, the ARR was 1.08. This shows that the sequence profiles are able to maintain the amino acid types of these conserved, buried sites, while recovery of the exposed, contacting residues requires the presence of the antigen-antibody interface. We tested RAbD experimentally on both a lambda and kappa antibody-antigen complex, successfully improving their affinities 10 to 50 fold by replacing individual CDRs of the native antibody with new CDR lengths and clusters.


The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data.
Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Bill & Melinda Gates Foundation.


Assessing the diagnostic accuracy of a sequence of tests.
We consider the assessment of the overall diagnostic accuracy of a sequence of tests (e.g. repeated screening tests). The complexity of diagnostic choices when two or more continuous tests are used in sequence is illustrated, and different approaches to reducing the dimensionality are presented and evaluated. For instance, in practice, when a single test is used repeatedly in routine screening, the same screening threshold is typically used at each screening visit. One possible alternative is to adjust the threshold at successive visits according to individual-specific characteristics. Such possibilities represent a particular slice of a receiver operating characteristic surface, corresponding to all possible combinations of test thresholds. We focus in the development and examples on the setting where an overall test is defined to be positive if any of the individual tests are positive ('believe the positive'). The ideas developed are illustrated by an example of application to screening for prostate cancer using prostate-specific antigen.


Ultrahigh Carrier Mobility Achieved in Photoresponsive Hybrid Perovskite Films via Coupling with Single-Walled Carbon Nanotubes.
Organolead trihalide perovskites have drawn substantial interest for photovoltaic and optoelectronic applications due to their remarkable physical properties and low processing cost. However, perovskite thin films suffer from low carrier mobility as a result of their structural imperfections such as grain boundaries and pinholes, limiting their device performance and application potential. Here we demonstrate a simple and straightforward synthetic strategy based on coupling perovskite films with embedded single-walled carbon nanotubes. We are able to significantly enhance the hole and electron mobilities of the perovskite film to record-high values of 595.3 and 108.7 cm2 V-1 s-1 , respectively. Such a synergistic effect can be harnessed to construct ambipolar phototransistors with an ultrahigh detectivity of 3.7 × 1014 Jones and a responsivity of 1 × 104 A W-1 , on a par with the best devices available to date. The perovskite/carbon nanotube hybrids should provide a platform that is highly desirable for fields as diverse as optoelectronics, solar energy conversion, and molecular sensing.


Fast approximate surface evolution in arbitrary dimension.
The level set method is a popular technique used in medical image segmentation; however, the numerics involved make its use cumbersome. This paper proposes an approximate level set scheme that removes much of the computational burden while maintaining accuracy. Abandoning a floating point representation for the signed distance function, we use integral values to represent the signed distance function. For the cases of 2D and 3D, we detail rules governing the evolution and maintenance of these three regions. Arbitrary energies can be implemented in the framework. This scheme has several desirable properties: computations are only performed along the zero level set; the approximate distance function requires only a few simple integer comparisons for maintenance; smoothness regularization involves only a few integer calculations and may be handled apart from the energy itself; the zero level set is represented exactly removing the need for interpolation off the interface; and evolutions proceed on the order of milliseconds per iteration on conventional uniprocessor workstations. To highlight its accuracy, flexibility and speed, we demonstrate the technique on intensity-based segmentations under various statistical metrics. Results for 3D imagery show the technique is fast even for image volumes.


Effects of melatonin on the proliferation and differentiation of human neuroblastoma cells in culture.
Since melatonin has direct inhibitory effects on some tumor cells in vitro, the aim of the present work was to study whether the growth and structural characteristics of the human neuroblastoma cell line SK-N-SH in vitro are influenced by this indoleamine. Concentrations of melatonin of 10(-9) and 10(-11) M significantly inhibited (P < 0.05) cell proliferation. Subphysiological (10(-13) M) or supraphysiological (10(-7) and 10(-5) M) concentrations of melatonin lacked this effect. After 8 days of exposure to melatonin (10(-9) M), cells showed significantly smaller cell and nuclear sizes than control cells. Melatonin-treated cells presented greater neurite outgrowth than control cells. These results support the hypothesis that melatonin, at physiological concentrations, exerts a direct antiproliferative effect on SK-N-SH cells, promoting the differentiation of neuroblastoma cells.


The problem of "significant risk": exploring the public health impact of criminalizing HIV non-disclosure.
Using criminal law powers to respond to people living with HIV (PHAs) who expose sexual partners to HIV or transmit the virus to them is a prominent global HIV public policy issue. While there are widespread concerns about the public health impact of HIV-related criminalization, the social science literature on the topic is limited. This article responds to that gap in knowledge by reporting on the results of qualitative research conducted with service providers and PHAs in Canada. The article draws on a studies in the social organization of knowledge perspective and insights from critical criminology and work on the "medico-legal borderland." It investigates the role played by the legal concept of "significant risk" in coordinating criminal law governance and its interface with public health and HIV prevention. In doing so, the article emphasizes that exploring the public health impact of criminalization must move past the criminal law--PHA dyad to address broader social and institutional processes relevant to HIV prevention. Drawing on individual and focus group interviews, this article explores how criminal law governance shapes the activities of providers engaged in HIV prevention counseling, conceptualized as a complex of activities linking clinicians, public health officials, front-line counselors, PHAs, and others. It emphasizes three key findings: (1) the concept of significant risk poses serious problems to risk communication in HIV counseling and contributes to contradictory advice about disclosure obligations; (2) criminalization discourages PHAs' openness about HIV non-disclosure in counseling relationships; and (3) the recontextualization of public health interpretations of significant risk in criminal proceedings can intensify criminalization.


Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers.
A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.


Regulatory barriers to equity in a health system in transition: a qualitative study in Bulgaria.
Health reforms in Bulgaria have introduced major changes to the financing, delivery and regulation of health care. As in many other countries of Central and Eastern Europe, these included introducing general practice, establishing a health insurance system, reorganizing hospital services, and setting up new payment mechanisms for providers, including patient co-payments. Our study explored perceptions of regulatory barriers to equity in Bulgarian child health services. 50 qualitative in-depth interviews with users, providers and policy-makers concerned with child health services in Bulgaria, conducted in two villages, one town of 70,000 inhabitants, and the capital Sofia. The participants in our study reported a variety of regulatory barriers which undermined the principles of equity and, as far as the health insurance system is concerned, solidarity. These included non-participation in the compulsory health insurance system, informal payments, and charging user fees to exempted patients. The participants also reported seemingly unnecessary treatments in the growing private sector. These regulatory failures were associated with the fast pace of reforms, lack of consultation, inadequate public financing of the health system, a perceived "commercialization" of medicine, and weak enforcement of legislation. A recurrent theme from the interviews was the need for better information about patient rights and services covered by the health insurance system. Regulatory barriers to equity and compliance in daily practice deserve more attention from policy-makers when embarking on health reforms. New financing sources and an increasing role of the private sector need to be accompanied by an appropriate and enforceable regulatory framework to control the behavior of health care providers and ensure equity in access to health services.


Physicians certified in family medicine. What are they doing 8 to 10 years later?
To determine field of medicine and location of a cohort of physicians certified in family medicine between 1989 and 1991 and residing in Ontario in 1993 and to gather information on the scope of practice of family physicians in the cohort in 1999. Responses to a mailed questionnaire sent in 1999 were compared with responses to a 1993 survey of this group. All family physicians in Ontario in 1993 who received certification in 1989, 1990, or 1991 after completing a family medicine residency. Seven of 557 respondents to the 1993 survey were ineligible; 293 physicians (53%) responded to the 1999 survey. Field, location, and scope of practice. About 91% of the cohort were still practising family medicine, although 11% of these had restricted their practices to certain areas within family medicine. Physicians migrated from Ontario (6%) in nearly equal numbers to other provinces and other countries, predominantly the United States. More family physicians offered counseling, shared antenatal care, and newborn care in 1999 than in 1993. Those with restricted family practices provided fewer types of services and were less likely to provide antenatal or intrapartum care or to provide in-hospital services. Receiving certification in family medicine does not guarantee that physicians will remain in family practice 8 to 10 years later. Loss from general family medicine to restricted practices within family medicine and specialization was greater than loss from migration.


Cellular basis of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-β (Aβ) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aβ peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing β- and γ-secretases. All these proteins involved in the production of Aβ peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.


Cylindrical vector beam generation in fiber with mode selectivity and wavelength tunability over broadband by acoustic flexural wave.
Theoretical analysis and experimental demonstration are presented for the generation of cylindrical vector beams (CVBs) via mode conversion in fiber from HE11 mode to TM01 and TE01 modes, which have radial and azimuthal polarizations, respectively. Intermodal coupling is caused by an acoustic flexural wave applied on the fiber, whereas polarization control is necessary for the mode conversion, i.e. HE11x→TM01 and HE11y→TE01 for acoustic vibration along the x-axis. The frequency of the RF driving signal for actuating the acoustic wave is determined by the phase matching condition that the period of acoustic wave equals the beatlength of two coupled modes. With phase matching condition tunability, this approach can be used to generate different types of CVBs at the same wavelength over a broadband. Experimental demonstration was done in the visible and communication bands.


Scaling community-based services in Gauteng, South Africa: A comparison of three workforce-planning scenarios.
The introduction of community-based services through community health workers is an opportunity to redefine the approach and practice of primary health care. Based on bestpractice community oriented primary care (COPC), a COPC planning toolkit has been developed to model the creation of a community-based tier in an integrated district health system. The article describes the methodologies and assumptions used to determine workforce numbers and service costs for three scenarios and applies them to the poorest 60% of the population in Gauteng, South Africa. The study derives from a Gauteng Department of Health, Family Medicine (University of Pretoria) partnership to support information and communication technology (ICT)-enabled COPC through community-based health teams (termed as ward-based outreach teams). The modelling uses national census age, gender and income data at small area level, provincial facility and national burden of disease data. Service calculations take into account multidimensional poverty, demand-adjusted burden of disease and available work time adjusted for conditions of employment and geography. Assuming the use of ICT for each, a health workforce of 14 819, 17 925 and 7303 is required per scenario (current practice, national norms and full-time employed COPC), respectively. Total service costs for the respective scenarios range from R1.1 billion, through R947 million to R783 million. Modelling shows that delivering ICT-enabled COPC with full-time employees is the optimal scenario. It requires the smallest workforce, is the most economical, even when individual community health worker costs of employment are twice those of current practice, and is systemically the most effective.


Mating patterns amongst Siberian reindeer herders: inferences from mtDNA and Y-chromosomal analyses.
The Evenks and Evens, who speak closely related languages belonging to the Northern Tungusic branch of the Tungusic family, are nomadic reindeer herders and hunters. They are spread over an immense territory in northeastern Siberia, and consequently different subgroups are in contact with diverse peoples speaking Samoyedic, Turkic, Mongolic, Chukotka-Kamchatkan, and Yukaghir languages. Nevertheless, the languages and culture of the Evenks and Evens are similar enough for them to have been classified as a single ethnic group in the past. This linguistic and cultural similarity indicates that they may have spread over their current area of habitation relatively recently, and thus may be closely related genetically. On the other hand, the great distances that separate individual groups of Evens and Evenks from each other might have led to preferential mating with geographic neighbors rather than with linguistically related peoples. In this study, we assess the correlation between linguistic and genetic relationship in three different subgroups of Evenks and Evens, respectively, via mtDNA and Y-chromosomal analyses. The results show that there is some evidence of a common origin based on shared mtDNA lineages and relatively similar Y-haplogroup frequencies amongst most of the Evenk and Even subgroups. However, there is little sharing of Y-chromosomal STR haplotypes, indicating that males within Evenk and Even subgroups have remained relatively isolated. There is further evidence of some female admixture in different Even subgroups with their respective geographic neighbors. However, the Tungusic groups, and especially the Evenks, show signs of genetic drift, making inferences about their prehistory difficult.


Rapid fabrication of microhole array structured optical fibers.
A microhole array in a common single-mode fiber is fabricated by selective chemical etching of femtosecond-laser-induced fiber Bragg grating (FBG), which has a laser-modified region extending from the fiber core to the cladding-air boundary due to laser self-focusing. The shape and size of the orderly microhole on the fiber surface are controlled via changing conditions of FBG fabrication and chemical etching. A simultaneous sensing for surrounding refractive index and temperature is demonstrated by this microhole array FBG through measurement of the transmission power change and Bragg resonant wavelength shift.


Digital health system for personalised COPD long-term management.
Recent telehealth studies have demonstrated minor impact on patients affected by long-term conditions. The use of technology does not guarantee the compliance required for sustained collection of high-quality symptom and physiological data. Remote monitoring alone is not sufficient for successful disease management. A patient-centred design approach is needed in order to allow the personalisation of interventions and encourage the completion of daily self-management tasks. A digital health system was designed to support patients suffering from chronic obstructive pulmonary disease in self-managing their condition. The system includes a mobile application running on a consumer tablet personal computer and a secure backend server accessible to the health professionals in charge of patient management. The patient daily routine included the completion of an adaptive, electronic symptom diary on the tablet, and the measurement of oxygen saturation via a wireless pulse oximeter. The design of the system was based on a patient-centred design approach, informed by patient workshops. One hundred and ten patients in the intervention arm of a randomised controlled trial were subsequently given the tablet computer and pulse oximeter for a 12-month period. Patients were encouraged, but not mandated, to use the digital health system daily. The average used was 6.0 times a week by all those who participated in the full trial. Three months after enrolment, patients were able to complete their symptom diary and oxygen saturation measurement in less than 1 m 40s (96% of symptom diaries). Custom algorithms, based on the self-monitoring data collected during the first 50 days of use, were developed to personalise alert thresholds. Strategies and tools aimed at refining a digital health intervention require iterative use to enable convergence on an optimal, usable design. 'Continuous improvement' allowed feedback from users to have an immediate impact on the design of the system (e.g., collection of quality data), resulting in high compliance with self-monitoring over a prolonged period of time (12-month). Health professionals were prompted by prioritisation algorithms to review patient data, which led to their regular use of the remote monitoring website throughout the trial. Trial registration: ISRCTN40367841 . Registered 17/10/2012.


Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development.
Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.


A network of trans-cortical capillaries as mainstay for blood circulation in long bones.
Closed circulatory systems (CCS) underlie the function of vertebrate organs, but in long bones their structure is unclear, although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil emigration from BM, we studied the vascular system of murine long bones. Here we show that hundreds of capillaries originate in BM, cross murine cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical-vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% arterial and 59% venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the CCS in long bones and may represent an important route for immune cell export from the BM.


Error analysis for the lidar backward inversion algorithm.
Here we depart from the inhomogeneous solution of a lidar equation using the backward inversion algorithm that is nowadays generally referred to as the Klett method. In particular, we develop an error sensitivity study that relates errors in the user-input parameters boundary extinction and exponential term in the extinction-to-backscatter relationship to errors in the inverted extinction profile. The validity of the analysis presented is limited only by the validity of application of the inversion algorithm itself, its numerical performance having been tested for optical depths in the 0.01-10 range. Toward this end, we focus on an introductory background about how uncertainties in these two parameters can apply to a family of inverted extinction profiles rather than a single profile and on its range-dependent behavior as a function of the optical thickness of the lidar inversion range. Next, we performed a mathematical study to derive the error span of the inverted extinction profile that is due to uncertainties in the above-mentioned user calibration parameters. This takes the form of upper and lower range-dependent error bounds. Finally, appropriate inversion plots are presented as application examples of this study to a parameterized set of atmospheric scenes inverted from both synthesized elastic-backscatter lidar signals and a live signal.


Hallmarks of cancer: the next generation.
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.


Regulation of rat bone sialoprotein gene transcription by enamel matrix derivative.
Enamel matrix derivative (EMD) has recently been developed for use as a periodontal regenerative treatment. While EMD is believed to induce regeneration of periodontal tissue, the precise mechanism is not known. Bone sialoprotein (BSP), an early phenotypic marker of osteoblast differentiation, has been implicated in the nucleation of hydroxyapatite during bone formation. In this study, we examined the ability of EMD to regulate BSP gene transcription in osteoblast-like cells. To determine the molecular basis of the transcriptional regulation of BSP gene transcription by EMD, we conducted Northern hybridization, transient transfection analyses with chimeric constructs of the rat BSP gene promoter linked to a luciferase reporter gene, and gel mobility shift assays. Using the osteoblastic cell line ROS 17/2.8, we determined that BSP mRNA levels increased approximately 2.8-fold by EMD. In transient transfection analyses, EMD (50 microg/ml, 12 hours) increased luciferase activities of pLUC4 (nt -425 to +60) and pLUC5 (nt -801 to +60), transfected into ROS 17/2.8 cells. Within the pLUC4 and 5, a homeodomain binding element (HOX) and a transforming growth factor (TGF)-beta activation element (TAE) are present. Gel mobility shift assays with radiolabeled HOX and TAE ds-oligonucleotides revealed increased binding of nuclear proteins from EMD stimulated ROS 17/2.8 cells. These studies have, therefore, identified EMD response elements in the rat BSP gene promoter that may mediates the effects of EMD on BSP gene transcription.


Analysis of epidemiology, lesions, treatment and outcome of 354 consecutive cases of blunt and penetrating trauma to the chest in an African setting.
The proportion of death and disability related to trauma is increasing in Third-World countries. Thoracic trauma is significantly involved, but few data are available on this issue in African countries with specific local conditions. The aim of the study is to analyse the diagnosis and management procedures in thoracic trauma in a typical African country. The records of 354 patients admitted to an emergency unit for chest trauma over a 13-year period were retrospectively analysed. The sample included patients with 231 cases of blunt and 123 of penetrating trauma to the chest; their mean age was 41.86 years, and the male:female ratio was 4.2:1. The majority (N=226) of the injuries were sustained in road traffic accidents, and the most common lesions were rib fractures (50.3%) and haemothorax (38.7%). The diagnosis was based on physical examination and standard chest radiographs in most cases. At least one associated lesion was found in 260 (73.45%) patients. The mean injury severity score (ISS) for our patients was 16.39. Most patients were managed conservatively (N=303); thoracotomy was performed mostly on penetrating trauma patients. Morbidity occurred in 49 patients, mainly affecting those treated with thoracic drainage, and 27 patients (7.6%) died. Factors related to mortality were ISS score and association with neurotrauma. Chest trauma can be managed in our Cameroonian environment, with morbidity and mortality comparable with that of Western countries. Diagnosis must still rely on physical examination, chest radiographs and thoracic echography, which are affordable tools.


Corticotropin-releasing factor receptors and stress-related alterations of gut motor function.
Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology.


Transmembrane biogenesis of Kv1.3.
Using a combination of protease protection, glycosylation, and carbonate extraction assays, we have characterized the topogenic determinants encoded by Kv1.3 segments that mediate translocation events during endoplasmic reticulum (ER) biogenesis. Transmembrane segments S1, S2, S3, S5, and S6 initiate translocation, only S1 and S2 strongly (>60%) anchor themselves in the membrane, S5 exhibits signal anchor activity and contains a cryptic cleavage site, and S3 and S6 fail to integrate into the membrane. Elongation of each single-transmembrane construct to include multiple transmembrane segments alters integration and translocation efficiencies, indicating that multiple topogenic determinants cooperate during Kv1. 3 topogenesis and assembly. Several surprising findings emerged from these studies. First, in the presence of T1, the N-terminal recognition domain, S1 was unable to initiate either translocation or membrane integration. As a result, S2 likely functions as the initial signal sequence to establish Kv1.3 N-terminus topology. Second, S4 independently integrates into the membrane. Third, S6 plus the C-terminus of Kv1.3 is a secretory protein but can be converted to a membrane-integrated protein with a correctly oriented, cytosolic C-terminus by linking S6 to S5 and the pore loop. These results have implications for the role of the N-terminus in Kv biogenesis and on the mechanisms of dominant negative suppression of Kv1.3 by truncated Kv1.3 fragments [Tu et al. (1996) J. Biol. Chem. 271, 18904-18911].


Converging endometrial and ovarian tumorigenesis in Lynch syndrome: Shared origin of synchronous carcinomas.
The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.


Where are general surgeons located in South Africa?
Human resources are the backbone of health-care delivery systems and the lack of surgical workforce in developing countries is often the greatest challenge to providing surgical care. The workforce availability and composition is an important indicator of the strength of the health system. This study aimed to analyse the distribution of general surgeons within South Africa. A descriptive analysis of the general surgical workforce in South Africa was performed. The total number of specialist and non-specialist general surgeons working in the public sector in South Africa was documented between the periods from the 1 October 2014 until 31 December 2014. There were significant disparities in the number and distribution of general surgeons in South Africa. There were 1.78 specialist general surgeons per 100 000, of which 0.69 per 100 000 specialist general surgeons were working in the public sector. There were 2.90 non-specialist general surgeons per 100 000. There were 6 specialist general surgeons per 100 000 insured population working in the private sector, which is comparable with the United States (US). Urban provinces such as Gauteng, the Western Cape and KwaZulu-Natal had the largest number of specialist general surgeons per 100 000. These areas had the largest number of medical aid beneficiaries and nearly 60% of specialist general surgeons were estimated to work exclusively in the private sector. There was a major shortage of surgical providers in South Africa, and in particular the public sector.


Monocarboxylic acid transport.
Monocarboxylates such as lactate, pyruvate, and the ketone bodies play major roles in metabolism and must be transported across both the plasma membrane and mitochondrial inner membrane. A family of five proton-linked MonoCarboxylate Transporters (MCTs) is involved in the former and the mitochondrial pyruvate carrier (MPC) mediates the latter. In the intestine and kidney, two Sodium-coupled MonoCarboxylate Transporters (SMCTs) provide active transport of monocarboxylates across the apical membrane of the epithelial cells with MCTs on the basolateral membrane transporting the accumulated monocarboxylate into the blood. The kinetics and substrate and inhibitor specificities of MCTs, SMCTs, and the MPC have been well characterized and the molecular identity of the MCTs and SMCTs defined unequivocally. The identity of the MPC is less certain. The MCTs have been extensively studied and the three-dimensional structure of MCT1 has been modeled and a likely catalytic mechanism proposed. MCTs require the binding of a single transmembrane glycoprotein (either embigin or basigin) for activity. Regulation of MCT activity involves both transcriptional and posttranscriptional mechanisms, examples being upregulation of MCT1 by chronic exercise in red muscle (which oxidizes lactate) and in T-lymphocytes upon stimulation. MCT4 has properties that make it especially suited for lactic acid export by glycolytic cells and is upregulated by hypoxia. Some disease states are associated with modulation of plasma membrane and mitochondrial monocarboxylate transport and MCTs are promising drug targets for cancer chemotherapy. They may also be involved in drug uptake from the intestine and subsequent transport across the blood brain barrier.


Crystallography of the hexagonal ferrites.
The hexagonal ferrites form an unusual group of complex, ferrimagnetic oxides embodying some 60 known crystal structures. These include phases for which the structural unit cell is larger than that in any known inorganic materials. The various hexagonal ferrite modifications fall into two distinct structural series, each formed by the ordered interlayering (stacking) of two discrete building blocks; these blocks stack along the c crystallographic axis in varying ratios and varying permutations to form strictly coherent, reproducible crystal structures. This mixed-layering aspect of the hexagonal ferrites permits direct, visual observation of the sequence of their subunit-cell stacking elements, after etching, by means of electron microscopy. The sequence of stacked blocks in such structures constitutes the only information lacking for a complete, three-dimensional structure determination. Direct access to this information provides an immediate, unique solution of the crystal structure problem in each case and thereby avoids the dilemmas of a classical diffraction approach to such large unit cells. Ferrite structures with hexagonal c dimensions of 1455 and 1577 angstroms have been uniquely solved by direct electron microscopic readout of surface etch features. One must exercise caution, however, in generalizing these findings to other materials. The method is successful in the case of the hexagonal ferrites because these are mixed-layer structures, wherein the building blocks react at different rates to a specific etchant. Mixed-layer systems are not uncommon in crystallography, and it is likely that similar techniques can be developed for other such materials. Regardless of the validity of this prognosis, however, it is quite evident that high-resolution replica electron microscopy is a most promising tool for the direct observation of surface structure on an ultramicro scale. During the studies reported here replica resolution capability was improved to about 10 angstroms; final resolution is limited by the particle size of the platinum shadowing material. Careful control of experimental conditions during replica preparation or an alternate choice of shadowing material, or both, might reasonably improve the resolution by a factor of 2. This resolution is within the range of most unit cell dimensions and approaches interatomic distances in solid-state materials. The potential of such an experimental capability needs no elaboration.


Pulmonary ventilation/perfusion defects induced by epinephrine during cardiopulmonary resuscitation.
Epinephrine has been shown to impair pulmonary excretion of CO2 during resuscitation. This phenomenon was investigated in a rodent model of cardiac arrest and conventional resuscitation. The effects of racemic epinephrine were compared with the selective alpha 1-agonist methoxamine and with saline placebo during cardiac resuscitation in 15 Sprague-Dawley rats mechanically ventilated with gas containing 70% oxygen. Epinephrine and methoxamine but not saline placebo significantly increased coronary perfusion pressure from approximately 32 to 55 mm Hg. Following epinephrine, end-tidal PCO2 decreased from approximately 10 to 5 mm Hg. This was associated with a time-coincident decrease in PaO2 from approximately 130 to 74 mm Hg and an increase in PaCO2 from approximately 26 to 40 mm Hg. These changes indicated increases in alveolar dead space ventilation concomitant with increases in pulmonary arteriovenous admixture. No such effects were observed after administration of either methoxamine or saline placebo. Each of the 15 rats was successfully resuscitated. However, a significantly larger number of transthoracic countershocks were required after epinephrine compared with methoxamine or placebo before return of spontaneous circulation. Epinephrine induced ventilation/perfusion during cardiopulmonary resuscitation as a result of redistribution of pulmonary blood flow.


Matrix interference reduction for the analysis of carbohydrate in wastewater using H-point standard addition method.
Soluble microbial products, consisting of protein, carbohydrate and humics, are generally considered as the main membrane foulants during the performance of membrane bioreactors. Nitrate and nitrite have been proved to affect the determination of carbohydrate when anthrone-sulfuric acid photometric method is used. In this study, three chemical analytical methods based on photometric assay, including the standard curve method, conventional standard addition method and H-point standard addition method, were assessed for the quantification of carbohydrate in order to reduce the interference. Three methods were carried out for both artificial and real wastewater sample analysis. The results indicated a significant amount of matrix interference, which could be eliminated through the use of H-point standard addition. This study proposed the H-point standard addition method as a more accurate and convenient option for carbohydrate determination.


Online faculty development for creating E-learning materials.
Faculty who want to develop e-learning materials face pedagogical challenges of transforming instruction for the online environment, especially as many have never experienced online learning themselves. They face technical challenges of learning new software and time challenges of not all being able to be in the same place at the same time to learn these new skills. The objective of the Any Day Any Place Teaching (ADAPT) faculty development program was to create an online experience in which faculty could learn to produce e-learning materials. The ADAPT curriculum included units on instructional design, copyright principles and peer review, all for the online environment, and units on specific software tools. Participants experienced asynchronous and synchronous methods, including a learning management system, PC-based videoconferencing, online discussions, desktop sharing, an online toolbox and optional face-to-face labs. Project outcomes were e-learning materials developed and participants' evaluations of the experience. Likert scale responses for five instructional units (quantitative) were analyzed for distance from neutral using one-sample t-tests. Interview data (qualitative) were analyzed with assurance of data trustworthiness and thematic analysis techniques. Participants were 27 interprofessional faculty. They evaluated the program instruction as easy to access, engaging and logically presented. They reported increased confidence in new skills and increased awareness of copyright issues, yet continued to have time management challenges and remained uncomfortable about peer review. They produced 22 new instructional materials. Online faculty development methods are helpful for faculty learning to create e-learning materials. Recommendations are made to increase the success of such a faculty development program.


Use and misuse of a discount voucher scheme as a subsidy for insecticide-treated nets for malaria control in southern Tanzania.
Since 1997, discount vouchers for insecticide-treated nets (ITNs) have been used in two rural districts of southern Tanzania as a way to target subsidies to children under 5 years and pregnant women. We assessed appropriate use and misuse of discount vouchers through a follow-up study of 104 randomly selected vouchers. We traced these vouchers from their original issue in mother-and-child health (MCH) clinics through to being redeemed at a sales agent. We found that all vouchers that reached the target population (100%, 56/56) were used to buy an ITN. Moreover, 94% of the ITNs bought with vouchers were used by those intended, women and children under 5 years. However, up to 48% (50/104) of the vouchers had been misused at the clinics that issued them. Nevertheless, large-scale misuse occurred only at three of 21 clinics. Although most women slept under a net while pregnant, the use of voucher-subsidized ITNs during pregnancy was low despite widespread knowledge of the scheme. Parents had apparently decided to buy the subsidized ITNs once the child was born and not during pregnancy. Importantly, in 20% of households the only existing net had been bought with a voucher. Our findings suggest that vouchers are properly used by the target population, and that to minimize voucher leakage, control measures are needed at MCH clinics and to a certain extent for commercial sales agents. Increased awareness among the whole community on the right to receive a discount voucher may also help to control misuse at health facilities.


Robust Recovery of Corrupted Low-RankMatrix by Implicit Regularizers.
Low-rank matrix recovery algorithms aim to recover a corrupted low-rank matrix with sparse errors. However, corrupted errors may not be sparse in real-world problems and the relationship between ℓ1 regularizer on noise and robust M-estimators is still unknown. This paper proposes a general robust framework for low-rank matrix recovery via implicit regularizers of robust M-estimators, which are derived from convex conjugacy and can be used to model arbitrarily corrupted errors. Based on the additive form of half-quadratic optimization, proximity operators of implicit regularizers are developed such that both low-rank structure and corrupted errors can be alternately recovered. In particular, the dual relationship between the absolute function in ℓ1 regularizer and Huber M-estimator is studied, which establishes a connection between robust low-rank matrix recovery methods and M-estimators based robust principal component analysis methods. Extensive experiments on synthetic and real-world data sets corroborate our claims and verify the robustness of the proposed framework.


Human pluripotent stem cell-derived limbal epithelial stem cells on bioengineered matrices for corneal reconstruction.
Corneal epithelium is renewed by limbal epithelial stem cells (LESCs), a type of tissue-specific stem cells located in the limbal palisades of Vogt at the corneo-scleral junction. Acute trauma or inflammatory disorders of the ocular surface can destroy these stem cells, leading to limbal stem cell deficiency (LSCD) - a painful and vision-threatening condition. Treating these disorders is often challenging and complex, especially in bilateral cases with extensive damage. Human pluripotent stem cells (hPSCs) provide new opportunities for corneal reconstruction using cell-based therapy. Here, we investigated the use of hPSC-derived LESC-like cells on bioengineered collagen matrices in serum-free conditions, aiming for clinical applications to reconstruct the corneal epithelium and partially replace the damaged stroma. Differentiation of hPSCs towards LESC-like cells was directed using small-molecule induction followed by maturation in corneal epithelium culture medium. After four to five weeks of culture, differentiated cells were seeded onto bioengineered matrices fabricated as transparent membranes of uniform thickness, using medical-grade porcine collagen type I and a hybrid cross-linking technology. The bioengineered matrices were fully transparent, with high water content and swelling capacity, and parallel lamellar microstructure. Cell proliferation of hPSC-LESCs was significantly higher on bioengineered matrices than on collagen-coated control wells after two weeks of culture, and LESC markers p63 and cytokeratin 15, along with proliferation marker Ki67 were expressed even after 30 days in culture. Overall, hPSC-LESCs retained their capacity to self-renew and proliferate, but were also able to terminally differentiate upon stimulation, as suggested by protein expression of cytokeratins 3 and 12. We propose the use of bioengineered collagen matrices as carriers for the clinically-relevant hPSC-derived LESC-like cells, as a novel tissue engineering approach for corneal reconstruction.


Loss of periodontal ligament fibroblasts by RIPK3-MLKL-mediated necroptosis in the progress of chronic periodontitis.
Periodontal homeostasis is maintained by the dynamic equilibrium between cell death, differentiation and proliferation of resident cells in the periodontal microenvironment. Loss of resident periodontal ligament fibroblasts (PDLFs) has been a major challenge in the periodontal treatment. This study aimed to investigate the exact role of necroptotic cell death in periodontal diseases. Elevated levels of receptor-interacting protein serine-threonine kinases -1 (RIPK1), phosphorylated RIPK3, mixed lineage kinase domain-like protein (MLKL), phosphorylated MLKL and FLIPL were observed in gingival tissues collected from patients with untreated chronic periodontitis; whereas no difference in caspase 8 was observed between the periodontitis and healthy control group. In contrast to the high incidence of necroptotic cell death in monocytes during live P. gingivalis infection with a low multiplicity of infection (MOI), necroptosis was only observed in PDLFs with a high MOI. Priming PDLFs with frozen thawed monocytes enhanced proinflammatory responses to P. gingivalis infection; moreover, frozen thawed monocytes stimulation triggered RIPK1, RIPK3 and MLKL-mediated-necroptotic cell death in PDLFs. These results indicated that RIPK3 and MLKL-mediated-necroptotic cell death participated in the pathogenesis of periodontitis, and DAMPs released from monocytes after P. gingivalis stimulation by necroptosis triggered not only inflammatory responses, but also necroptosis of PDLFs.


Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading.
Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPARγ and C/EBPα binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between PPARγ and C/EBPα at shared binding sites, we established a fibroblastic model system in which PPARγ and C/EBPα can be independently expressed. Using RNA sequencing, we demonstrate that coexpression of PPARγ and C/EBPα leads to synergistic activation of many key metabolic adipocyte genes. This is associated with extensive C/EBPα-mediated reprogramming of PPARγ binding and vice versa in the vicinity of these genes, as determined by chromatin immunoprecipitation combined with deep sequencing. Our results indicate that this is at least partly mediated by assisted loading involving chromatin remodeling directed by the leading factor. In conclusion, we report a novel mechanism by which the key adipogenic transcription factors, PPARγ and C/EBPα, cooperate in activation of the adipocyte gene program.


B-type cytochromes in plasma membranes isolated from rat liver, in comparison with those of endomembranes.
Fractions of plasma membranes, Golgi apparatus, endoplasmic reticulum (ER), and nuclear envelope were isolated from rat liver and were characterized by electron microsocpe and biochemical methods. The purity of the fractions was controlled by morphometry and by marker enzyme activities. Amounts of cytochromes b5, P-450, and P-420 were measured, as well as the NADPH- and NADPH-cytochrome c reductase activities. The pigments of the microsomal electron transport system were found in all membrane fractions in relatively high amounts, thus excluding an origin by microsomal contamination. Purified preparations of plasma membrane and Golgi apparatus contained approximately 30% of the cytochrome b5 and cytochrome P-450 + P-420 found in ER membranes. Plasma membranes were also characterized by a high ratio of P-420/450. Degradation of cytochromes P-450 and P-420 was relatively rapid in all fractions, except in the ER. Cytochrome b5 extracted from plasma membranes was spectrophotometrically and enzymatically indistinguishable from ER cytochrome b5. However, immunnlogical characterization with rabbit antibodies against the trypsin-resistant core of microsomal cytochrome b5 showed the presence of at least two types of cytochrome b5 in ER membranes, in contrast to the plasma membranes in which only one of these components was detected. This immunological differentiation also demonstrates that the plasma membrane-bound cytochrome b5 is endogenous to this membrane and does not reflect contamination by ER elements. We conclude that cytochromes b5, P-450, and P-420 are not confined only to ER and nuclear membranes but also occur in signficant amounts in Golgi apparatus and plasma membranes. The findings are discussed in relation to observations of similar redox components in Golgi apparatus, secretory vesicles, and plasma membranes of other cells.


An AT mutational bias in the tiny GC-rich endosymbiont genome of Hodgkinia.
The fractional guanine + cytosine (GC) contents of sequenced bacterial genomes range from 13% to 75%. Despite several decades of research aimed at understanding this wide variation, the forces controlling GC content are not well understood. Recent work has suggested that a universal adenine + thymine (AT) mutational bias exists in all bacteria and that the elevated GC contents found in some bacterial genomes is due to genome-wide selection for increased GC content. These results are generally consistent with the low GC contents observed in most strict endosymbiotic bacterial genomes, where the loss of DNA repair mechanisms combined with the population genetic effects of small effective population sizes and decreased recombination should lower the efficacy of selection and shift the equilibrium GC content in the mutationally favored AT direction. Surprisingly, the two smallest bacterial genomes, Candidatus Hodgkinia cicadicola (144 kb) and Candidatus Tremblaya princeps (139 kb), have the unusual combination of highly reduced genomes and elevated GC contents, raising the possibility that these bacteria may be exceptions to the otherwise apparent universal bacterial AT mutational bias. Here, using population genomic data generated from the Hodgkinia genome project, we show that Hodgkinia has a clear AT mutational bias. These results provide further evidence that an AT mutational bias is universal in bacteria, even in strict endosymbionts with elevated genomic GC contents.


Sample entropy analysis of EEG signals via artificial neural networks to model patients' consciousness level based on anesthesiologists experience.
Electroencephalogram (EEG) signals, as it can express the human brain's activities and reflect awareness, have been widely used in many research and medical equipment to build a noninvasive monitoring index to the depth of anesthesia (DOA). Bispectral (BIS) index monitor is one of the famous and important indicators for anesthesiologists primarily using EEG signals when assessing the DOA. In this study, an attempt is made to build a new indicator using EEG signals to provide a more valuable reference to the DOA for clinical researchers. The EEG signals are collected from patients under anesthetic surgery which are filtered using multivariate empirical mode decomposition (MEMD) method and analyzed using sample entropy (SampEn) analysis. The calculated signals from SampEn are utilized to train an artificial neural network (ANN) model through using expert assessment of consciousness level (EACL) which is assessed by experienced anesthesiologists as the target to train, validate, and test the ANN. The results that are achieved using the proposed system are compared to BIS index. The proposed system results show that it is not only having similar characteristic to BIS index but also more close to experienced anesthesiologists which illustrates the consciousness level and reflects the DOA successfully.


The 2017 Dutch Physical Activity Guidelines.
The objective of this study was to derive evidence-based physical activity guidelines for the general Dutch population. Two systematic reviews were conducted of English language meta-analyses in PubMed summarizing separately randomized controlled trials and prospective cohort studies on the relation between physical activity and sedentary behaviour on the one hand and the risk of all-cause mortality and incidence of 15 major chronic diseases and conditions on the other hand. Other outcome measures were risk factors for cardiovascular disease and type 2 diabetes, physical functioning, and fitness. On the basis of these reviews, an expert committee derived physical activity guidelines. In deriving the guidelines, the committee first selected only experimental and observational prospective findings with a strong level of evidence and then integrated both lines of evidence. The evidence found for beneficial effects on a large number of the outcome measures was sufficiently strong to draw up guidelines to increase physical activity and reduce sedentary behaviour, respectively. At the same time, the current evidence did not provide a sufficient basis for quantifying how much physical activity is minimally needed to achieve beneficial health effects, or at what amount sedentary behaviour becomes detrimental. A general tenet was that at every level of current activity, further increases in physical activity provide additional health benefits, with relatively larger effects among those who are currently not active or active only at light intensity. Three specific guidelines on (1) moderate- and vigorous-intensity physical activity, (2) bone- and muscle-strengthening activities, and (3) sedentary behaviour were formulated separately for adults and children. There is an unabated need for evidence-based physical activity guidelines that can guide public health policies. Research in which physical activity is measured both objectively (quantity) and subjectively (type and quality) is needed to provide better estimates of the type and actual amount of physical activity required for health.


Prostate specific antigen.
This article forms part of our 'Tests and results' series for 2011 which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results.


NMR structure of the chimeric hybrid duplex r(gcaguggc).r(gcca)d(CTGC) comprising the tRNA-DNA junction formed during initiation of HIV-1 reverse transcription.
A high-quality NMR solution structure of the chimeric hybrid duplex r(gcaguggc).r(gcca)d(CTGC) was determined using the program DYANA with its recently implemented new module FOUND, which performs exhaustive conformational grid searches for dinucleotides. To ensure conservative data interpretation, the use of 1H-1H lower distance limit constraints was avoided. The duplex comprises the tRNA-DNA junction formed during the initiation of HIV-1 reverse transcription. It forms an A-type double helix that exhibits distinct structural deviations from a standard A-conformation. In particular, the minor groove is remarkably narrow, and its width decreases from about 7.5 A in the RNA/RNA stem to about 4.5 A in the RNA/DNA segment. This is unexpected, since minor groove widths for A-RNA and RNA/DNA hybrid duplexes of approximately 11 A and approximately 8.5 A, respectively, were previously reported. The present, new structure supports that reverse transcriptase-associated RNaseH specificity is related primarily to conformational adaptability of the nucleic acid in 'induced-fit'-type interactions, rather than the minor groove width of a predominantly static nucleic acid duplex.


RAGE and cardiovascular disease.
RAGE is pattern recognizing receptors for diverse endogenous ligands. RAGE activation by RAGE ligands is known to be associated with reactive oxygen species generation, activation of NF kappa B, as well as recruitment of proinflammatory cells. Activated endothelial cells, vascular smooth muscle cells in atherosclerotic plaques and activated inflammatory cells all have increased expression of RAGE, which with its interaction with RAGE ligands increases the secretion of proinflammatory cytokines and cell adhesion molecules. Furthermore, RAGE may have a significant role in leukocyte recruitment into the intima of the atherosclerosis. Initial insults resulting in endothelial dysfunction will result in leukocyte infiltration, oxidative stress and vascular inflammation that is amplified by RAGE activation. RAGE and its interaction with RAGE ligands may be important for initializing and maintaining the pathological processes that result in various entities of cardiovascular disease. Soluble RAGE competitively inhibits the binding of RAGE ligands to RAGE and attenuates the development of atherosclerosis in vivo. Thus RAGE may be a promising target for treatment of cardiovascular disease in the future.


Gold nanoparticles stabilized by cationic carbosilane dendrons: synthesis and biological properties.
Gold nanoparticles (AuNPs) and polycationic macromolecules are used as gene carriers. Their behaviour is dependent on several factors, such as the size and type of the framework, charge, etc. We have combined both types of systems and prepared AuNPs covered with cationic carbosilane dendrons with the aim to evaluate their biocompatibility. Water soluble dendronized cationic AuNPs were prepared following a straightforward procedure from dendrons, a gold precursor and a reducing agent in water and were characterized by 1H NMR, transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), ultraviolet spectroscopy (UV), and zeta potential (ZP). The biological properties of dendrons and AuNPs were determined by hemolysis, platelet aggregation and lymphocyte proliferation. These assays reflect modification of dendron properties when covering nanoparticles. For dendrons, hemolysis and platelet aggregation are generation dependent whilst, for AuNPs these properties are related to the bigger size of NPs. On the other hand, none of the systems induced lymphocyte proliferation. Selected cationic dendrons and AuNPs were chosen for gene delivery experiments employing a small interference RNA (siRNA Nef) against human immunodeficiency virus (HIV).


Tailoring radiative and non-radiative losses of thin nanostructured plasmonic waveguides.
Thin nanostructured metal films allow to control radiative and non-radiative losses of surface plasmon polariton modes without changing their group velocities. This effect is studied in plasmonic waveguides made of thin gold films drilled with very narrow slits and deposited on a GaAs substrate. The analysis is supported by high-resolution angle-resolved transmission measurements and rigorous electromagnetic calculations. We show that the excitation of air/gold and gold/GaAs surface waves leads to Fano-type resonances with specific light localization into the slits. As a result, gold/GaAs surface waves induce a modulation of radiative and non-radiative losses of air/gold surface waves. The minimum and maximum of the Fano-type resonance introduce two propagation regimes. In the radiative propagation regime, the losses due to the absorption are negligible, whereas an efficient inhibition of free-space coupling is demonstrated in low-loss propagation regime.


Occupational Health and the Performing Arts: An Introduction.
Workplace hazards in the performing arts cause injuries, disabilities, and deaths every year. Occupational health professionals are familiar with most of these hazards and are particularly qualified to contribute to efforts to reduce them. This article reviews current health issues in the performing arts and highlights opportunities for occupational health contributions. Recognized experts in performing arts medicine were consulted and articles illustrating performing arts health issues were reviewed. Literature sources included medical databases, unindexed art-health publications, and popular press articles. Resources discussing hazards and health issues in theater, dance, voice, and instrumental musicians were located and reviewed. Treatment providers have a history of involvement with segments of the performing arts. The occupational health approach to workplace health issues can effectively complement these efforts. Sources of further information on performing arts health concerns are available.


The fate of metals in wastewater treated by the activated sludge process and membrane bioreactors: a brief review.
The fate of metals in wastewater treatment by the conventional activated sludge process (ASP) and membrane bioreactors (MBRs) is reviewed. The review outlines the environmental and health impacts of metals, but focuses primarily on data reported for removal of toxic metals, and some other high-profile inorganic micropollutants such as aluminium and arsenic, by wastewater treatment processes. Information from pilot and full scale plants is included, with corroboratory reports from bench-scale tests. General trends in removal across different metals are considered, along with the impact of the key process operating determinant of solids retention time. It is concluded that the only consistent trend in metals removal is that it is most effectively achieved through efficient solids separation, and that this represents the primary advantage offered by the MBR. As such, MBRs achieve averaged metals removals which are consistently but not dramatically higher than the ranges reported by the ASP: 64-92% vs. 51-87%, with no more than a 55% decrease on average in effluent concentration. The slightly greater removal attained is attributable to the additional suspended solids retention attained by the membrane process. In either case, further removal of metals would demand a tertiary process for removal of the dissolved material.


Personally measured weekly exposure to NO2 and respiratory health among preschool children.
Nitrogen dioxide is known as a deep lung irritant. The aim of this study was to find out whether the relatively low ambient air NO2 concentrations in the northern city of Helsinki had an impact on the respiratory health of children. The association between personal exposure to ambient air NO2 and respiratory health was investigated in a 13-week follow-up study among 163 preschool children aged 3-6 yrs. Personal weekly average exposure to NO2 was measured by passive diffusion samplers attached to the outer garments. Symptoms were recorded daily in a diary by the parents. Among 53 children, peak expiratory flow (PEF) was measured at home in the mornings and evenings. The association between NO2 exposure and respiratory symptoms was examined with Poisson regression. The median personal NO2 exposure was 21.1 microg x m(-3) (range 4-99 microg x m(-3)). An increased risk of cough was associated with increasing NO2 exposure (risk ratio = 1.52; 95% confidence interval 1.00-2.31). There was no such association between personal weekly NO2 exposure and nasal symptoms, but a nonsignificant negative association was found between the exposure and the weekly average deviation in PEF. In conclusion, even low ambient air NO2 concentrations can increase the risk of respiratory symptoms among preschool children.


Journal impact factor in the era of expanding literature.
The Journal Citation Reports (JCR) of the Science Citation Index (SCI), published by the Institute of Scientific Information (ISI), provides a comprehensive database for analysis of journals. Recent use of JCR's journal impact factor for evaluation of journals and authors has provoked strongly mixed reactions among investigators. This paper examines the effects of the rapidly expanding literature on the impact factor over the past decade and examines the limitations of journal impact factor for evaluating individual author's contributions. The JCR analyzed 6088 journals in 2005, a 32% increase in new listings since 1995. During the same period, there was a 39% increase in new journal listings in the infectious diseases category. The phenomenon of journal proliferation has had a profound effect on the journal impact factor. During the past decade an increased impact factor was observed in 92% of the top ranking major journals, especially in young and rapidly expanding research fields. Certain highly cited new journals published primarily review articles - not original contributions. There was no increase in impact factor among some of the best known journals, such as Journal of Experimental Medicine, Proceedings of the National Academy of Sciences (USA), and Journal of Infectious Diseases. Clearly, journal impact factor is an imperfect tool for measuring the quality of articles, and its use in evaluating authors has inherent risks. In spite of its limitations, journal impact factor can be used as a rough indicator of scientific quality in specific subject categories and for serious reading and learning.


Bacterial quorum sensing: signals, circuits, and implications for biofilms and disease.
Communication between bacteria, belonging to the same species or to different species, is mediated through different chemical signals that are synthesized and secreted by bacteria. These signals can either be cell-density related (autoinducers) or be produced by bacteria at different stages of growth, and they allow bacteria to monitor their environment and alter gene expression to derive a competitive advantage. The properties of these signals and the response elicited by them are important in ensuring bacterial survival and propagation in natural environments (e.g., human oral cavity) where hundreds of bacterial species coexist. First, the interaction between a signal and its receptor is very specific, which underlies intraspecies communication and quorum sensing. Second, when multiple signals are synthesized by the same bacterium, the signaling circuits utilized by the different signals are coordinately regulated with distinct overall circuit architecture so as to maximize the overall response. Third, the recognition of a universal communication signal synthesized by different bacterial species (interspecies communication), as well that of signals produced by eukaryotic cells (interkingdom communication), is also integral to the formation of multispecies biofilm communities that are important in infection and disease. The focus of this review is on the principles underlying signal-mediated bacterial communication, with specific emphasis on the potential for using them in two applications-development of synthetic biology modules and circuits, and the control of biofilm formation and infection.


Incidence and predictors of vancomycin-associated nephrotoxicity.
Earlier studies reported a low incidence of vancomycin-associated nephrotoxicity (VAN); however, recent studies have reported higher incidences exceeding 30%. Predictors of nephrotoxicity are not well defined. In this study we aimed to better estimate the incidence and evaluate predictors of VAN in a cohort of patients predominated by long treatment courses. We conducted a retrospective study on patients treated with vancomycin while in the hospital and who were observed closely through the Outpatient Parenteral Antibiotic Therapy program. Nephrotoxicity was defined as an increase in the serum creatinine level of 0.5 mg/dL or 50% from baseline on at least two consecutive readings while taking vancomycin. We compared the patients who developed nephrotoxicity with those who did not with regard to vancomycin dosing, trough levels, baseline serum creatinine, underlying infection, residence in the critical care unit, comorbid conditions, concurrent nephrotoxic treatments, and baseline characteristics. Of 579 patients, 154 (26.6%) developed nephrotoxicity. Ninety patients developed VAN within the first 14 days of treatment, whereas 64 patients developed nephrotoxicity after 14 days of treatment. The median time to development of nephrotoxicity was 9 days. Admission to the intensive care unit, concurrent use of loop diuretics, and comorbidity with cirrhosis were independently associated with nephrotoxicity. A higher baseline creatinine value was unexpectedly associated with a lower incidence of nephrotoxicity (P = 0.0016). VAN is not an uncommon outcome in both short- and long-term treatment courses. Admission to the intensive care unit while receiving treatment, concurrent treatment with a loop diuretic, an underlying diagnosis of cirrhosis, and the initial trough level appear to be the main risk factors for nephrotoxicity. Unexpectedly, elevated baseline creatinine levels appeared to be protective and this could be the result of careful use of vancomycin among individuals with relatively higher baseline creatinine values.


Palladium-catalyzed carbon-sulfur or carbon-phosphorus bond metathesis by reversible arylation.
Compounds bearing aryl-sulfur and aryl-phosphorus bonds have found numerous applications in drug development, organic materials, polymer science, and homogeneous catalysis. We describe palladium-catalyzed metathesis reactions of both compound classes, each of which proceeds through a reversible arylation manifold. The synthetic power and immediate utility of this approach are demonstrated in several applications that would be challenging to achieve by means of traditional cross-coupling methods. The C(sp2)-S bond metathesis protocol was used in the depolymerization of a commercial thermoplastic polymer and in the late-stage derivatization of a drug. The C(sp2)-P variant led to the convenient preparation of a variety of phosphorus heterocycles, including a potential chiral ligand and fluorescent organic materials, via a ring-closing transformation.


Effects of the oral administration of mosapride citrate on capsule endoscopy completion rate.
In capsule endoscopy (CE), the capsule does not always reach the cecum within its battery life, which may reduce its diagnostic yield. We evaluated the effect of mosapride citrate, a 5-hydroxytryptamine-4 agonist that increases gastrointestinal motility, on CE completion. In a retrospective study, we performed univariate and multivariate analyses for 232 CE procedures performed at our hospital. To identify factors that affect CE completion, the following data were systematically collected: gender, age, gastric transit time (GTT), nonsteroidal anti-inflammatory drug administration, previous abdominal surgery, hospitalization, use of a polyethylene glycol solution, use of mosapride citrate (10 mg), body mass index (BMI), and total recording time. The univariate analysis showed that oral mosapride citrate, GTT, and BMI were associated with improved CE completion. Multivariate analyses showed that oral mosapride citrate (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.01 to 3.91) and GTT (OR, 2.34; 95% CI, 1.13 to 4.87) were significant factors for improving the CE completion. Oral mosapride citrate significantly shortened the GTT and small bowel transit time (SBTT). Oral mosapride citrate reduced the GTT and SBTT during CE and improved the CE completion rate.


Triggered activity induced by K(+)-free, Na(+)-deficient solution in guinea pig ventricular muscle: the effects of ouabain, lidocaine, and Ca2+ channel blockers.
Triggered activity induced by delayed afterdepolarizations has been suggested as a cellular mechanism for some arrhythmias. The development of triggered activity should be favored by conditions that increase myoplasmic Ca2+ and increase membrane resistance. A solution which could create these conditions was devised. After perfusion with normal Tyrode's solution, 24 trabeculae were exposed to the experimental solution. All preparations developed triggered activity after exposure to the experimental solution, 83% developed delayed afterdepolarizations before the onset of triggered activity, and triggered activity stopped in all trabeculae after reperfusion with normal Tyrode's solution. The interaction of ouabain, lidocaine, and three Ca2+ channel blockers with triggered activity induced by the experimental solution is described. Verapamil inhibited triggered activity but not underlying voltage oscillations, whereas nisoldipine and Mn2+ inhibited both triggered activity and voltage oscillations. Lidocaine did not inhibit afterdepolarizations or triggered activity. Exposure to ouabain for 10 min caused delayed afterdepolarizations but not triggered activity. Our results show that the experimental solution induced triggered activity, which was highly reliable and readily reversible. The high reproducibility of this activity enables the study of interactions of pharmacological agents with this triggered activity. This may contribute to the further understanding of the mechanism underlying some arrhythmias.


Phylogeny and classification of the New World suboscines (Aves, Passeriformes).
Here we present a phylogenetic hypothesis for the New World suboscine radiation, based on a dataset comprising of 219 terminal taxa and five nuclear molecular markers (ca. 6300 bp). We also estimate ages of the main clades in this radiation. This study corroborates many of the recent insights into the phylogenetic relationships of New World suboscines. It further clarifies a number of cases for which previous studies have been inconclusive, such as the relationships of Conopophagidae, Melanopareiidae and Tityridae. We find a remarkable difference in age of the initial divergence events in Furnariida and Tyrannida. The deepest branches in Furnariida are of Eocene age, whereas the extant lineages of Tyrannida have their origin in the Oligocene. Approximately half of the New World suboscine species are harboured in 5 large clades that started to diversify around the Mid Miocene Climatic Optimum (16-12 Mya). Based on our phylogenetic results we propose a revised classification of the New World suboscines. We also erect new family or subfamily level taxa for four small and isolated clades: Berlepschiinae, Pipritidae, Tachurididae and Muscigrallinae.