Cockroach GABAB receptor subtypes: molecular characterization, pharmacological properties and tissue distribution.
γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the central nervous system (CNS). Its effects are mediated by either ionotropic GABAA receptors or metabotropic GABAB receptors. GABAB receptors regulate, via Gi/o G-proteins, ion channels, and adenylyl cyclases. In humans, GABAB receptor subtypes are involved in the etiology of neurologic and psychiatric disorders. In arthropods, however, these members of the G-protein-coupled receptor family are only inadequately characterized. Interestingly, physiological data have revealed important functions of GABAB receptors in the American cockroach, Periplaneta americana. We have cloned cDNAs coding for putative GABAB receptor subtypes 1 and 2 of P. americana (PeaGB1 and PeaGB2). When both receptor proteins are co-expressed in mammalian cells, activation of the receptor heteromer with GABA leads to a dose-dependent decrease in cAMP production. The pharmacological profile differs from that of mammalian and Drosophila GABAB receptors. Western blot analyses with polyclonal antibodies have revealed the expression of PeaGB1 and PeaGB2 in the CNS of the American cockroach. In addition to the widespread distribution in the brain, PeaGB1 is expressed in salivary glands and male accessory glands. Notably, PeaGB1-like immunoreactivity has been detected in the GABAergic salivary neuron 2, suggesting that GABAB receptors act as autoreceptors in this neuron.


An fMRI study measuring analgesia enhanced by religion as a belief system.
Although religious belief is often claimed to help with physical ailments including pain, it is unclear what psychological and neural mechanisms underlie the influence of religious belief on pain. By analogy to other top-down processes of pain modulation we hypothesized that religious belief helps believers reinterpret the emotional significance of pain, leading to emotional detachment from it. Recent findings on emotion regulation support a role for the right ventrolateral prefrontal cortex (VLPFC), a region also important for driving top-down pain inhibitory circuits. Using functional magnetic resonance imaging in practicing Catholics and avowed atheists and agnostics during painful stimulation, here we show the existence of a context-dependent form of analgesia that was triggered by the presentation of an image with a religious content but not by the presentation of a non-religious image. As confirmed by behavioral data, contemplation of the religious image enabled the religious group to detach themselves from the experience of pain. Critically, this context-dependent modulation of pain specifically engaged the right VLPFC, whereas group-specific preferential liking of one of the pictures was associated with activation in the ventral midbrain. We suggest that religious belief might provide a framework that allows individuals to engage known pain-regulatory brain processes.


Power scaling of supercontinuum seeded megahertz-repetition rate optical parametric chirped pulse amplifiers.
Optical parametric chirped-pulse amplifiers with high average power are possible with novel high-power Yb:YAG amplifiers with kW-level output powers. We demonstrate a compact wavelength-tunable sub-30-fs amplifier with 11.4 W average power with 20.7% pump-to-signal conversion efficiency. For parametric amplification, a beta-barium borate crystal is pumped by a 140 W, 1 ps Yb:YAG InnoSlab amplifier at 3.25 MHz repetition rate. The broadband seed is generated via supercontinuum generation in a YAG crystal.


Magnitude and causes of mortality differences between married and unmarried men.
To determine the effect of marital status on mortality for men. In particular, to examine whether subgroups of unmarried men (widowed, single, and divorced/separated men) have a similar mortality to married men. Cohort study. Whitehall civil service, London, between 1967 and 1969. A total of 18,403 men aged 40-64 years with 18 years' follow up. Cause-specific mortality rates and risk factors at baseline were determined. Overall mortality was greater for all groups of unmarried men. Patterns of mortality were different in the subgroups of unmarried men. Widowed men had a significantly greater risk of dying from ischaemic heart disease (relative risk (RR) 1.46, 95% confidence interval (CI) 1.08, 1.97) which persisted after exclusion of deaths that occurred in the first two years. Divorced men had greater cancer mortality (RR 1.49; 95% CI 1.06, 2.10) that could not be explained simply by their greater consumption of cigarettes. The initial increased mortality for single men was no longer evident after adjustment for other risk factors, suggesting that single status in itself may not increase the risk. The risk for single men may have been underestimated, however, by over adjustment for possible intermediary factors. Previous studies, which have examined total mortality only or have grouped all unmarried men, have masked interesting differences in the cause of death between subgroups of unmarried men. The extent to which the findings are explicable by psychosocial factors or the role of other environmental factors, which may also differ in relation to marital status, is unclear. Future work should not assume that all unmarried men have similar mortality risks and must examine the life course of each subgroup to advance our understanding of the possible causal role of marital status in disease aetiology.


Effect of a mass casualty incident: clinical outcomes and hospital charges for casualty patients versus concurrent inpatients.
A mass casualty incident (MCI) may strain a health care system beyond surge capacity, affecting patterns of care for casualties and other patients. Prior studies of MCIs have assessed clinical care for casualty patients, but have not examined outcomes or expenditures for noncasualty inpatients in the same time period. This was a retrospective analysis of administrative hospital claims in a state where an MCI with over 200 casualties occurred; two hospitals that admitted casualties of >5% of their inpatient capacity were studied. The "surge period" was defined as 7 days after the MCI. Using diagnostic codes, patients admitted on the MCI day with diagnoses of burns or inhalation injury were included in the "MCI surge cohort." Patients admitted within a time frame of 7 days prior to 7 days after the MCI who were inpatients during the surge period were included in the "non-MCI surge cohort." The authors compared the MCI and non-MCI surge cohorts to a mutually exclusive reference cohort (all inpatients during 6 weeks prior to the MCI), regarding key outcomes of hospital length of stay (LOS) and hospital charges adjusted for age, sex, race/ethnicity, and severity of illness. Fifty-five patients met criteria for the MCI surge cohort, 1,369 for the non-MCI surge cohort, and 5,980 for the reference group. Compared with the reference group and adjusted for covariates, the mean (±SD) hospital LOS was 4.90 (±1.85) days longer for the MCI surge cohort (95% confidence interval [CI] = 1.67 to 8.84) and 1.34 (±0.16) days longer for the non-MCI surge cohort (95% CI = 1.00 to 1.65). The MCI cohort also had significantly longer mean hospital LOS than the non-MCI surge cohort (difference = 3.56 days; 95% CI = 0.36 to 7.36). Also adjusted for covariates, mean (±SD) total hospital charges for the MCI surge cohort were $22,349 (±$8,342) greater than for the reference group (95% CI = $8,182 to $39,485). Mean (±SD) charges for the non-MCI surge cohort were $4,028 (±$633) greater than for the reference group (95% CI = $2,792 to $5,196). The MCI cohort also had higher mean total charges than the non-MCI surge cohort (difference = $18,321; 95% CI = $4,488 to $34,980). When adjusted for severity of illness, casualty patients and noncasualty patients receiving concurrent hospital care have significantly longer LOS and higher charges than typical hospital patients at times unaffected by MCIs. Spillover effects from MCIs for noncasualty patients have not been previously described and have implications for clinical and hospital management in MCI and other high-surge circumstances.


Witches' Broom Disease of Lime Contributes to Phytoplasma Epidemics and Attracts Insect Vectors.
An insect-transmitted phytoplasma causing Witches' Broom Disease of Lime (WBDL) is responsible for the drastic decline in lime production in several countries. However, it is unclear how WBDL phytoplasma (WBDLp) induces witches' broom symptoms and if these symptoms contribute to the spread of phytoplasma. Here we show that the gene encoding SAP11 of WBDLp (SAP11WBDL) is present in all WBDLp isolates collected from diseased trees. SAP11WBDL interacts with acid lime (Citrus aurantifolia) TCP transcription factors, specifically members of the TB1/CYC class that have a role in suppressing axillary branching in plants. Sampling of WBDLp-infected lime trees revealed that WBDLp titers and SAP11WBDL expression levels were higher in symptomatic leaves compared with asymptomatic sections of the same trees. Moreover, the witches' brooms were found to attract the vector leafhopper. Defense genes that have a role in plant defense responses to bacteria and insects are more downregulated in witches' brooms compared with asymptomatic sections of trees. These findings suggest that witches' broom-affected parts of the trees contribute to WBDL epidemics by supporting higher phytoplasma titers and attracting insect vectors.


Experimental Demonstration of an Electrostatic Orbital Angular Momentum Sorter for Electron Beams.
The component of orbital angular momentum (OAM) in the propagation direction is one of the fundamental quantities of an electron wave function that describes its rotational symmetry and spatial chirality. Here, we demonstrate experimentally an electrostatic sorter that can be used to analyze the OAM states of electron beams in a transmission electron microscope. The device achieves postselection or sorting of OAM states after electron-material interactions, thereby allowing the study of new material properties such as the magnetic states of atoms. The required electron-optical configuration is achieved by using microelectromechanical systems technology and focused ion beam milling to control the electron phase electrostatically with a lateral resolution of 50 nm. An OAM resolution of 1.5ℏ is realized in tests on controlled electron vortex beams, with the perspective of reaching an optimal OAM resolution of 1ℏ in the near future.


NK cell immune responses differ after prime and boost vaccination.
A better understanding of innate responses induced by vaccination is critical for designing optimal vaccines. Here, we studied the diversity and dynamics of the NK cell compartment after prime-boost immunization with the modified vaccinia virus Ankara using cynomolgus macaques as a model. Mass cytometry was used to deeply characterize blood NK cells. The NK cell subphenotype composition was modified by the prime. Certain phenotypic changes induced by the prime were maintained over time and, as a result, the NK cell composition prior to boost differed from that before prime. The key phenotypic signature that distinguished NK cells responding to the boost from those responding to the prime included stronger expression of several cytotoxic, homing, and adhesion molecules, suggesting that NK cells at recall were functionally distinct. Our data reveal potential priming or imprinting of NK cells after the first vaccine injection. This study provides novel insights into prime-boost vaccination protocols that could be used to optimize future vaccines.


Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer.
Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-kappaB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.


Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis.
Reactive oxygen species (ROS) are involved in a variety of pathophysiological conditions of the testis, and oxidative stress is known to inhibit ovarian and testicular steroidogenesis. The site of ROS-mediated inhibition of steroidogenesis in the corpus luteum and MA-10 tumor Leydig cells was shown to be the hormone-sensitive mitochondrial cholesterol transfer step. The purpose of this study was to examine the effects of ROS on steroidogenic acute regulatory (StAR) protein in MA-10 cells and determine the extent to which MA-10 cell mitochondria are sensitive to oxidative stress. cAMP-stimulated progesterone production was inhibited in a dose-dependent manner in MA-10 cells exposed to H(2)O(2). StAR protein, but not mRNA levels, was decreased in parallel to changes in progesterone production. Even at the highest concentrations of H(2)O(2) tested, there was no effect on P450 side-chain cleavage enzyme protein levels. Oxidative stress from exposure to exogenous xanthine oxidase and xanthine resulted in the inhibition of both progesterone production and StAR protein expression. The mature 30- and 32-kDa intramitochondrial forms of StAR were decreased relative to the 37-kDa extramitochondrial precursor form of StAR, indicating that the ROS-mediated inhibition of StAR protein was due, in part, to the inhibition of mitochondrial import and processing. Vital staining with the fluorescent dye tetramethylrhodamine ethyl ester was used to visualize changes in the mitochondrial electrochemical gradient-dependent membrane potential (Deltapsim). ROS caused a significant dissipation of Deltapsi(m) and time-dependent loss of tetramethylrhodamine ethyl ester fluorescence. The inhibitory effects of H(2)O(2) were transient. There was no evidence for ROS-induced cell death, and following H(2)O(2) removal in the presence of continuous treatment with 8-bromo-cAMP, StAR protein levels and progesterone production were restored. In addition, there was no loss of cell viability following treatment with H(2)O(2) or xanthine/xanthine oxidase as determined by trypan blue exclusion. H(2)O(2) did not cause a significant decrease in total cellular ATP levels. These data indicate that oxidative stress-mediated perturbation of the mitochondria and dissipation of Deltapsi(m) results in the inhibition of StAR protein expression and its import, processing, and cholesterol transfer activity. These findings confirm earlier studies demonstrating the requirement for maintenance of an intact Deltapsi(m) for StAR protein function in cholesterol transport. The significant reduction in the 32- to 30-kDa mature forms of StAR, cessation of cholesterol transport, and loss of Deltapsi(m) are consistent with mitochondrial perturbation because of oxidative stress. This mechanism likely contributes to a host of pathophysiological events evident in testicular disorders such as infection, reperfusion injury, aging, cryptorchidism, and varicocele.


A new walking aid with axillary support for children with cerebral palsy: electromyographic evaluation.
To present a new walking aid with axillary support (WAAS) for children with cerebral palsy (CP) and to investigate its impact on the lower limb muscles activation in the gait of children with CP. Six children with spastic diparesis due to CP performed a straight line walking course in two situations: with and without using the WAAS. Each course was repeated three times for both situations, and electromyography (EMG) activity of quadriceps, hamstrings, tibialis anterior and gastrocnemius were recorded during all trials. The use of WAAS significantly increased the EMG activity of the quadriceps and hamstrings during stance phase and tibialis anterior during swing phase, with no significant increase in gastrocnemius activation. The use of WAAS improved the synergism of lower limbs muscles of children with CP by reducing the coactivation of antagonistic muscles, especially during the swing phase of gait. Providing a walking aid with improved trunk stability may enable children with CP to improve muscular synergism and walking ability, thus favoring independent mobility, with possible gains in social participation and quality of life. Children with cerebral palsy have problems with the development of normal gait, as a result of the reduced motor control and the impaired muscle synergism of the lower limbs. Standard walking aids do not provide proper trunk stability for this group of children. In a relatively small sample of children with cerebral palsy, a walking aid with axillary support was shown to be beneficial for the muscular synergism of the lower limbs during gait.


Synthesis and Characterization of Hydroxyapatite/Fullerenol Nanocomposites.
Fullerenols are polyhydroxylated, water soluble derivatives of fullerene C60, with potential application in medicine as diagnostic agents, antioxidants or nano drug carriers. This paper describes synthesis and physical characterization of a new nanocomposite hydroxyapatite/fullerenol. Surface of the nanocomposite hydroxyapatite/fullerenol is inhomogeneous with the diameter of the particles in the range from 100 nm to 350 nm. The ζ potential of this nanocomposite is ten times lower when compared to hydroxyapatite. Surface phosphate groups of hydroxyapatite are prone to forming hydrogen bonds, when in close contact with hydroxyl groups, which could lead to formation of hydrogen bonds between hydroxyapatite and hydroxyl groups of fullerenol. The surface of hydroxyapatite particles (-2.5 mV) was modified by fullerenol particles, as confirmed by the obtained ζ potential value of the nanocomposite biomaterial hydroxyapatite/fullerenol (-25.0 mV). Keywords: Hydroxyapatite, Fullerenol, Nanocomposite, Surface Analysis.


Controlling hair follicle signaling pathways through polyubiquitination.
Hair follicle development and maintenance require precise reciprocal signaling interactions between the epithelium and underlying dermis. Three major developmental signaling pathways, Wnt, Sonic hedgehog, and NF-kappaB/Edar, are indispensable for this process and, when aberrantly activated, can lead to skin and appendage neoplasms. Recent data point to protein polyubiquitination as playing a central role in regulating the timing, duration, and location of signaling. Here we review how polyubiquitination regulates the stability and interaction of key signaling components that control hair follicle development and regeneration.


The utility of six over-the-counter (home) pregnancy tests.
The home pregnancy market is rapidly evolving. It has moved from detection of pregnancy on the day of missed menstrual bleeding, to detection claims 4 days prior. It is moving from all manual tests to digital tests, with a monitor reading the bands and informing women they are pregnant. A thorough study is needed to investigate the validity of claims and evolving usefulness of devices. Studies were proposed to examine the sensitivity and specificity of home tests and their abilities to detect pregnancy. Methods examined the abilities of tests to detect human chorionic gonadotropin (hCG), hyperglycosylated hCG, free β-subunit, a mixture of these antigens in 40 individual early pregnancy urines. Using a mixture of hCG, hyperglycosylated hCG and free β-subunit typical for early pregnancy, the sensitivity of the First Response manual and digital tests was 5.5 mIU/mL, while the sensitivities of the EPT and ClearBlue brand manual and digital tests was 22 mIU/mL. On further evaluation, the First Response manual and digital tests both detected 97% of 120 pregnancies on the day of missed menstrual bleeding. The EPT manual and digital devices detected 54% and 67% of pregnancies, respectively, and the ClearBlue manual and digital devices detected 64% and 54% of pregnancies, respectively. First Response manual and digital claim >99% detection on the day of missed menses. The results here suggest similar sensitivity for these two tests. The EPT and ClearBlue manual and digital test make similar >99% claims, the data presented here disputes their elevated claim.


Role of the retinal vascular endothelial cell in ocular disease.
Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell.


Evolution of Tandem Repeats Is Mirroring Post-polyploid Cladogenesis in Heliophila (Brassicaceae).
The unigeneric tribe Heliophileae encompassing more than 100 Heliophila species is morphologically the most diverse Brassicaceae lineage. The tribe is endemic to southern Africa, confined chiefly to the southwestern South Africa, home of two biodiversity hotspots (Cape Floristic Region and Succulent Karoo). The monospecific Chamira (C. circaeoides), the only crucifer species with persistent cotyledons, is traditionally retrieved as the closest relative of Heliophileae. Our transcriptome analysis revealed a whole-genome duplication (WGD) ∼26.15-29.20 million years ago, presumably preceding the Chamira/Heliophila split. The WGD was then followed by genome-wide diploidization, species radiations, and cladogenesis in Heliophila. The expanded phylogeny based on nuclear ribosomal DNA internal transcribed spacer (ITS) uncovered four major infrageneric clades (A-D) in Heliophila and corroborated the sister relationship between Chamira and Heliophila. Herein, we analyzed how the diploidization process impacted the evolution of repetitive sequences through low-coverage whole-genome sequencing of 15 Heliophila species, representing the four clades, and Chamira. Despite the firmly established infrageneric cladogenesis and different ecological life histories (four perennials vs. 11 annual species), repeatome analysis showed overall comparable evolution of genome sizes (288-484 Mb) and repeat content (25.04-38.90%) across Heliophila species and clades. Among Heliophila species, long terminal repeat (LTR) retrotransposons were the predominant components of the analyzed genomes (11.51-22.42%), whereas tandem repeats had lower abundances (1.03-12.10%). In Chamira, the tandem repeat content (17.92%, 16 diverse tandem repeats) equals the abundance of LTR retrotransposons (16.69%). Among the 108 tandem repeats identified in Heliophila, only 16 repeats were found to be shared among two or more species; no tandem repeats were shared by Chamira and Heliophila genomes. Six "relic" tandem repeats were shared between any two different Heliophila clades by a common descent. Four and six clade-specific repeats shared among clade A and C species, respectively, support the monophyly of these two clades. Three repeats shared by all clade A species corroborate the recent diversification of this clade revealed by plastome-based molecular dating. Phylogenetic analysis based on repeat sequence similarities separated the Heliophila species to three clades [A, C, and (B+D)], mirroring the post-polyploid cladogenesis in Heliophila inferred from rDNA ITS and plastome sequences.


Rapid increase in dichloromethane emissions from China inferred through atmospheric observations.
With the successful implementation of the Montreal Protocol on Substances that Deplete the Ozone Layer, the atmospheric abundance of ozone-depleting substances continues to decrease slowly and the Antarctic ozone hole is showing signs of recovery. However, growing emissions of unregulated short-lived anthropogenic chlorocarbons are offsetting some of these gains. Here, we report an increase in emissions from China of the industrially produced chlorocarbon, dichloromethane (CH2Cl2). The emissions grew from 231 (213-245) Gg yr-1 in 2011 to 628 (599-658) Gg yr-1 in 2019, with an average annual increase of 13 (12-15) %, primarily from eastern China. The overall increase in CH2Cl2 emissions from China has the same magnitude as the global emission rise of 354 (281-427) Gg yr-1 over the same period. If global CH2Cl2 emissions remain at 2019 levels, they could lead to a delay in Antarctic ozone recovery of around 5 years compared to a scenario with no CH2Cl2 emissions.


'Thinking on my feet': an improvisation course to enhance students' confidence and responsiveness in the medical interview.
Effective patient-centred communication requires physicians to respond 'in the moment' to comments and questions. It is a valuable skill to be able to react to unexpected patient utterances with empathy and support, and these surprises may be most common in general practice where patients are encouraged to speak to their doctor about anything. We developed an elective for medical students to learn and practise improvisational skills that would optimise their communications with patients during medical encounters. Nineteen second-year medical students during two consecutive years (n =38) participated in a four-session elective that introduced and allowed them to practise the principles and skills of improvisation, and reflect on the role of those skills in their communication with patients. Specific skills that were practised and emphasised included listening, affirmation, vocal tone modulation, nonverbal communication, agreement, collaboration, acceptance and validation. In addition to previously developed 'Improv' exercises, students created their own improvisation exercises targeted at specific communication skills. Twenty-seven (71%) of all participating students completed the post-curriculum assessment survey. Twenty-two (81%) rated their enjoyment as 'tremendous'. The desire to experience something new and different from the standard medical curriculum served as the motivation for many of the students (67%) to sign up for the course. Most students (23/27; 85%) thought that the concepts that were addressed were either 'very much' or 'tremendously' relevant to the care of patients. We have found that an improvisational workshop geared towards enhancing medical student communication skills has the potential to impart valuable skills that are essential to providing empathic, supportive patient-centred care. Communication skills training programmes have become a cornerstone in medical student and postgraduate medical education over the past 20 years. Both national accreditation and expert panel consensus guidelines have stressed the importance and framed the structure for best communication practices. Exemplary curricula for teaching medical trainees in core communication strategies to use with patients have been published; many emphasise patient-centred and/or relationshipcentred strategies. Simulated patient technologies with video review can allow learners to practise their skills through both self-assessment and feedback from others. However, despite these newer learning resources, frameworks and behavioural checklists, learners naïve to clinical patient encounters must still learn how to function and adapt within the interpersonal communicative space that is created by the learner and patient. At its core, this is an iterative, spontaneous process created by the dyad and yielding, from moment to moment, to unique and unanticipated outcomes. Thus, repetitive practice will improve confidence but may miss the mark in learning the essential skills of intuitive and improvised interpersonal responsiveness. One could argue that existing approaches in teaching medical learners communication skills may promote rigid and stereotyped responses. Haidet proposes that there are significant parallels between the patient-physician dialogue (when a physician attempts to learn details about a patient and their illness) and improvisational jazz. 11 He contends that effective clinicians who are committed to relationship-centred practice depart from overarching principles of biomedical inquiry when necessary to respond spontaneously and without script to the particular circumstances of each encounter. It is believed that successful doctor-patient relationships are founded upon trusting and open communication, as well as genuine respect that can be shown by a willingness to listen or respond to the issues raised by patients. 12 The nature of the comprehensive care in family medicine makes it likely that GPs will regularly be surprised by concerns raised by patients such that they must be adept at improvising. Because of the gap that currently exists in interview skills training programmes, we hypothesised that the field of improvisational theatre would effectively supplement the traditional curriculum. Improvisation relies on listening, confidence and responding instinctively and spontaneously. 13,14 In this paper, we describe our efforts to develop a brief curriculum for medical students providing training in the art of theatre improvisation, with the goal of enhancing students' confidence and performance in clinical encounters. We hoped that this innovative curricular experience would establish a venue where secondyear medical students could learn and practise improvisational skills that might prove helpful in their communications with patients during medical encounters.


Transcriptional and posttranscriptional control of connexin mRNAs in periportal and pericentral rat hepatocytes.
Distinct patterns of expression of gap junction, or connexin, mRNAs were observed in periportal vs. pericentral hepatocytes. The two cellular fractions (isolated from rat livers by perfusion) were more than 90% parenchymal, as determined by flow cytometry for a hepatocyte-specific marker. The periportal and pericentral fractions were identifiable due to enrichment in enzymatic activities previously shown to be differentially expressed in the respective regions of liver. Northern blot analyses revealed that mRNA encoding connexin 26 was 2.8 times more abundant in the periportal than in the pericentral cells, while connexin 32 mRNA was equally distributed. Messenger RNA from each fraction was radiolabeled in order to compare the relative abundance of the connexin mRNAs in each fraction. The ratio of connexin 26 to connexin 32 mRNA in the portal fraction was about 0.085, and in the central fraction about 0.038. Connexin 26 mRNA was transcribed, however, at a faster rate than connexin 32 mRNA by nuclei isolated from both cellular fractions. Connexin 26 mRNA was transcribed at 3.9 times the rate in nuclei from the periportal than from the pericentral cells. These data suggest that while the zonation of connexin 26 mRNA synthesis in liver appears to be controlled transcriptionally, posttranscriptional regulatory mechanisms determine the relative abundance of the connexin mRNAs.


Ozone partially prevents diabetic neuropathy in rats.
Neuropathy is one of the most common complications of diabetes mellitus. Although the beneficial effects of good blood glucose control on diabetic neuropathy are known, this control cannot completely prevent the occurrence and progression of diabetic neuropathy. The aim of this study was to investigate whether ozone prevents diabetic neuropathy. 36 adult female Sprague-Dawley rats were randomly divided into 6 groups (n=6): control (C), ozone (O), diabetic (D), ozone-treated diabetic (DO), insulin-treated diabetic (DI), and ozone- and insulin-treated diabetic (DOI). Diabetes was induced by a single injection of streptozotocin (60 mg/kg, intraperitoneal [i.p.]), after which insulin was administered (3 IU, i.p.) to the DI and DOI groups for 28 days, and 1.1 mg/kg (50 µg/ml) ozone was given to the O, DO, and DOI groups for 15 days. 4 weeks after the induction of diabetes, the nerve conduction velocity (NCV), amplitude of the compound action potential (CAP), total oxidant status (TOS), and total antioxidant status (TAS) were measured, and the oxidative stress index (OSI) was calculated. The NCV, amplitude of CAP, and TAS of the DI and DOI groups were higher than those of the D group; the amplitudes of CAP and TAS of the DO group were higher than those of the D group; and the TOS and OSI of the DO, DI, and DOI groups were lower than those of the D group. These findings indicate that ozone partially prevents diabetic neuropathy in rats. It appears that the preventive effects of ozone are mediated through oxidant/antioxidant mechanisms.


Analysis of Schistosoma mansoni population structure using total fecal egg sampling.
Many parasite populations are difficult to sample because they are not uniformly distributed between several host species and are often not easily collected from the living host, thereby limiting sample size and possibly distorting the representation of the population. For the parasite Schistosoma mansoni, we investigated the use of eggs, in aggregate, from the stools of infected individuals as a simple and representative sample. Previously, we demonstrated that microsatellite allele frequencies can be accurately estimated from pooled DNA of cloned S. mansoni adults. Here, we show that genotyping of parasite populations from reproductively isolated laboratory strains can be used to identify these specific populations based on characteristic patterns of allele frequencies, as observed by polyacrylamide gel electrophoresis and automated sequencer analysis of fluorescently labeled PCR products. Microsatellites used to genotype aggregates of eggs collected from stools of infected individuals produced results consistent with the geographic distribution of the samples. Preferential amplification of smaller alleles, and stutter PCR products, had negligible effect on measurement of genetic differentiation. Direct analysis of total stool eggs can be an important approach to questions of population genetics for this parasite by increasing the sample size to thousands per infected individual and by reducing bias.


The effects of salt consumption habits on iodine status and thyroid functions during pregnancy
Iodine is the basic substrate for thyroid hormone synthesis and is vital for the general population and especially pregnant women. Iodine deficiency may cause severe health problems for a foetus. This study aimed to determine the relationship, if any, between iodine level and thyroid function tests, and to determine the relationship between consumption of salt types and its effects on thyroid function tests in the first trimester of pregnancy. Three hundred and six pregnant women in the first trimester of pregnancy, who had known no thyroid disease history and had not received iodine supportive therapy, were included in the study. All patients were questioned for their preferred table salt or rock salt in daily use and urine iodine concentrations (UICs) were analysed in spot urine. The results were evaluated statistically according to salt usage preferences. The median age of patients in the study was 27.8 (± 5.4). In terms of salt consumption habits, 235 (76.8%) of patients reported using table salt, and 71 (23.2%) reported using rock salt. Iodine deficiency was found in 75.81% (n = 232) of all cases according to urinalysis. Median UICs of table salt group were significantly higher than rock salt group (123.7 μg/L and 70.9 μg/L respectively, P < 0.001). Although large-scale salt iodination began long time ago, iodine deficiency is still a serious health problem among pregnant women. According to this study, use of rock salt is associated with low urinary iodine concentration in pregnant women and TSH values within the reference limits are not a good indicator for determining the iodine level.


Circadian desynchronization triggers premature cellular aging in a diurnal rodent.
Chronic jet lag or shift work is deleterious to human metabolic health, in that such circadian desynchronization is associated with being overweight and the prevalence of altered glucose metabolism. Similar metabolic changes are observed with age, suggesting that chronic jet lag and accelerated cell aging are intimately related, but the association remains to be determined. We addressed whether jet lag induces metabolic and cell aging impairments in young grass rats (2-3 mo old), using control old grass rats (12-18 mo old) as an aging reference. Desynchronized young and control old subjects had impaired glucose tolerance (+60 and +280%) when compared with control young animals. Despite no significant variation in liver DNA damage, shorter telomeres were characterized, not only in old animal liver cells (-18%), but also at an intermediate level in desynchronized young rats (-9%). The same pattern was found for deacetylase sirtuin (SIRT)-1 (-57 and -29%), confirming that jet-lagged young rats have an intermediate aging profile. Our data indicate that an experimental circadian desynchronization in young animals is associated with a precocious aging profile based on 3 well-known markers, as well as a prediabetic phenotype. Such chronic jet lag-induced alterations observed in a diurnal species constitute proof of principle of the need to develop preventive treatments in jet-lagged persons and shift workers.


On the evaluation of the non-interacting kinetic energy in density functional theory.
The utility of both an orbital-free and a single-orbital expression for computing the non-interacting kinetic energy in density functional theory is investigated for simple atomic systems. The accuracy of both expressions is governed by the extent to which the Kohn-Sham equation is solved for the given exchange-correlation functional and so special attention is paid to the influence of finite Gaussian basis sets. The orbital-free expression is a statement of the virial theorem and its accuracy is quantified. The accuracy of the single-orbital expression is sensitive to the choice of Kohn-Sham orbital. The use of particularly compact orbitals is problematic because the failure to solve the Kohn-Sham equation exactly in regions where the orbital has decayed to near-zero leads to unphysical behaviour in regions that contribute to the kinetic energy, rendering it inaccurate. This problem is particularly severe for core orbitals, which would otherwise appear attractive due to their formally nodeless nature. The most accurate results from the single-orbital expression are obtained using the relatively diffuse, highest occupied orbitals, although special care is required at orbital nodes.


Robotic Arm-assisted Total Hip Arthroplasty is More Cost-Effective Than Manual Total Hip Arthroplasty: A Markov Model Analysis.
Total hip arthroplasty (THA) is the benchmark surgical treatment of advanced and symptomatic hip osteoarthritis. Preliminary evidence suggests that the robotic arm-assisted (RAA) technology yields more accurate and reproducible acetabular cup placement, which may improve survival rate and clinical results, but economic considerations are less well-defined. The purpose of this study was to compare the cost effectiveness of the RAA THA with manual THA (mTHA) modalities, considering direct medical costs and utilities from a payer's perspective. A Markov model was constructed to analyze two potential interventions for hip osteoarthritis and degenerative joint disorder: RAA THA and mTHA. Potential outcomes of THA were categorized into the transition states: infection, dislocation, no major complications, or revision. Cumulative costs and utilities were assessed using a cycle length of 1 year over a time horizon of 5 years. RAA THA cohort was cost effective relative to mTHA cohort for cumulative Medicare and cumulative private payer insurance costs over the 5-year period. RAA THA cost saving had an average differential of $945 for Medicare and $1,810 for private insurance relative to mTHA while generating slightly more utility (0.04 quality-adjusted life year). The preferred treatment was sensitive to the utilities generated by successful RAA THA and mTHA. Microsimulations indicated that RAA THA was cost effective in 99.4% of cases. In the Medicare and private payer scenarios, RAA THA is more cost effective than conventional mTHA when considering direct medical costs from a payer's perspective. Economic Level III. Computer simulation model (Markov model).


Noninvasive ventilation in children: a review.
To assess the use of noninvasive ventilation (NIV) in children and its application in the acute and chronic setting of pediatric respiratory failure. Search of pertinent articles within PubMed, Cochrane and Ovid MEDLINE databases from 1950 to 2007, using the keywords pediatrics, noninvasive ventilation and positive airway pressure. There is a paucity of published data on pediatric NIV. The majority of the data available are case reports or small case series, with a number of small, randomized studies reported. Although the use of NIV is increasingly recognized in pediatrics, there are currently still no generally accepted guidelines for its use. In the chronic setting, its use has mainly been proven in obstructive sleep apnea and respiratory failure secondary to neuromuscular disorders. It would appear that the major challenge is ensuring compliance, and this can be enforced by patient/caregiver education, use of a suitable interface, heated humidifiers and by minimizing the side effects of NIV. In the setting of acute respiratory failure, it would appear from available data that success is usually predicted by the rapidity of response. Patients placed on NIV should be monitored closely and this mode of ventilation should be reviewed if there is a lack of response within a few hours after commencement of therapy.


Bladder wall thickness in the assessment of neurogenic bladder: a translational discussion of current clinical applications.
The prospective trial by Kim et al. "Can Bladder Wall Thickness Predict Videourodynamic Findings in Children with Spina Bifida?" published in Journal of Urology investigated the measurement of bladder wall thickness (BWT) as a non-invasive assessment tool for lower urinary tract changes in neurogenic bladder (NGB). In this study, no significant association was observed between BWT and high-risk urodynamic parameters. This editorial discusses the basic science of bladder wall thickening as well as prior studies relating wall thickness to clinical parameters. Although Kim et al. provide a unique literature contribution in terms of assessment of BWT at defined percent cystometric capacity, specific aspects of study methodology and population may have contributed to a lack of correlation with high-risk urodynamic findings. The application of non-invasive modalities to lower urinary tract assessment of NGB remains a promising and relevant area of future research to prevent progression to end stage lower urinary tract changes for all individuals with spina bifida.


Comparative efficacy and acceptability of bibliotherapy for depression and anxiety disorders in children and adolescents: a meta-analysis of randomized clinical trials.
Depression and anxiety are the most common mental disorders in children and adolescents. Bibliotherapy is a treatment using written materials for mental health problems. Its main advantages are ease of use, low cost, low staffing demands, and greater privacy. Yet few meta-analyses have focused on the effect of bibliotherapy on depression and anxiety disorders in children and adolescents. We included randomized controlled trials comparing bibliotherapy with control conditions for depression and anxiety in children and adolescents (aged ≤18 years). Five electronic databases (PubMed, Embase, Cochrane, Web of Science, and PsycINFO) were searched from inception to January 2017. Efficacy was defined as mean change scores in depression and anxiety symptoms. Acceptability was defined as the proportion of participants who discontinued the treatment. Random effects model was used. An intention-to-treat analysis was conducted. Eight studies with 979 participants were selected. At posttreatment, bibliotherapy was significantly more effective than the control conditions in reducing the symptoms of depression or anxiety (standardized mean difference, -0.52; 95% confidence interval [CI], -0.89 to -0.15). Bibliotherapy did not have statistically significantly more all-cause discontinuations than controls (risk ratios, 1.66; 95% CI, 0.93 to 2.95). We also performed subgroup analyses for efficacy outcomes in different categories (types of disorder, mean age, control conditions, and parental involvement) of studies and found that bibliotherapy has been more effective in depressive adolescents. Limited studies were eligible in this review and hence there was potential publication bias. According to the findings in this review, bibliotherapy may be more beneficial in treating depression in adolescents, but shows less robust effects for anxiety in children. Further well-defined clinical studies should be performed to confirm these outcomes.


Characteristics and reactivity of ruthenium-oxo complexes.
In this perspective, we have surveyed the synthetic procedure, characteristics, and reactivity of high-valent ruthenium-oxo complexes. The ruthenium-oxo complexes have served as ideal species to elucidate the characteristics of metal-oxo complexes in terms of not only geometrical and electronic structures but also oxidation reactivity and mechanisms of oxidation reactions. Due to the high stability and excellent reversibility of redox processes, ruthenium-oxo complexes have provided significant mechanistic insights into the oxidation of organic compounds including alcohols, alkenes, and alkanes and also water on the basis of detailed kinetic analysis.


Age and gender differences in the use of behavior management techniques by pediatric dentists.
This study evaluated differences in the use of behavior management techniques among older and younger male and female pediatric dentists. We surveyed all active members of the American Academy of Pediatric Dentistry residing in the U.S. and Canada. Responses were received from 2467 (59%). The survey contained items on age, gender, and use of behavior management techniques. Males respondents outnumbered females 2:1. Age categories were dichotomized as < 46 and > or = 46 years. Females constituted 53% of the younger group and 14% of the older group. Four gender/age categories were used. A minority indicated that they used hand-over-mouth and active immobilization of sedated patients. No significant differences by groups were seen for use of most basic behavior management techniques. Significant differences by gender/age distribution were seen for the use of non-verbal communication and advanced techniques. Most differences in anticipated changes in technique use were age-related. Most favored parental presence in the operatory, though older males were significantly less likely to allow parental presence for some procedures. Some statistically significant differences in the use of behavior management techniques exist between older and younger male and female pediatric dentists. Overall, however, the 4 gender/age groups report similar frequencies of use of the techniques surveyed in this study.


Elevated left mid-frontal cortical activity prospectively predicts conversion to bipolar I disorder.
Bipolar disorder is characterized by a hypersensitivity to reward-relevant cues and a propensity to experience an excessive increase in approach-related affect, which may be reflected in hypo/manic symptoms. The present study examined the relationship between relative left-frontal electroencephalographic (EEG) activity, a proposed neurophysiological index of approach-system sensitivity and approach/reward-related affect, and bipolar course and state-related variables. Fifty-eight individuals with cyclothymia or bipolar II disorder and 59 healthy control participants with no affective psychopathology completed resting EEG recordings. Alpha power was obtained and asymmetry indices computed for homologous electrodes. Bipolar spectrum participants were classified as being in a major/minor depressive episode, a hypomanic episode, or a euthymic/remitted state at EEG recording. Participants were then followed prospectively for an average 4.7-year follow-up period with diagnostic interview assessments every 4 months. Sixteen bipolar spectrum participants converted to bipolar I disorder during follow-up. Consistent with hypotheses, elevated relative left-frontal EEG activity at baseline (a) prospectively predicted a greater likelihood of converting from cyclothymia or bipolar II disorder to bipolar I disorder over the 4.7-year follow-up period, (b) was associated with an earlier age-of-onset of first bipolar spectrum episode, and (c) was significantly elevated in bipolar spectrum individuals in a hypomanic episode at EEG recording. This is the first study to our knowledge to identify a neurophysiological marker that prospectively predicts conversion to bipolar I disorder. The fact that unipolar depression is characterized by decreased relative left-frontal EEG activity suggests that unipolar depression and vulnerability to hypo/mania may be characterized by different profiles of frontal EEG asymmetry.


Evidence for true fall-mating in Japanese newt Cynops pyrrhogaster.
The mating season of Japanese newt Cynops pyrrhogaster is generally thought to occur once a year in spring to early summer, during the months of April to June, as in many other Japanese amphibians. However, in fall, from September to October, we often observed breeding colored males demonstrating a mating behavior with females in the field. In this study, in order to identify their true mating season, we anatomically and histologically investigated the annual maturation cycle of gonads and reproductive organs, including cloacal spermathecae in females, and, using a molecular marker, identified the seasonal origins of sperm, which are released in spring to perform insemination. We found that, in fall, ovaries are somewhat immature, while the testes were mature and the sperm already stored in the deferent ducts. Females stored a significant amount of sperm in around 80% of the spermatechae examined in October and 100% in December. When artificially ovulated in March before contact with male partners after hibernation, the females spawned fertilized eggs and these developed normally. Finally, we identified heterozygous genotypes of the visual pigment gene for the two different population types in the embryos, which were derived from a female who established contact with males of the same population in fall and then switched to males from another population until oviposition in spring. We therefore, conclude that the true mating season of this species occurs from fall to early summer, interrupted only by winter, and lasts six months longer (from October to June) than generally believed.


Impact of managed care on publicly insured children with special health care needs.
The aim of this review was to evaluate the impact of managed care on publicly insured children with special health care needs (CSHCN). We conducted a review of the extant literature. Using a formal computerized search, with search terms reflecting 7 specific outcome categories, we summarized study findings and study quality. We identified 13 peer-reviewed articles that evaluated the impact of Medicaid and State Children's Health Insurance program (SCHIP) Managed Care (MSMC) on health services delivery to populations of CSHCN, with all studies observational in design. Considered in total, the available scientific evidence is varied. Findings concerning care access demonstrate a positive effect of MSMC; findings concerning care utilization were mixed. Little information was identified concerning health care quality, satisfaction, costs, or health status, whereas no study yielded evidence on family impact. The available studies suggest that the evaluated record of MSMC for CSHCN has been mixed, with considerable heterogeneity in the definition of CSHCN, program design, and measured outcomes. These findings suggest caution should be exercised in implementing MSMC for CSHCN and that greater emphasis on health outcomes and cost evaluations is warranted.


Lynch syndrome in the 21st century: clinical perspectives.
Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes- MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI). Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS.


Tuberculosis and Guillain-Barre syndrome: A chance association?
An 18-year-old boy presented with acute-onset quadriparesis that had developed 4 weeks prior. He had an intermittent fever and significant weight loss during this period. After extensive investigations, the patient was diagnosed with an acute motor and sensory axonal neuropathy (AMSAN) variant of Guillain-Barre syndrome (GBS) and disseminated tuberculosis with mediastinal lymphadenopathy, pericarditis, and pleural effusion. Plasmapheresis was performed and first-line anti-tubercular therapy was administered. At the follow-up at 6 months, the patient was asymptomatic, he had no residual weakness and could walk without support, and tuberculosis had completely resolved on X-rays. Many infectious agents have been known to trigger GBS, but only a few cases of GBS and tuberculosis have been reported. This association needs to be evaluated further.


Processing genome scale tabular data with wormtable.
Modern biological science generates a vast amount of data, the analysis of which presents a major challenge to researchers. Data are commonly represented in tables stored as plain text files and require line-by-line parsing for analysis, which is time consuming and error prone. Furthermore, there is no simple means of indexing these files so that rows containing particular values can be quickly found. We introduce a new data format and software library called wormtable, which provides efficient access to tabular data in Python. Wormtable stores data in a compact binary format, provides random access to rows, and enables sophisticated indexing on columns within these tables. Files written in existing formats can be easily converted to wormtable format, and we provide conversion utilities for the VCF and GTF formats. Wormtable's simple API allows users to process large tables orders of magnitude more quickly than is possible when parsing text. Furthermore, the indexing facilities provide efficient access to subsets of the data along with providing useful methods of summarising columns. Since third-party libraries or custom code are no longer needed to parse complex plain text formats, analysis code can also be substantially simpler as well as being uniform across different data formats. These benefits of reduced code complexity and greatly increased performance allow users much greater freedom to explore their data.


The vaginal microbiota: what have we learned after a decade of molecular characterization?
We conducted a systematic review of the Medline database (U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD, U.S.A) to determine if consistent molecular vaginal microbiota (VMB) composition patterns can be discerned after a decade of molecular testing, and to evaluate demographic, behavioral and clinical determinants of VMB compositions. Studies were eligible when published between 1 January 2008 and 15 November 2013, and if at least one molecular technique (sequencing, PCR, DNA fingerprinting, or DNA hybridization) was used to characterize the VMB. Sixty three eligible studies were identified. These studies have now conclusively shown that lactobacilli-dominated VMB are associated with a healthy vaginal micro-environment and that bacterial vaginosis (BV) is best described as a polybacterial dysbiosis. The extent of dysbiosis correlates well with Nugent score and vaginal pH but not with the other Amsel criteria. Lactobacillus crispatus is more beneficial than L. iners. Longitudinal studies have shown that a L. crispatus-dominated VMB is more likely to shift to a L. iners-dominated or mixed lactobacilli VMB than to full dysbiosis. Data on VMB determinants are scarce and inconsistent, but dysbiosis is consistently associated with HIV, human papillomavirus (HPV), and Trichomonas vaginalis infection. In contrast, vaginal colonization with Candida spp. is more common in women with a lactobacilli-dominated VMB than in women with dysbiosis. Cervicovaginal mucosal immune responses to molecular VMB compositions have not yet been properly characterized. Molecular techniques have now become more affordable, and we make a case for incorporating them into larger epidemiological studies to address knowledge gaps in etiology and pathogenesis of dysbiosis, associations of different dysbiotic states with clinical outcomes, and to evaluate interventions aimed at restoring and maintaining a lactobacilli-dominated VMB.


The effectiveness of water treatment processes against schistosome cercariae: A systematic review.
Schistosomiasis is one of the most disabling neglected tropical diseases, ranking second in terms of years lived with disability. While treatment with the drug praziquantel can have immediate beneficial effects, reinfection can occur rapidly if people are in contact with cercaria-infested water. Water treatment for schistosomiasis control seeks to eliminate viable cercariae from water, thereby providing safe alternative water supplies for recreational and domestic activities including laundry and bathing. This provision may reduce contact with infested water, which is crucial for reducing reinfection following chemotherapy and cutting schistosome transmission. A qualitative systematic review was carried out to summarize the existing knowledge on the effectiveness of water treatment in removing or inactivating human schistosome cercariae. Four online databases were searched. Studies were screened and categorized into five water treatment processes: storage, heating, chlorination, filtration, and ultraviolet (UV) disinfection. All five water treatment methods can remove or inactivate cercariae in water, and hence produce cercaria-free water. However, reliable design guidelines for treating water do not exist as there are insufficient data. Overall, the review found that cercariae are inactivated when storing water for 10-72 hours (depending on temperature), or with chlorination values of 3-30 mg-min/l. UV fluences between 3-60 mJ/cm2 may significantly damage or kill cercariae, and sand filters with 0.18-0.35 mm grain size have been shown to remove cercariae. This systematic review identified 67 studies about water treatment and schistosomiasis published in the past 106 years. It highlights the many factors that influence the results of water treatment experiments, which include different water quality conditions and methods for measuring key parameters. Variation in these factors limit comparability, and therefore currently available information is insufficient for providing complete water treatment design recommendations.


Multimodality Treatment of Skull Base Chondrosarcomas: The Role of Histology Specific Treatment Protocols.
Limited data exist to guide the multimodality management of chondrosarcomas (CSAs) arising in the skull base. To determine the impact of histological subtype/grade on progression-free survival (PFS) and the indications for surgery, radiation, and chemotherapy based on histology. A retrospective review was performed of 37 patients (conventional type: 81%, mesenchymal: 16.2%, dedifferentiated: 2.7%) treated at The University of Texas M.D. Anderson Cancer Center. Of the conventional subtype, 23% were grade 1, 63% were grade 2, and 14% were grade 3. In addition to surgery, mesenchymal/dedifferentiated CSAs (18% of the cohort) underwent neoadjuvant chemotherapy and 48.6% of the overall cohort received adjuvant radiotherapy. Histological grade/subtype and treatment factors were assessed for impact on median PFS (primary outcome). Conventional subtype vs mesenchymal/dedifferentiated was positively associated with median PFS (166 vs 24 months, P < .05). Increasing conventional grade inversely correlated with median PFS ( P < .05). Gross total resection positively impacted PFS in conventional CSAs (111.8 vs 42.9 months, P = .201) and mesenchymal/dedifferentiated CSAs (58.2 vs 1.0 month, P < .05). Adjuvant radiotherapy significantly impacted PFS in conventional grades 2 and 3 (182 vs 79 months, P < .05) and a positive trend with mesenchymal/dedifferentiated CSAs (43.5 vs 22.0 months). Chemotherapy improved PFS for mesenchymal/dedifferentiated CSAs (50 vs 9 months, P = .089). There is a potential need for histological subtype/grade specific treatment protocols. For conventional CSAs, surgery alone provides optimal results grade 1 CSAs, while resection with adjuvant radiotherapy yields the best outcome for grade 2 and 3 CSAs. Improvements in PFS seen with neoadjuvant therapy in mesenchymal/dedifferentiated CSAs indicate a potential role for systemic therapies. Larger studies are necessary to confirm the proposed treatment protocols.


Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart.
Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as to determine the pathologic consequences of chronic disruption of this circadian clock component. To address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 [Bdh1]) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase [Pik3r1]) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in life span. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.


Severe cutaneous adverse reactions: acute generalized exanthematous pustulosis, toxic epidermal necrolysis and Stevens-Johnson syndrome.
Most drug hypersensitivity reactions show skin symptoms. The most severe cutaneous manifestations include pustular and bullous skin eruptions. These 2 manifestations can lead to acute generalized exanthematous pustulosis or Stevens-Johnson syndrome and toxic epidermal necrolysis. These complications are rare, but should be known to any doctor prescribing drugs because they are life threatening and early stoppage of treatment is mandatory.


Compensation of spectral and RF errors in swept-source OCT for high extinction complex demodulation.
We provide a framework for compensating errors within passive optical quadrature demodulation circuits used in swept-source optical coherence tomography (OCT). Quadrature demodulation allows for detection of both the real and imaginary components of an interference fringe, and this information separates signals from positive and negative depth spaces. To achieve a high extinction (∼60 dB) between these positive and negative signals, the demodulation error must be less than 0.1% in amplitude and phase. It is difficult to construct a system that achieves this low error across the wide spectral and RF bandwidths of high-speed swept-source systems. In a prior work, post-processing methods for removing residual spectral errors were described. Here, we identify the importance of a second class of errors originating in the RF domain, and present a comprehensive framework for compensating both spectral and RF errors. Using this framework, extinctions >60 dB are demonstrated. A stability analysis shows that calibration parameters associated with RF errors are accurate for many days, while those associated with spectral errors must be updated prior to each imaging session. Empirical procedures to derive both RF and spectral calibration parameters simultaneously and to update spectral calibration parameters are presented. These algorithms provide the basis for using passive optical quadrature demodulation circuits with high speed and wide-bandwidth swept-source OCT systems.


Molecular detection of vertebrates in stream water: a demonstration using Rocky Mountain tailed frogs and Idaho giant salamanders.
Stream ecosystems harbor many secretive and imperiled species, and studies of vertebrates in these systems face the challenges of relatively low detection rates and high costs. Environmental DNA (eDNA) has recently been confirmed as a sensitive and efficient tool for documenting aquatic vertebrates in wetlands and in a large river and canal system. However, it was unclear whether this tool could be used to detect low-density vertebrates in fast-moving streams where shed cells may travel rapidly away from their source. To evaluate the potential utility of eDNA techniques in stream systems, we designed targeted primers to amplify a short, species-specific DNA fragment for two secretive stream amphibian species in the northwestern region of the United States (Rocky Mountain tailed frogs, Ascaphus montanus, and Idaho giant salamanders, Dicamptodon aterrimus). We tested three DNA extraction and five PCR protocols to determine whether we could detect eDNA of these species in filtered water samples from five streams with varying densities of these species in central Idaho, USA. We successfully amplified and sequenced the targeted DNA regions for both species from stream water filter samples. We detected Idaho giant salamanders in all samples and Rocky Mountain tailed frogs in four of five streams and found some indication that these species are more difficult to detect using eDNA in early spring than in early fall. While the sensitivity of this method across taxa remains to be determined, the use of eDNA could revolutionize surveys for rare and invasive stream species. With this study, the utility of eDNA techniques for detecting aquatic vertebrates has been demonstrated across the majority of freshwater systems, setting the stage for an innovative transformation in approaches for aquatic research.


Decreased serum sulphydryl levels as a sign of increased oxidative stress in generalized anxiety disorder.
In recent years, many published studies have focused on the relationship between oxidative stress and psychiatric disorders. However, studies in generalized anxiety disorder (GAD) are few despite relatively high prevalence rates. In an attempt to fill this gap in the literature we aimed to measure serum levels of free sulphydryl, an important member of antioxidant defense mechanisms, of the patients with GAD. A total of 35 (23 female, 12 male) GAD patients without any other co-morbid medical or psychiatric disorder and 35 (23 female, 12 male) healthy controls have been included in the study. Disease severity of the patients were quantified by using the Hamilton Anxiety Rating Scale (HAM-A). Serum free sulphydryl group levels of patients and healthy controls were measured in an appropriate way. Mean level of serum sulphydryl groups was significantly lower in the patient group. There was a negative correlation between their level and the disease duration. However, they did not show any significant correlation with the disease severity. Decreased serum sulphydryl level observed in pure GAD patients suggests an increased oxidative stress in these patients. Well designed future researches are needed to replicate our findings and to test the implications of the present study.


Fibrin glue from stored human plasma. An inexpensive and efficient method for local blood bank preparation.
European surgeons have used fibrin glue extensively during thoracic, cardiovascular, and general surgical operations. Until now, however, it has been available only as a commercial preparation made from pooled human plasma, and it has not been approved by the U.S. Food and Drug Administration for use in the United States because of a high associated risk of hepatitis and acquired immune deficiency syndrome. Methods of obtaining fibrinogen, an essential component of fibrin glue, from cryoprecipitate or fresh frozen plasma have been published recently. However, the cryoprecipitate method results in relatively low concentrations of fibrinogen, which can reduce glue effectiveness. The fresh frozen plasma method is more expensive and does not meet the standards of the American Association of Blood Banks for the "closed" system required for safe handling and management of blood component products. Both the cryoprecipitate and the fresh frozen plasma methods result in waste of unstable clotting factors. These factors are necessary to replace human plasma clotting deficiencies but are not necessary for the production of fibrin glue. The authors have developed an efficient, high-concentration blood bank method for producing and maintaining a local supply of a safer and less expensive but equally effective material derived from stored human plasma. This material is produced using approved blood bank techniques for a "closed" system in blood component production, thus reducing the risks of contamination and infection, and its fibrinogen concentration is higher than that of standard cryoprecipitate. The cost of 1 unit of this fibrin glue is comparable to that for 1 unit of cryoprecipitate and less than that for 1 unit of fresh frozen plasma.(ABSTRACT TRUNCATED AT 250 WORDS)


Early oral sensory experiences and feeding development in children with CHARGE syndrome: a report of five cases.
Children with CHARGE syndrome commonly experience feeding and swallowing problems. Difficulties may be associated with congenital structural anomalies, motor impairment, and/or oral sensory impairment. For many children with CHARGE syndrome, the introduction of functional oral feeding is delayed and there are often long-term feeding complications. Oral aversion or defensiveness is a frequent serious issue; however, it is uncertain whether this is a primary sensory disorder or secondary to delayed and/or negative oral sensory and feeding experiences. This article examines in detail the early oral sensory and feeding experiences of five children with CHARGE syndrome, through a review of medical records and caregiver questionnaires. Findings indicate variable early oral sensory experiences in this group of children, with all of the children having some difficulty or delay in the development of oral feeding and swallowing. The nature of these difficulties and the potential contributory factors are discussed.


Associations between a polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene, neuroticism and postpartum depression.
This study examined the association between a single nucleotide polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene and neuroticism, as well as the possible mediatory role of neuroticism in the association between the polymorphism and postpartum depressive symptoms. 769 women received questionnaires containing the Edinburgh Postnatal Depression Scale (EPDS) at six weeks postpartum and demographic data at pregnancy week 17 and 32 and at six weeks postpartum, as well as the Swedish universities Scales of Personality at pregnancy week 32. Linear regression models showed an association between the GG genotype and depressive symptoms. When neuroticism was introduced in the model, it was associated with EPDS score, whereas the association between the GG genotype and EPDS became borderline significant. A path analysis showed that neuroticism had a mediatory role in the association between the polymorphism and EPDS score. The use of the EPDS, which is a self-reporting instrument. Neuroticism was associated with the polymorphism and had a mediatory role in the association between the polymorphism and postpartum depression. This finding elucidates the genetic background of neuroticism and postpartum depression.


Key informant views of a free delivery and caesarean policy in Senegal.
This article presents the findings of one component of an evaluation of the national policy for free deliveries and caesareans in Senegal. The policy was introduced in 2005 in five more deprived regions of the country. It aimed to reduce the financial barriers to using maternity services and to increase the number of facility-based deliveries. The findings are drawn from 54 semi-structured interviews with key informants who had technical and administrative or political responsibility for the policy at national, regional, district and health post level. These were carried out from November 2006 to January 2007. The evaluation findings emphasise the importance of careful planning and communication before a major national policy is implemented, and also of simple and clear definition of the package of 'free' services on offer. Long-term investment in supply will also be needed to increase access for the most remote areas.


Effects of infusion time and addition of milk on content and absorption of polyphenols from black tea.
Epidemiological studies assessing the health benefits of drinking black tea are equivocal. Such disparity may reflect an inability of semiquantitative assessment to consider how infusion time and addition of milk affect the bioavailability of potentially beneficial antioxidant polyphenols. Six brands of tea demonstrated similar increases in antioxidant capacity and total phenolic and catechin contents with increasing infusion time. These results were unaffected by the addition of milk. Consumption of black tea (400 mL) was associated with significant increases in plasma antioxidant capacity (10%) and concentrations of total phenols (20%), catechins (32%), and the flavonols quercetin (39%) and kaempferol (45%) (all p < 0.01) within 80 min. This was unaffected by adding milk. Infusion time may therefore be a more important determinant in the absorption of polyphenols from black tea. Observational studies assessing the health benefits of tea consumption require recording of brewing methods as well as frequency of consumption.


Metastable liquid-liquid transition in a molecular model of water.
Liquid water's isothermal compressibility and isobaric heat capacity, and the magnitude of its thermal expansion coefficient, increase sharply on cooling below the equilibrium freezing point. Many experimental, theoretical and computational studies have sought to understand the molecular origin and implications of this anomalous behaviour. Of the different theoretical scenarios put forward, one posits the existence of a first-order phase transition that involves two forms of liquid water and terminates at a critical point located at deeply supercooled conditions. Some experimental evidence is consistent with this hypothesis, but no definitive proof of a liquid-liquid transition in water has been obtained to date: rapid ice crystallization has so far prevented decisive measurements on deeply supercooled water, although this challenge has been overcome recently. Computer simulations are therefore crucial for exploring water's structure and behaviour in this regime, and have shown that some water models exhibit liquid-liquid transitions and others do not. However, recent work has argued that the liquid-liquid transition has been mistakenly interpreted, and is in fact a liquid-crystal transition in all atomistic models of water. Here we show, by studying the liquid-liquid transition in the ST2 model of water with the use of six advanced sampling methods to compute the free-energy surface, that two metastable liquid phases and a stable crystal phase exist at the same deeply supercooled thermodynamic condition, and that the transition between the two liquids satisfies the thermodynamic criteria of a first-order transition. We follow the rearrangement of water's coordination shell and topological ring structure along a thermodynamically reversible path from the low-density liquid to cubic ice. We also show that the system fluctuates freely between the two liquid phases rather than crystallizing. These findings provide unambiguous evidence for a liquid-liquid transition in the ST2 model of water, and point to the separation of time scales between crystallization and relaxation as being crucial for enabling it.


Spinal posture in the sagittal plane is associated with future dependence in activities of daily living: a community-based cohort study of older adults in Japan.
Accumulated evidence shows how important spinal posture is for aged populations in maintaining independence in everyday life. However, the cross-sectional designs of most previous studies prevent elucidation of the relationship between spinal posture and future dependence in activities of daily living (ADL). We tried to clarify the association by measuring spinal posture noninvasively in a community-based prospective cohort study of older adults, paying particular attention to thoracic curvature, lumbar curvature, sacral hip angle, and inclination to determine which parameter is most strongly associated with dependence in ADL. Spinal posture was evaluated in 804 participants (338 men, 466 women, age range: 65-94 years) who were independent in ADL at baseline. We defined dependence in ADL as admission to a nursing home or need of home assistance. During the 4.5-year follow-up period, 126 (15.7%) participants became dependent in ADL. The relationship between the spinal posture parameters and outcome was assessed by dividing the participants into sex-specific quartiles of the parameters. Only inclination (angle subtended between the vertical and a line joining C7 to the sacrum) was associated with outcome, although lumbar curvature also showed a marginal association. The age- and sex-adjusted odds ratio for a 1 unit increase in the quartiles of inclination was 1.79 (confidence interval: 1.44, 2.23). After mutual adjustment for the 4 parameters, statistical significance for inclination still remained, with no substantial changes in the association estimates. This study indicates that spinal inclination is associated with future dependence in ADL among older adults.


Fitz-Hugh-Curtis Syndrome Caused by Gonococcal Infection in a Patient with Systemic Lupus Erythematous: A Case Report and Literature Review.
BACKGROUND Fitz-Hugh-Curtis (FHC) syndrome is a perihepatitis linked to inflammatory pelvic disease. It can be caused by Neisseria gonorrhoeae or Chlamydia trachomatis infections. FHC syndrome usually presents with pain in the right hypochondrium and fever, associated with symptoms and signs of pelvic infection in women. CASE REPORT We present the case of a 22-year-old woman with systemic lupus erythematous (SLE) who presented with polyarthritis, cutaneous lesions, and abdominal pain. The diagnosis of FHC syndrome was based on the findings of abdominal computerized tomography (CT) and the isolation of Neisseria gonorrhoeae (NG) in blood cultures. The association of arthritis and cutaneous lesions was diagnosed as a syndrome of arthritis-dermatitis, also caused by systemic NG infection. The patient had a favorable outcome with antibiotic treatment. CONCLUSIONS FHC syndrome should be considered in sexually active young patients, mainly women, with pelvic infection and perihepatitis. It may be caused by disseminated gonococcal infection. An important risk factor is the serum complement deficit, which may predispose to severe forms. Low serum complement level is a frequent manifestation of active SLE. CT images showing the typical findings of perihepatitis allow making the correct diagnosis.


Care of acute conditions and chronic diseases in Canada and the United States: Rapid systematic review and meta-analysis.
This study tested the hypothesis that socioeconomically vulnerable Canadians with diverse acute conditions or chronic diseases have health care access and survival advantages over their counterparts in the USA. A rapid systematic review retrieved 25 studies (34 independent cohorts) published between 2003 and 2018. They were synthesized with a streamlined meta-analysis. Very low-income Canadian patients were consistently and highly advantaged in terms of health care access and survival compared with their counterparts in the USA who lived in poverty and/or were uninsured or underinsured. In aggregate and controlling for specific conditions or diseases and typically 4 to 9 comorbid factors or biomarkers, Canadians' chances of receiving better health care were estimated to be 36% greater than their American counterparts (RR=1.36, 95% CI 1.35-1.37). This estimate was significantly larger than that based on general patient or non-vulnerable population comparisons (RR=1.09, 95% CI 1.08-1.10). Contrary to prevalent political rhetoric, three studies observed that Americans experience more than twice the risk of long waits for breast or colon cancer care or of dying while they wait for an organ transplant (RR=2.36, 95% CI 2.09-2.66). These findings were replicated across externally valid national studies and more internally valid, metropolitan or provincial/state comparisons. Socioeconomically vulnerable Canadians are consistently and highly advantaged on health care access and outcomes compared to their American counterparts. Less vulnerable comparisons found more modest Canadian advantages. The Affordable Care Act ought to be fully supported including the expansion of Medicaid across all states. Canada's single payer system ought to be maintained and strengthened, but not through privatization.


Biomarkers for predicting clinical responses to HDAC inhibitors.
Post-translational modifications of histone and non-histone proteins by acetylation are known to play a key role in tumourigenesis. Pharmacological manipulation of acetylation has been possible with the identification of small molecule inhibitors of histone deacetylases (HDAC), the enzymes responsible for deacetylating lysine residues. An explosion of drug discovery efforts in recent years has led to the development of an extensive group of HDAC inhibitors, many of which have been shown pre-clinically to have potent anti-tumour activity. Clinical trials using these agents are now underway, with Vorinostat (suberoylanilide hydroxamic acid) having been approved by the FDA for treating cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent or recurrent disease. This review discusses how biomarkers are being identified and used to expand our knowledge of the mechanisms by which HDAC inhibitors exhibit their anti-cancer effects. In the longer term, biomarkers will provide a means towards achieving patient stratification in tumour types that will respond favourably to HDAC inhibitors.


The natural statistics of audiovisual speech.
Humans, like other animals, are exposed to a continuous stream of signals, which are dynamic, multimodal, extended, and time varying in nature. This complex input space must be transduced and sampled by our sensory systems and transmitted to the brain where it can guide the selection of appropriate actions. To simplify this process, it's been suggested that the brain exploits statistical regularities in the stimulus space. Tests of this idea have largely been confined to unimodal signals and natural scenes. One important class of multisensory signals for which a quantitative input space characterization is unavailable is human speech. We do not understand what signals our brain has to actively piece together from an audiovisual speech stream to arrive at a percept versus what is already embedded in the signal structure of the stream itself. In essence, we do not have a clear understanding of the natural statistics of audiovisual speech. In the present study, we identified the following major statistical features of audiovisual speech. First, we observed robust correlations and close temporal correspondence between the area of the mouth opening and the acoustic envelope. Second, we found the strongest correlation between the area of the mouth opening and vocal tract resonances. Third, we observed that both area of the mouth opening and the voice envelope are temporally modulated in the 2-7 Hz frequency range. Finally, we show that the timing of mouth movements relative to the onset of the voice is consistently between 100 and 300 ms. We interpret these data in the context of recent neural theories of speech which suggest that speech communication is a reciprocally coupled, multisensory event, whereby the outputs of the signaler are matched to the neural processes of the receiver.


Cardiovascular effects of noninsulin, glucose-lowering agents: need for more outcomes data.
Macrovascular complications of type 2 diabetes mellitus (DM) are primarily driven by the combination of underlying atherosclerosis and propensity for thrombosis. Prevention of macrovascular complications in DM relies on therapies directed at multiple coexisting intermediary pathophysiologies that contribute to cardiovascular events, including hyperglycemia, lipoprotein abnormalities, hypertension, inflammation, and propensity for thrombosis. Multiple noninsulin, glucose-lowering agents have been developed that effectively lower blood glucose levels. This review explores the literature on the cardiovascular benefits and harms associated with these therapies, with an emphasis on cardiovascular outcomes when available. The lack of long-term data on cardiovascular outcomes regarding safety and efficacy of available traditional glucose-lowering agents has led to recommendations for more thorough evaluations of new therapies before approval. Furthermore, recent data suggest harm from intensive hemoglobin A(1c) reductions. Accordingly, there are multiple, large, cardiovascular-event driven phase 3-4 trials of therapies from the incretin axis currently enrolling. Recommendations for a therapeutic approach with noninsulin, glucose-lowering agents for the prevention of cardiovascular events in patients with type 2 DM are provided based on current data. Ultimately, multifactorial risk interventions, including lifestyle modifications, antihyperglycemic agents, antihypertensives, statins, and aspirin remain the primary focus to prevent macrovascular complications in patients with type 2 DM.


Molecular analysis of the maize anthocyanin regulatory locus C1.
The C1 gene of maize plays a regulatory role in the production of anthocyanin pigments in the aleurone layer of the endosperm. As an initial step toward understanding the molecular details of how C1 controls pigment biosynthesis, we cloned the C1 gene. This was accomplished by first cloning a mutable allele of C1, c1-m5, which contains the transposable element Spm. A combination of molecular and genetic analysis was used to identify the Spm at the C1 locus. Individual genomic DNAs from a population in which the c1-mutable phenotype was segregating with the recessive c1 phenotype were digested with methyl-sensitive restriction enzymes and probed with a small DNA fragment derived from a defective Spm. One Sal I restriction fragment complementary to the Spm probe was shown to be present in the DNA of individuals with the c1-m5 phenotype but absent from DNA of individuals with a recessive c1 phenotype. Subsequent cloning and restriction analysis of this fragment revealed sequences flanking the Spm that proved to be C1-specific. A DNA fragment derived from the flanking sequences was then used as a probe to clone the wild-type C1 gene and several additional alleles of C1, including one stable recessive, two mutations caused by Ds insertions, one mutation induced by insertion of a defective Spm, and two dominant mutations, C1-S and C1-I. RNA blot hybridization analysis of three C1 alleles indicates that C1 regulation of the Bz1 and A1 structural genes in the anthocyanin biosynthetic pathway is at the transcriptional level.


Stenting and medical therapy for atherosclerotic renal-artery stenosis.
Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.).


Manganese superoxide dismutase and breast cancer recurrence: a Danish clinical registry-based case-control study, and a meta-analysis.
Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses. We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990-2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR. The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively. Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.


Serum levels of placental protein 14 do not accurately reflect histologic maturation of the endometrium.
To determine whether serum levels of placental protein 14, a major product of the progesterone-induced secretory endometrium, accurately reflect histologic maturation of the endometrium. Daily serum levels of placental protein 14 were compared in 50 normally cycling women with normal or delayed endometrial maturation, as assessed by histologic dating of an endometrial biopsy in the midluteal phase of the same cycle. Ten of these subjects had placental protein 14 measurements but no biopsy in an additional cycle to examine the potential effects of the biopsy on secretion of this protein. Serum placental protein 14 concentrations started to increase 8 days after the LH surge and peaked at similar levels on the first day of the next menses in biopsy and non-biopsy cycles. The biopsy cycles had a shorter luteal phase but a slightly faster increase in placental protein 14 concentrations. Both the integrated secretion of this protein and single measurements on the day of the biopsy or at the onset of the next menses overlapped substantially in women with different degrees of endometrial development, even when differentiation of the endometrium was severely delayed. Serum measurements of placental protein 14 do not accurately predict, and thus should not replace, histologic evaluation of the endometrium at nidation.


Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles.
The recent technological evolution of reaction monitoring techniques has not been paralleled by the development of modern kinetic analyses. The analyses currently used disregard part of the data acquired, thus requiring an increased number of experiments to obtain sufficient kinetic information for a given chemical reaction. Herein, we present a simple graphical analysis method that takes advantage of the data-rich results provided by modern reaction monitoring tools. This analysis uses a variable normalization of the time scale to enable the visual comparison of entire concentration reaction profiles. As a result, the order in each component of the reaction, as well as kobs , is determined with just a few experiments using a simple and quick mathematical data treatment. This analysis facilitates the rapid extraction of relevant kinetic information and will be a valuable tool for the study of reaction mechanisms.