Epidemiology and mortality of pelvic and femur fractures-a nationwide register study of 417,840 fractures in Sweden across 16 years: diverging trends for potentially lethal fractures.
Background and purpose - Fractures of the pelvis and femur are serious and potentially lethal injuries affecting primarily older, but also younger individuals. Long-term trends on incidence rates and mortality might diverge for these fractures, and few studies compare trends within a complete adult population. We investigated and compared incidence and mortality rates of pelvic, hip, femur shaft, and distal femur fractures in the Swedish adult population.Patients and methods - We analyzed data on all adult patients ≥ 18 years in Sweden with a pelvic, hip, femur shaft, or distal femur fracture, through the Swedish National Patient Register. The studied variables were fracture type, age, sex, and 1-year mortality.Results - While incidence rates for hip fracture decreased by 18% (from 280 to 229 per 105 person-years) from 2001 to 2016, incidence rates for pelvic fracture increased by 25% (from 64 to 80 per 105 person-years). Incidence rates for femur shaft and distal femur fracture remained stable at rates of 15 and 13 per 105 person-years respectively. 1-year mortality after hip fracture was 25%, i.e., higher than for pelvic, femur shaft, and distal femur fracture where mortality rates were 20-21%. Females had an almost 30% lower risk of death within 1 year after hip fracture compared with males.Interpretation - Trends on fracture incidence for pelvic and femur fractures diverged considerably in Sweden between 2001 and 2016. While incidence rates for femur fractures (hip, femur shaft, and distal femur) decreased or remained constant during the studied years, pelvic fracture incidence increased. Mortality rates were different between the fractures, with the highest mortality among patients with hip fracture.


Equine herpesvirus 1 utilizes a novel herpesvirus entry receptor.
The well-described herpesvirus entry receptors HveA (TNFRSF14), HveB (nectin 2), and HveC (nectin 1) have been shown to mediate the entry of alphaherpesviruses. Our findings showed that the alphaherpesvirus equine herpesvirus 1 (EHV-1) efficiently entered and replicated in CHO-K1 cells that lack the entry receptors HveA, HveB, and HveC, demonstrating that EHV-1 utilizes a unique entry receptor. As with other alphaherpesviruses, efficient EHV-1 entry was dependent on glycoprotein D and cell surface glycosaminoglycans.


Progressive Collateral Stenosis Leading to Symptomatic Chronic Total Occlusion.
We present a case of chronic total occlusion (CTO) in a functional 79-year-old female with no past history of coronary artery disease, who was previously asymptomatic due to robust collateral circulation. A 79-year-old Caucasian female presented to the emergency department complaining of chest pain radiating to the neck, jaw, left arm with associated numbness in the left fingers, that had started earlier in the day. She has no previous cardiac history and never had similar symptoms before. Troponin levels were negative. Nuclear stress test showed findings worrisome for ischemia and was a high-risk exam. The patient underwent diagnostic angiography. There was complete total occlusion of the mid right coronary artery, with collateral circulation supplying the distal right coronary artery territory. Ultimately, it found that progressive stenosis of the left anterior descending (LAD) artery led to inadequate collateral circulation and completely occluded the right coronary artery's territory, causing the patient's new-onset angina. Afterwards, the patient underwent percutaneous coronary intervention (PCI). Successful implantation of two drug-eluting stents occurred. The final angiographic result was 0% residual stenosis and Thrombolysis in Myocardial Infarction (TIMI)-3 flow. CTO affecting one or more coronary arteries is not uncommon in patients taken to the catheterization laboratory. However, despite recent advancements in PCI outcomes, treatment of CTO by PCI remains relatively low, due to fear of adverse outcomes such as cardiac perforations. Recent research has supported the safety of performing PCIs on patients with CTO. This case report further reinforces the need to approach treating CTO via angioplasty.


Optical calibration of the SuperCam instrument body unit spectrometers.
The SuperCam remote sensing instrument on NASA's Perseverance rover is capable of four spectroscopic techniques, remote micro-imaging, and audio recording. These analytical techniques provide details of the chemistry and mineralogy of the rocks and soils probed in the Jezero Crater on Mars. Here we present the methods used for optical calibration of the three spectrometers covering the 243-853 nm range used by three of the four spectroscopic techniques. We derive the instrument optical response, which characterizes the instrument sensitivity to incident radiation as a function of a wavelength. The instrument optical response function derived here is an essential step in the interpretation of the spectra returned by SuperCam as it converts the observed spectra, reported by the instrument as "digital counts" from an analog to digital converter, into physical values of spectral radiance.


Animal Models in Eye Research: Focus on Corneal Pathologies.
The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on laboratory animals are essential to ensure the safety of therapeutic products directly applied or injected into the eye to treat ocular diseases before eventually proceeding to clinical trials. Among these tissues, the cornea has unique homeostatic and regenerative mechanisms for maintaining transparency and refraction of external light, which are essential for vision. However, being the outermost tissue of the eye and directly exposed to the external environment, the cornea is particularly susceptible to injury and diseases. This review highlights the evidence for selecting appropriate animals to better understand and treat corneal diseases, which rank as the fifth leading cause of blindness worldwide. The development of reliable and human-relevant animal models is, therefore, a valuable research tool for understanding and translating fundamental mechanistic findings, as well as for assessing therapeutic potential in humans. First, this review emphasizes the unique characteristics of animal models used in ocular research. Subsequently, it discusses current animal models associated with human corneal pathologies, their utility in understanding ocular disease mechanisms, and their role as translational models for patients.


Habitat type and interannual variation shape unique fungal pathogen communities on a California native bunchgrass.
The role of infectious disease in regulating host populations is increasingly recognized, but how environmental conditions affect pathogen communities and infection levels remains poorly understood. Over 3 y, we compared foliar disease burden, fungal pathogen community composition, and foliar chemistry in the perennial bunchgrass Stipa pulchra occurring in adjacent serpentine and nonserpentine grassland habitats with distinct soil types and plant communities. We found that serpentine and nonserpentine S. pulchra experienced consistent, low disease pressure associated with distinct fungal pathogen communities with high interannual species turnover. Additionally, plant chemistry differed with habitat type. The results indicate that this species experiences minimal foliar disease associated with diverse fungal communities that are structured across landscapes by spatially and temporally variable conditions. Distinct fungal communities associated with different growing conditions may shield S. pulchra from large disease outbreaks, contributing to the low disease burden observed on this and other Mediterranean grassland species.


Golfer's swing leads to a spontaneous subcapsular liver haematoma.
We report the rare case of a patient presenting with a spontaneous hepatic subcapsular haematoma after playing golf. The patient had no underlying predisposing conditions. A CT scan of the abdomen/pelvis demonstrated a 1 cm deep low-attenuation subcapsular collection around the anterolateral aspect of the liver. The patient was treated conservatively and was discharged from inpatient care after 72 h. This is only the second reported case of a spontaneous subcapsular haematoma.


Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: The special case of molnupiravir.
This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.


Single-frequency master-oscillator photonic crystal fiber amplifier with 148 W output power.
We report on a high-power ytterbium doped photonic crystal fiber amplifier using a single-frequency Nd:YAG non-planar ring oscillator seed source. With a large-mode-area photonic crystal fiber, operation below the threshold of stimulated Brillouin scattering is demonstrated with up to 148 W of continuous-wave output power and a slope efficiency of 75%. At maximum output power the amplified spontaneous emission was suppressed by more than 40 dB and the polarization extinction ratio was better than 22 dB. In order to investigate the overlap of the photonic crystal fiber transverse-mode with a Gaussian fundamental mode, sensitive beam quality measurements with a Fabry-Perot ring-cavity are presented.


A new method for the measurement of bile acid turnover and pool size by a double label, single intubation technique.
A new method is described for measuring the cholic acid turnover and pool size by a single duodenal intubation technique. The method is based on determination in a single bile sample of the ratio of the specific activities of [14C]cholic acid and [3H]cholic acid administered intravenously with an interval of 24 hr. With this ratio the fractional turnover rate (k) of cholic acid can easily be calculated as well as the half-life and pool size. Studies in ten normal subjects indicate that the cholic acid half life and pool size, determined by this single intubation technique, correlate very well (r greater than or equal to 0.98) with the results obtained by Lindstedt's method. Unlike the other methods using a single intubation, this method allows a good estimate of the bile acid turnover as well as the bile acid pool size.


[Isolation and quantitative analysis of the alpha-amylase inhibitor in Lagerstroemia speciosa (L.) Pers. (Banaba)].
Banaba [Lagerstroemia speciosa (L.) Pers.] has been used as a folk medicine for diabetes in the Philippines. Using bioassay-guided separation, valoneaic acid dilactone (1) was isolated from the leaves as a potent alpha-amylase inhibitor. A simple and efficient method for the quantitative determination of valoneaic acid and its derivatives in Banaba extract was established. Valoneaic acid exists as the structural part of the polyphenols, which like flosin A, reginin A, and lagerstroemin, are characteristic constituents of Banaba. These derivatives were hydrolyzed to valoneaic acid by HCl and extracted with 2-butanone. This extract was subjected to HPLC analysis, and the contents of valoneaic acid determined as the whole valoneaic acid contents. Using this method, the whole valoneaic acid contents were measured in eight Banaba leaf decoctions. The alpha-amylase-inhibiting activities of the decoctions were dependent on the whole valoneaic acid contents. In addition, a strong linear correlation was observed between the whole valoneaic acid contents and total polyphenol contents. This analytical procedure is applicable to the chemical evaluation of Banaba.


Neighboring trees regulate the root-associated pathogenic fungi on the host plant in a subtropical forest.
Root-associated fungi and host-specific pathogens are major determinants of species coexistence in forests. Phylogenetically related neighboring trees can strongly affect the fungal community structure of the host plant, which, in turn, will affect the ecological processes. Unfortunately, our understanding of the factors influencing fungal community composition in forests is still limited. In particular, investigation of the relationship between the phytopathogenic fungal community and neighboring trees is incomplete. In the current study, we tested the host specificity of members of the root-associated fungal community collected from seven tree species and determined the influence of neighboring trees and habitat variation on the composition of the phytopathogenic fungal community of the focal plant in a subtropical evergreen forest. Using high-throughput sequencing data with respect to the internal transcribed spacer (ITS) region, we characterized the community composition of the root-associated fungi and found significant differences with respect to fungal groups among the seven tree species. The density of conspecific neighboring trees had a significantly positive influence on the relative abundance of phytopathogens, especially host-specific pathogens, while the heterospecific neighbor density had a significant negative impact on the species richness of host-specific pathogens, as well as phytopathogens. Our work provides evidence that the root-associated phytopathogenic fungi of a host plant depend greatly on the tree neighbors of the host plant.


Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells.
NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.


The neuroendocrine recovery function of sleep.
The hypothalamo-pituitary-adrenal (HPA) system is a most important mediator of the organism's response to stress. Secretory activity of this endocrine system displays a specific regulation during normal nocturnal sleep in humans. Pituitary release of adrenocorticotropin (ACTH) as well as adrenocortical release of cortisol decreases to a minimum during early sleep which is simultaneously characterized by maximum release of growth hormone (GH) and a predominance of slow wave sleep (SWS). In contrast, release of ACTH and cortisol reaches a maximum during late sleep which is simultaneously characterized by minimum plasma concentrations of GH and a predominance of rapid eye movement (REM) sleep. The nadir activity of the pituitary-adrenal system during early sleep reflects an active inhibition of this 'stress' system. One of the factors mediating this inhibition presumably is the sleep associated hypothalamic secretion of a release inhibiting factor of ACTH. In addition, limbic-hippocampal neuronal networks contribute to the inhibitory control over HPA activity during early sleep. Those structures appear to coordinate HPA inhibition and cortical activity (with prevalent SWS) during early sleep, thereby facilitating the formation of memories in sleep. As indicated by studies testing the effects of elevated plasma glucocorticoid levels, the inhibition of HPA activity during early sleep is an essential prerequisite for the memory function of sleep. Possibly, immunological memory formation likewise benefits from this inhibition. The suppression of pituitary-adrenal secretory activity during early sleep can be significantly weakened after profound acute stress as well as in states of chronic stress (including normal aging) which thereby disturb regular memory formation in sleep.


Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer.
Prior studies have suggested a higher prevalence of high grade, ER-negative, HER2-positive, and basal-like carcinomas in young women with breast cancer. However, the precise distribution of poor prognostic features in this population remains unclear. We examined the pathologic features and distribution of molecular phenotype in relation to patient age in a large group of young women (≤40 years) with invasive breast cancer. Medical records were reviewed for clinical characteristics, tumor stage, and receptor status. Pathologic features, including those features associated with basal-like carcinomas, were examined by central review. Using tumor grade and biomarker expression, cancers were categorized as luminal A (ER+ and/or PR+ and HER2-, histologic grade 1 or 2); luminal B (ER+ and/or PR+ and HER2+, or ER and/or PR+, HER2- and grade 3); HER2 (ER and PR- and HER2+); and triple negative (ER-, PR-, and HER2-). Among 399 women of ≤40 years, 33% had luminal A tumors, 35% luminal B, 11% HER2 (ER-negative), and 21% triple negative. Compared to published results for all breast cancers, a greater proportion of young women had luminal B tumors, and a lesser proportion had luminal A. There were no significant differences in molecular phenotype, tumor stage or grade among the different age groups of young women. However, this population of young women presented with a different distribution of molecular phenotypes compared to the general population of women with breast cancer. These findings may have implications with regard to the etiology and prognosis of breast cancer in young women.


The Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias: an interdisciplinary approach.
Skeletal dysplasias are a group of over 300 genetic conditions often marked by short stature and a range of orthopedic problems. To meet the diverse medical, orthopedic, and psychosocial needs of individuals with skeletal dysplasias, the Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias was organized at Hospital for Special Surgery in 2003. The center is the only one of its kind in the New York City metropolitan area and is dedicated to providing comprehensive medical care for individuals with skeletal dysplasias. The center is staffed by an interdisciplinary core team of health professionals consisting of an orthopedic surgeon, a medical geneticist, a genetic counselor/clinical coordinator, and a social worker. This interdisciplinary team of health professionals is committed to improving the quality of life for people with skeletal dysplasias through clinical care, research, education, and patient advocacy. Goals are achieved through a collaborative process that utilizes the expertise of the different professionals.


Re-Evaluating Clonal Dominance in Cancer Evolution.
Tumours are composed of genetically heterogeneous subclones which may diverge early during tumour growth. However, our strategies for treating and assessing outcome for patients are overwhelmingly based upon the classical linear paradigm for cancer evolution. Increasing numbers of studies are finding that minor subclones can determine clinical disease course, and that temporal and spatial heterogeneity needs to be considered in disease management. In this article we review evidence for cancer clonal heterogeneity, evaluating the importance of tumour subclones and their growth through both Darwinian and neutral evolution. Major shifts in current clinical practice and trial designs, aimed at understanding cancer evolution on a patient-by-patient basis, may be necessary to achieve more successful treatment of heterogeneous metastatic disease.


Optimizing modelling in iterative image reconstruction for preclinical pinhole PET.
The recently developed versatile emission computed tomography (VECTor) technology enables high-energy SPECT and simultaneous SPECT and PET of small animals at sub-mm resolutions. VECTor uses dedicated clustered pinhole collimators mounted in a scanner with three stationary large-area NaI(Tl) gamma detectors. Here, we develop and validate dedicated image reconstruction methods that compensate for image degradation by incorporating accurate models for the transport of high-energy annihilation gamma photons. Ray tracing software was used to calculate photon transport through the collimator structures and into the gamma detector. Input to this code are several geometric parameters estimated from system calibration with a scanning (99m)Tc point source. Effects on reconstructed images of (i) modelling variable depth-of-interaction (DOI) in the detector, (ii) incorporating photon paths that go through multiple pinholes ('multiple-pinhole paths' (MPP)), and (iii) including various amounts of point spread function (PSF) tail were evaluated. Imaging (18)F in resolution and uniformity phantoms showed that including large parts of PSFs is essential to obtain good contrast-noise characteristics and that DOI modelling is highly effective in removing deformations of small structures, together leading to 0.75 mm resolution PET images of a hot-rod Derenzo phantom. Moreover, MPP modelling reduced the level of background noise. These improvements were also clearly visible in mouse images. Performance of VECTor can thus be significantly improved by accurately modelling annihilation gamma photon transport.


Effects of beta-adrenergic blockade on lateral hypothalamic lesion-induced thermogenesis.
Oxygen consumption is markedly elevated in rats with lesions of the lateral hypothalamus (LH), a response typically associated with hyperactivity. To test for involvement of adrenergic systems in this hypermetabolic state, propranolol was administered before and immediately after LH lesions. Propranolol attenuated both the lesion-induced rise in oxygen consumption and activity in the 12 h after surgery. A second experiment evaluated the contribution of activity to this thermic response by lesioning rats immobilized by a continuous barbiturate infusion. The persistence of lesion-induced increases in oxygen consumption in the absence of activity and the attenuation of this response by propranolol demonstrated that 1) LH lesions directly alter metabolic heat production, and 2) this effect is at least partly mediated by beta-adrenergic systems. The functional significance of increased energy expenditure after LH lesions is discussed in light of the known effects of this lesion on the level of regulated body weight.


The causes of preterm neonatal deaths in India and Pakistan (PURPOSe): a prospective cohort study.
Preterm birth remains the major cause of neonatal death worldwide. South Asia contributes disproportionately to deaths among preterm births worldwide, yet few population-based studies have assessed the underlying causes of deaths. Novel evaluations, including histological and bacteriological assessments of placental and fetal tissues, facilitate more precise determination of the underlying causes of preterm deaths. We sought to assess underlying and contributing causes of preterm neonatal deaths in India and Pakistan. The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe) was a prospective cohort study done in three hospitals in Davangere, India, and two hospitals in Karachi, Pakistan. All pregnant females older than 14 years were screened at the time of presentation for delivery, and those with an expected or known preterm birth, defined as less than 37 weeks of gestation, were enrolled. Liveborn neonates with a weight of 1000 g or more who died by 28 days after birth were included in analyses. Placentas were collected and histologically evaluated. In addition, among all neonatal deaths, with consent, minimally invasive tissue sampling was performed for histological analyses. PCR testing was performed to assess microbial pathogens in the placental, blood, and fetal tissues collected. An independent panel reviewed available data, including clinical description of the case and all clinical maternal, fetal, and placental findings, and results of PCR bacteriological investigation and minimally invasive tissue sampling histology, from all eligible preterm neonates to determine the primary and contributing maternal, placental, and neonatal causes of death. Between July 1, 2018, and March 26, 2020, of the 3470 preterm neonates enrolled, 804 (23%) died by 28 days after birth, and, of those, 615 were eligible and had their cases reviewed by the panel. Primary maternal causes of neonatal death were hypertensive disease (204 [33%] of 615 cases), followed by maternal complication of pregnancy (76 [12%]) and preterm labour (76 [11%]), whereas the primary placental causes were maternal and fetal vascular malperfusion (172 [28%] of 615) and chorioamnionitis, funisitis, or both (149 [26%]). The primary neonatal cause of death was intrauterine hypoxia (212 [34%] of 615) followed by congenital infections (126 [20%]), neonatal infections (122 [20%]), and respiratory distress syndrome (126 [20%]). In south Asia, intrauterine hypoxia and congenital infections were the major causes of neonatal death among preterm babies. Maternal hypertensive disorders and placental disorders, especially maternal and fetal vascular malperfusion and placental abruption, substantially contributed to these deaths. Bill & Melinda Gates Foundation.


The normal function of a speciation gene, Odysseus, and its hybrid sterility effect.
To understand how postmating isolation is connected to the normal process of species divergence and why hybrid male sterility is often the first sign of speciation, we analyzed the Odysseus (OdsH) gene of hybrid male sterility in Drosophila. We carried out expression analysis, transgenic study, and gene knockout. The combined evidence suggests that the sterility phenotype represents a novel manifestation of the gene function rather than the reduction or loss of the normal one. The gene knockout experiment identified the normal function of OdsH as a modest enhancement of sperm production in young males. The implication of a weak effect of OdsH on the normal phenotype but a strong influence on hybrid male sterility is discussed in light of Haldane's rule of postmating isolation.


SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis.
Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the sine oculis-related homeobox Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here, we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 knockout mice (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior muscle. Mutant stem cells contribute to hypotrophic myofibers that are not innervated but retain the ability to self-renew.


Organic Pollutants in Shale Gas Flowback and Produced Waters: Identification, Potential Ecological Impact, and Implications for Treatment Strategies.
Organic contaminants in shale gas flowback and produced water (FPW) are traditionally expressed as total organic carbon (TOC) or chemical oxygen demand (COD), though these parameters do not provide information on the toxicity and environmental fate of individual components. This review addresses identification of individual organic contaminants in FPW, and stresses the gaps in the knowledge on FPW composition that exist so far. Furthermore, the risk quotient approach was applied to predict the toxicity of the quantified organic compounds for fresh water organisms in recipient surface waters. This resulted in an identification of a number of FPW related organic compounds that are potentially harmful namely those compounds originating from shale formations (e.g., polycyclic aromatic hydrocarbons, phthalates), fracturing fluids (e.g., quaternary ammonium biocides, 2-butoxyethanol) and downhole transformations of organic compounds (e.g., carbon disulfide, halogenated organic compounds). Removal of these compounds by FPW treatment processes is reviewed and potential and efficient abatement strategies are defined.


Validation study of health administrative data algorithms to identify individuals experiencing homelessness and estimate population prevalence of homelessness in Ontario, Canada.
To validate case ascertainment algorithms for identifying individuals experiencing homelessness in health administrative databases between 2007 and 2014; and to estimate homelessness prevalence trends in Ontario, Canada, between 2007 and 2016. A population-based retrospective validation study. Ontario, Canada, from 2007 to 2014 (validation) and 2007 to 2016 (estimation). Our reference standard was the known housing status of a longitudinal cohort of housed (n=137 200) and homeless or vulnerably housed (n=686) individuals. Two reference standard definitions of homelessness were adopted: the housing episode and the annual housing experience (any homelessness within a calendar year). Sensitivity, specificity, positive and negative predictive values and positive likelihood ratios of 30 case ascertainment algorithms for detecting homelessness using up to eight health service databases. Sensitivity estimates ranged from 10.8% to 28.9% (housing episode definition) and 18.5% to 35.6% (annual housing experience definition). Specificities exceeded 99% and positive likelihood ratios were high using both definitions. The most optimal algorithm estimates that 59 974 (95% CI 55 231 to 65 208) Ontarians (0.53% of the adult population) experienced homelessness in 2016, a 67.3% increase from 2007. In Ontario, case ascertainment algorithms for identifying homelessness had low sensitivity but very high specificity and positive likelihood ratio. The use of health administrative databases may offer opportunities to track individuals experiencing homelessness over time and inform efforts to improve housing and health status in this vulnerable population.


Expanding beyond ICP-MS to better understand selenium biochemistry.
Selenium is an essential trace element in human health and therefore its concentration in biological samples (biofluids and tissues) is used as an indicator of health and nutritional status. In humans, selenium's biological activity occurs through the 25 identified selenoproteins. As total selenium concentration encompasses both functional selenoproteins, small selenocompounds and other selenium-binding proteins, selenium speciation, rather than total concentration, is critical in order to assess functional selenium. Previously, quantitative analysis of selenoproteins required laborious techniques that were often slow and costly. However, more recent advancements in tandem mass spectrometry have facilitated the qualitative and quantitative identification of these proteins. In light of the current alternatives for understanding selenium biochemistry, we aim to provide a review of the modern applications of electrospray ionisation mass spectrometry (ESI-MS) as an alternative to inductively coupled plasma mass spectrometry (ICP-MS) for qualitative and quantitative selenium speciation.


The Effects of the Affordable Care Act on Health Care Access and Utilization Among Asian American Subgroups.
We examined changes in health care access and utilization associated with the Patient Protection and Affordable Care Act (ACA) for different Asian American subgroups relative to non-Latino whites (whites). Using 2003-2017 California Health Interview Survey data, we examined changes in 4 health care access measures and 2 utilization measures among whites and 7 Asian American subgroups. We estimated the unadjusted and adjusted percentage point changes on the absolute scale from the pre-ACA to post-ACA periods. Adjusted estimates were obtained from multivariable logistic regression models that controlled for predisposing, enabling, and need factors. We also estimated the pre-ACA to post-ACA changes between whites and Asian American subgroups using a difference-in-difference approach. After the ACA was implemented, uninsurance decreased among all Asian American subgroups, but improvements in disparities relative to whites in these measures were limited. In particular, Koreans had the largest absolute reduction in uninsurance (-16.8 percentage points) and were the only subgroup with a significant reduction in terms of disparities relative to whites (-10.1 percentage points). However, little or no improvement was observed in the other 3 access measures (having a usual source of care, delayed medical care in past year, or delayed prescription drug use in past year) and 2 utilization measures (having a physician visit or emergency department visit in past year). Despite coverage gains among Asian American subgroups, especially Koreans, disparities in access and utilization persisted across all Asian American subgroups.


Subconjunctival fat prolapse and dermolipoma of the orbit: differentiation on CT and MR imaging.
Subconjunctival fat prolapse and dermolipoma of the orbit are unfamiliar to radiologists and yet should be differentiated because their treatments are different. The purpose of this study was to investigate the CT and MR imaging findings that distinguish these 2 conditions. Between 1995 and 2009, we found 33 patients (27 men, 6 women; mean age, 63 years) with surgically proved subconjunctival fat prolapse and 27 patients (3 males, 24 females; mean age, 17 years) with dermolipoma in our hospital. Among them, 8 patients with subconjunctival fat prolapse and 6 patients with dermolipoma underwent CT and/or MR imaging examinations. We retrospectively reviewed CT scans and MR images in these patients. In all of the 8 patients with subconjunctival fat prolapse, CT and MR images demonstrated the herniated fat at the superotemporal epibulbar area, continuous with the intraconal fat, extending forward between the lateral wall of the globe medially and the lateral rectus muscle and the lacrimal gland laterally, either bilaterally (n = 7) or unilaterally (n = 1). In contrast, all 6 patients with dermolipoma had a unilateral, crescent- (n = 5), or triangle-shaped (n = 1) fatty mass at the temporal or superotemporal epibulbar area, which lay on the lateral wall of the globe, anterior to the insertion of the lateral rectus muscle and medial to the lacrimal gland, without connection to the intraconal fat. The characteristic CT and MR imaging findings may help easily differentiate subconjunctival fat prolapse and dermolipoma, both of which usually present as an epibulbar fatty mass in the lateral canthal area.


Impact of hepatitis C viral infection in primary cadaveric liver allograft versus primary living-donor allograft in 100 consecutive liver transplant recipients receiving tacrolimus.
There has been concern that adult living-donor liver transplantation (LLTx) for hepatitis C virus (HCV) infection may lead to recurrent disease that is more severe compared with the results of cadaveric LTx (CLTx), because the smaller sized graft in LLTx regenerates and may increase viral replication. This study examines the survival outcome and HCV recurrence in CLTx versus LLTx performed at a single institution. A total of 100 consecutive adult recipients (75 men and 25 women; mean age 49.9+/-8.4 years) of LTx (65 CLTxs and 35 LLTxs performed July 2000-July 2002) who tested positive for HCV by polymerase chain reaction were examined retrospectively until October 2003. All patients received tacrolimus-based immunosuppression with mycophenolate mofetil and steroids. The overall actual patient survival was 85% (83.1% for CLTx vs. 88.6% for LLTx). The 39-month Kaplan-Meier actuarial patient survivals were 75.1% for CLTx and 88.6% for LLTx. Of 15 deaths, 6 were the result of recurrent HCV (five CLTxs and one LLTx), and of 10 retransplants, 2 were related to recurrent HCV (one CLTx and one LLTx). The rates of recurrence were 72.3% and 77.1%, the hepatitis activity indices were 5.4 + 2.4 and 6.2 + 2.8, the fibrosis scores were 1.4+/-1.4 and 1.5+/-1.3, and the times to recurrence were 318+/-269 days and 394+/-250 days for CLTx and LLTx, respectively. None of the differences between the two groups were significant. No detrimental effect of HCV infection was found in LLTx recipients when compared with contemporaneous CLTx recipients. Patient survival, graft survival, rate of HCV recurrence, severity of HCV recurrence, graft loss from HCV, and interval for recurrence in CLTx and LLTx were similar.


Dexmedetomidine Regulates the miR-146a-5p/NF-κB Axis to Alleviate Electroconvulsive Therapy-Induced Cognitive Impairments.
Electroconvulsive therapy (ECT) is a nonpharmacological treatment for depressive episodes and other psychiatric disorders. It is used to control the condition by causing a transient loss of consciousness through electrical stimulation. Dexmedetomidine (DEX) is a novel and highly selective adrenergic agonist with sedative, sympathetic nerve activity inhibiting and stress-responsive effects. This study focused on the effect of DEX on cerebral protection after ECT treatment. 68 depression patients were enrolled and divided into control group and DEX group. The occurrence of delirium after ECT treatment in depression cases was recorded. In vivo, we constructed chronic mild and unpredictable stress (CUMS) rats to mimic depression model. Meanwhile, ECT treatment and DEX injection were administrated in CUMS rats. Learning and memory in rats were measured by Morris water maze test, open field test (OFT), and forced swimming test (FST). Finally, the expression of miR-146a-5p and NF-κB was determined by RT-qPCR and western blot assay. The incidence of delirium after ECT treatment was prominently reduced in DEX group in relation to control group. In vivo, DEX injection had no effect on ECT treatment efficacy against depression conditions. After ECT treatment, the cognitive impairment was ameliorated in CUMS rats accomplished with decreased miR-146a-5p and increased NF-κB level. Finally, compared with ECT treatment, DEX injection could protect against depression-like behaviors by increasing miR-146a-5p level and inactivated NF-κB pathway. Overall, ECT-induced cognitive impairment in depression rats could be ameliorated by DEX injection via miR-146a-5p/NF-κB axis.


Disturbances in Insulin-Glucose Metabolism in Patients With Advanced Renal Disease With and Without Diabetes.
Use of insulin in patients with diabetes and advanced chronic kidney disease (CKD; stages 4 to 5) is challenging and shows great variability among individuals. We explored the mechanisms underlying this variability. PubMed was searched for articles in English from 1960 to 2018 for advanced CKD and diabetes, glucose and insulin metabolism, insulin clearance, secretion and resistance, plasma insulin concentration, glycemic control, hypoglycemia, insulin dosage, and continuous glucose monitoring (CGM) in CKD. The evidence shows that in most patients the daily dose of insulin needs to be significantly reduced with a high degree of variability; in some the dose remains unchanged, and rarely it is increased. The premise that the marked reduction in insulin requirement is essentially attributable to decreased insulin clearance by kidneys leading to prolongation of its plasma half-life, elevated blood insulin concentration, and hypoglycemia is not entirely correct. Other factors including decreases in food intake, insulin secretion, insulin clearance by peripheral tissues, and renal gluconeogenesis play important roles. There is also heightened resistance to insulin due to metabolic acidosis, uremic toxins, inflammatory state, and vitamin D deficiency. Importantly, the magnitude of changes in each of these factors varies between individuals with the same degree of CKD. In the presence of diabetes with advanced CKD, the insulin regimen should be individualized based on knowledge of the daily glucose patterns. The use of CGM is promising for safer glycemic control in patients with advanced CKD and diabetes and helps prevent extremes of hypoglycemia and hyperglycemia.


Acute Fatty Liver of Pregnancy.
Acute fatty liver of pregnancy is a rare, but potentially fatal obstetric disorder characterized principally by varying degrees of hepatic failure with an onset typically in late pregnancy. This review outlines the etiopathogenesis and describes the multiorgan involvement that often results in a number of clinical and laboratory aberrations. These laboratory derangements provide distinct features to differentiate from other obstetric complications, such as hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Once recognized, central to the management of acute fatty liver of pregnancy is delivery planning and meticulous supportive care. One particularly dangerous complication is profound coagulopathy. After delivery, the coagulation defect resolves over 1-2 days, and hepatic and renal function are restored soon thereafter. This report offers anticipated recovery and management strategies for commonly associated complications. Application of these factors has served to decrease mortality from as high as 80% down to 10%; however, given the seriousness of this condition, severe maternal morbidities are frequently associated with this obstetric emergency.


Different contributions of PROG1 and TAC1 to the angular kinematics of the main culm and tillers of wild rice (Oryza rufipogon).
PROG1 is necessary but insufficient for the main culm inclination while TAC1 partially takes part in it, and both genes promote tiller inclination in Asian wild rice. Asian wild rice (Oryza rufipogon), the ancestor of cultivated rice (O. sativa), has a prostrate architecture, with tillers branching from near the ground. The main culm of each plant grows upward and then tilts during the vegetative stage. Genes controlling tiller angle have been reported; however, their genetic contributions to the culm movement have not been quantified. Here, we quantified their genetic contributions to angular kinematics in the main culm and tillers. For the main culm inclination, one major QTL surrounding the PROG1 region was found. In cultivated rice, tillers firstly inclined and lately rose, while it kept inclining in wild rice. It was suggested that PROG1 affected the tiller elevation angle in the later kinematics, whereas TAC1 was weakly associated with the tiller angle in the whole vegetative stage. Micro-computed tomography (micro-CT) suggested that these angular changes are produced by the bending of culm bases. Because near-isogenic lines (NILs) of wild rice-type Prog1 and Tac1 alleles in the genetic background of cultivated rice did not show the prostrate architecture, the involvement of another gene(s) for inclination of the main culm was suggested. Our findings will not only contribute to the understanding of the morphological transition during domestication but also be used in plant breeding to precisely reproduce the ideal plant architecture by combining the effects of multiple genes.


An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L.
FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem duplication (ITD) mutations in the juxtamembrane region. Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. Midostaurin is a first-generation FLT3 inhibitor with minimal activity as monotherapy. Midostaurin lacks selectivity and is only approved by the USFDA for use in combination with other chemotherapy agents. The second-generation inhibitors quizartinib and gilteritinib display improved specificity and selectivity, and have been approved for use as monotherapy. However, their clinical efficacies are limited in part due to the emergence of drug-resistant FLT3 secondary mutations in the tyrosine kinase domain at positions D835 and F691. Therefore, in order to overcome drug resistance and further improve outcomes, new compounds targeting FLT3-ITD with secondary mutants are urgently needed. In this study, through the structural modification of a reported compound Ling-5e, we identified compound 24 as a FLT3 inhibitor that is equally potent against FLT3-ITD and the clinically relevant mutants FLT3-ITD/D835Y, and FLT3-ITD/F691L. Its inhibitory effects were demonstrated in both cell viability assays and western blots analyses. When tested against cell lines lacking activating mutations in FLT3, no non-specific cytotoxicity effect was observed. Interestingly, molecular docking results showed that compound 24 may adopt different binding conformations with FLT3-F691L compared to FLT3, which may explain its retained activity against FLT3-ITD/F691L. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.


Meta-analysis of multi-modality therapies in sinonasal undifferentiated carcinoma-A timely update.
Sinonasal undifferentiated carcinoma (SNUC) is a rare but aggressive tumour with very poor prognosis. There are currently no well-established clinical trials to guide therapy and the impact of various treatment modalities on survival is not well defined. We aim to provide an updated systematic review on current treatment modalities on survival outcomes. Individual patient data were extracted, and survival data pooled in a one-stage meta-analysis. Descriptive statistics were analysed using the Kaplan-Meier method. Patient-level comparisons stratified by treatment modalities, adjusted for demographics, were conducted using shared-frailty Cox regression. Participants include all patients diagnosed with SNUC based on histological evidence. We looked at the overall cumulative survival outcome for different treatment modalities and overall survival by treatment modality in low versus high stage SNUC patients. Seventeen studies were identified, comprising 208 patients from 1993 to 2020. There was no significant difference in cumulative overall survival in low versus high stage patients, and no significant difference in outcomes by treatment modality. The overall cumulative survival of SNUC is 30% at 95 months. Among patients treated with various combinations of treatment modalities, patients with chemoradiotherapy had the highest cumulative survival of 42% at 40 months. Definitive chemoradiotherapy was associated with improved disease survival rate. Regardless of tumour stage, patients should be treated early and aggressively, with no superiority of one treatment regimen over another. Trimodality treatment does not confer survival advantage over bimodality treatment.


Alternatives to complete nail plate avulsion.
Successful nail surgery requires exposure of the underlying tissues. In many cases, partial nail plate avulsion is preferable compared with traditional total distal and proximal plate avulsions. The techniques described herein include partial distal, lateral, proximal, and window techniques, and two variation of the total plate avulsion termed the trap door and lateral nail plate curl avulsion. By using these methods, the surgeon is able to access the targeted nail unit while minimizing trauma to adjacent, uninvolved tissue.


Hemangioma of the interatrial septum: CT and MRI features.
Hemangioma of the heart is a rare primary benign tumor mainly appearing as enhancing, homogenous, well-circumscribed mass. We report a case of a 61-year-old asymptomatic woman, whose echocardiography showed a cardiac mass, which was described as the atypical myxoma of the right atrium. For further imaging, contrast-enhanced computed tomography and cardiac magnetic resonance imaging were undertaken, which showed a tumor located in the interatrial septum with imaging characteristics of hemangioma. In the literature, cardiac hemangioma is usually described as an intensely enhancing mass. In our opinion, early peripheral puddling of contrast material with filling in on delayed images is a typical pattern of its enhancement. This characteristic, in addition to high signal intensity on T2-weighted images, allows differentiation of a hemangioma from other benign and malignant tumors.


Computational studies of transport in ion channels using metadynamics.
Molecular dynamics simulations have played a fundamental role in numerous fields of science by providing insights into the structure and dynamics of complex systems at the atomistic level. However, exhaustive sampling by standard molecular dynamics is in most cases computationally prohibitive, and the time scales accessible remain significantly shorter than many biological processes of interest. In particular, in the study of ion channels, realistic models to describe permeation and gating require accounting for large numbers of particles and accurate interaction potentials, which severely limits the length of the simulations. To overcome such limitations, several advanced methods have been proposed among which is metadynamics. In this algorithm, an external bias potential to accelerate sampling along selected collective variables is introduced. This bias potential discourages visiting regions of the configurational space already explored. In addition, the bias potential provides an estimate of the free energy as a function of the collective variables chosen once the simulation has converged. In this review, recent contributions of metadynamics to the field of ion channels are discussed, including how metadynamics has been used to search for transition states, predict permeation pathways, treat conformational flexibility that underlies the coupling between gating and permeation, or compute free energy of permeation profiles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.


Topography of EEG multivariate phase synchronization in early Alzheimer's disease.
Alzheimer's disease (AD) is likely to disrupt the synchronization of the bioelectrical processes in the distributed cortical networks underlying cognition. We analyze the surface topography of the multivariate phase synchronization (MPS) of multichannel EEG in 17 patients (Clinical Dementia Rating (CDR) Scale: 0.5-1; Functional Assessment Staging (FAST): 3-4) compared to 17 controls by applying a combination of global and regional MPS measures to the resting EEG. In early AD, whole-head mapping reveals a specific landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region and an increase over the temporo-parieto-occipital region predominantly of the left hemisphere. These features manifest themselves through the EEG delta-beta bands and discriminate patients from controls with an accuracy of up to 94%. Moreover, the abnormal MPS in both anterior and posterior clusters correlates with the Mini Mental State Examination score, binding regional EEG synchronization to cognitive decline in AD patients. The MPS technique reveals that the EEG phenotype of early AD is relevant to the clinical picture and may ultimately become its sensitive and specific biomarker.


Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics.
The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature.


Discrimination between bacterial phenotypes using glyco-nanoparticles and the impact of polymer coating on detection readouts.
The identification and treatment of bacterial infections remains a major healthcare challenge, especially to ensure appropriate application of a limited spectrum of antibiotics. Here we describe a system capable of discriminating between different strains of Escherichia coli using multivalent, carbohydrate-functionalised, gold nanoparticles based on their different expression levels of the FimH adhesin. Upon binding of the glycosylated nanoparticles to FimH positive bacteria, the nanoparticles' optical properties change enabling the identification of bacteria strain. Comparison between direct conjugation, or via a linker, of the carbohydrate to the nanoparticle revealed significant effects on the performance of the detection system. Using a poly(ethylene glycol) spacer increased the stability, and specificity, of the glycosylated nanoparticles but also reduced aggregation upon bacterial binding. This prevented the well-known red-blue gold colour change, meaning spectrophometric, rather than optical, assessment methods were required. Using this method, FimH positive bacteria could be detected at approximately 1.5 × 107 colony forming units per mL.


Reference Ranges for Hematological and Biochemical Profile of Martina Franca Donkeys.
The Martina Franca donkey (MFd) is one of the largest Italian donkey breeds, considered as endangered breed. To support the conservation strategies, knowledge about the physiologic hematological parameters of MFds is needed. The aims of the study were to determine reference value for hematological and major serum parameters in a population of healthy MFds and to estimate the influence of age on these parameters. Eighty-one clinically healthy MFds (17 males and 64 females) in different ages were enrolled: group A (foals, n° 16, animals < 1 year old) group B (young animals, n° 36, from 1 to 3 years old), and group C (adult animals, n° 29, over 3 years old). Red blood cell count (RBC); hematocrit value (HCT); hemoglobin concentration (HGB); mean corpuscular volume (MCV); mean corpuscular hemoglobin (MCH); hemoglobin concentration distribution width (HDW); RBC distribution width (RDW); total white blood cell (WBC); WBC differential count for neutrophils, lymphocytes, monocytes, eosinophils and basophils, and platelets (PLT); mean platelet volume (MPV); platelet volume distribution width; and plateletcrit (PCT) were analyzed. The biochemistry panel included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total serum protein (TP), albumin (ALB), cholesterol (CHOL), triglyceride (TGL), blood urea nitrogen (BUN), creatinine (CREA), glucose (GLU), Ca2+, phosphorus, Na+, Cl-, K+, and Mg2+. The effect of age on hematological parameters was investigated using one-way ANOVA test. Age of donkeys does not influence total WBC, HGB, HCT, platelet count and MPV, and PCT (P > 0.05). Some leukocyte populations such as eosinophils, monocytes, and basophils showed age-linked variations (P < 0.05). RBC count, RDW, and HDW decrease with age whereas MCV and MCH increase. Na+, K+, Cl-, Ca2+, phosphorus, ALP, GGT, CREA, GLUC, and CHOL decrease with age (P < 0.05), while AST and TP showed an increase with aging (P < 0.05). ALB reaches the lowest values in young donkeys and returns to values of foals in older animals (P < 0.05). Finally, a difference among groups for BUN and TGL was not found (P < 0.05). The results suggest how even for the MFd breed, age is a variable that affects different hematological and biochemical parameters. Compared to other donkey and horses, the MFd breed showed some differences that clinicians involved during conservation strategies need to be consider.


Chylous ascites occurring after low anterior resection of the rectum successfully treated with an oral fat-free elemental diet (Elental(®)).
Chylous ascites occurring after abdominal surgery is rare. Despite being potentially critical, there is no definite treatment guideline because of its rarity. Here we present a case of massive chylous ascites occurring after rectal surgery which was successfully treated with an oral fat-free elemental diet (ED). A 67-year-old man underwent low anterior resection with para-aortic lymphadenectomy for advanced rectal cancer. Early postoperative course was uneventful and the patient was discharged from hospital 10 days after surgery; however, after discharge, abdominal distension rapidly developed. Abdominal computed tomography (CT) performed 3 weeks after surgery revealed massive ascites and laboratory findings showed remarkable hypoproteinemia and lymphopenia. Urgent diagnostic paracentesis showed the ascites to be a white milky fluid containing high levels of triglycerides (564 mg/dl), leading to a diagnosis of chyloperitoneum. Daily nutrition of the patient was entirely with a fat-free ED (30 kcal/kg/day of Elental(®), Ajinomoto Pharmaceutical Co. Ltd, Tokyo, Japan). After the initiation of oral Elental(®), abdominal distension, hypoproteinemia, and lymphopenia gradually improved. Abdominal CT performed 7 weeks after surgery showed no ascitic fluid in the abdomen, and thereafter a normal diet was initiated. Since then, no relapse of chyloperitoneum has been proven. As a result, the chylous ascites was successfully treated in the outpatient clinic.


Ring Opening Copolymerization of Boron-Containing Anhydride with Epoxides as a Controlled Platform to Functional Polyesters.
Boron-functionalized polymers are used in opto-electronics, biology, and medicine. Methods to produce boron-functionalized and degradable polyesters remain exceedingly rare but relevant where (bio)dissipation is required, for example, in self-assembled nanostructures, dynamic polymer networks, and bio-imaging. Here, a boronic ester-phthalic anhydride and various epoxides (cyclohexene oxide, vinyl-cyclohexene oxide, propene oxide, allyl glycidyl ether) undergo controlled ring-opening copolymerization (ROCOP), catalyzed by organometallic complexes [Zn(II)Mg(II) or Al(III)K(I)] or a phosphazene organobase. The polymerizations are well controlled allowing for the modulation of the polyester structures (e.g., by epoxide selection, AB, or ABA blocks), molar masses (9.4 < Mn < 40 kg/mol), and uptake of boron functionalities (esters, acids, "ates", boroxines, and fluorescent groups) in the polymer. The boronic ester-functionalized polymers are amorphous, with high glass transition temperatures (81 < Tg < 224 °C) and good thermal stability (285 < Td < 322 °C). The boronic ester-polyesters are deprotected to yield boronic acid- and borate-polyesters; the ionic polymers are water soluble and degradable under alkaline conditions. Using a hydrophilic macro-initiator in alternating epoxide/anhydride ROCOP, and lactone ring opening polymerization, produces amphiphilic AB and ABC copolyesters. Alternatively, the boron-functionalities are subjected to Pd(II)-catalyzed cross-couplings to install fluorescent groups (BODIPY). The utility of this new monomer as a platform to construct specialized polyesters materials is exemplified here in the synthesis of fluorescent spherical nanoparticles that self-assemble in water (Dh = 40 nm). The selective copolymerization, variable structural composition, and adjustable boron loading represent a versatile technology for future explorations of degradable, well-defined, and functional polymers.


Using front-end kinetics to optimize target-controlled drug infusions.
The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target. Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated. Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters. Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.


Expression of human frataxin is regulated by transcription factors SRF and TFAP2.
Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression. We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2. We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia.


Impact of Applied Suicide Intervention Skills Training on the National Suicide Prevention Lifeline.
We examined the impact of the implementation of Applied Suicide Intervention Skills Training (ASIST) across the National Suicide Prevention Lifeline's national network of crisis hotlines. Data were derived from 1,507 monitored calls from 1,410 suicidal individuals to 17 Lifeline centers in 2008-2009. Callers were significantly more likely to feel less depressed, less suicidal, less overwhelmed, and more hopeful by the end of calls handled by ASIST-trained counselors. Few significant changes in ASIST-trained counselors' interventions emerged; however, improvements in callers' outcomes were linked to ASIST-related counselor interventions, including exploring reasons for living and informal support contacts. ASIST training did not yield more comprehensive suicide risk assessments.


Assessing the risk of venous thromboembolism in patients with haematological cancers using three prediction models.
Assessment of individual VTE risk in cancer patients prior to chemotherapy is critical for determining necessity of interventions. Risk assessment models (RAM) are available but have not been validated for haematological malignancy. We aimed to assess the validity of the Vienna Cancer and Thrombosis Study (V-CATS) score in prediction of VTE in a variety of haematological malignancies. This is a prospective cohort study conducted on 81 newly diagnosed cancer patients undergoing chemotherapy. Demographic, clinical and cancer related data were collected, patients were followed up for 6 months, and VTE events were recorded. Khorana score (KS) was calculated. Plasma D-dimer and sP-selectin were measured, and then, V-CATS score was calculated. Receiver operator curve (ROC) was used to assess the sensitivity and specificity of RAMs. A modified V-CATS was generated and subsequently assessed by using new cut-off levels of d-dimer and sP-selectin based on ROC curve of the patients' results and compared the probability of VTE occurrence using all three RAMs. Among the 81 patients included in this study, a total of 2.7% were diagnosed with advanced metastatic cancer. The most frequent cancer was non-Hodgkin lymphoma (39.5%), and 8 patients (9.8%) developed VTE events. The calculated probability of VTE occurrence using KS, V-CATS and modified V-CATS scores at cut-off levels ≥ 3 was 87.5%, 87.5% and 100%, respectively. The AUC in ROC curve of modified Vienna CATS score showed significant difference when compared to that of V-CATS and KS (P = 0.047 and 0.029, respectively). The findings of our study highlight the value of three VTE risk assessment models in haematological malignancies. The modified V-CATS score demonstrated higher specificity compared to both V-CATS and KS, while all three scores exhibited similar sensitivity. We encourage the implementation of RAMs in haematological cancers for an appropriate use of thromboprophylaxis.


Bimanual force control strategies in chronic stroke: finger extension versus power grip.
Stroke leads to motor asymmetries in the flexor and extensor muscles of the hand. Typically, the strength deficits in the extensors are greater than the flexors. The impact of differential motor abilities of these muscle groups on the execution of bimanual force control tasks in individuals with stroke is unknown. The primary purpose of this study was to determine the influence of task constraints on visually guided bimanual force control in chronic stroke. Stroke survivors and age-matched individuals performed bimanual isometric contractions for 20s to match target submaximal force levels. Online visual feedback of the total force (sum of the forces produced by both hands) was provided. The task constraints were manipulated by (a) finger extension, and (b) finger flexion (power grip). Force asymmetry was indexed by the proportion of force contributed by the paretic hand to the total force. The stroke group demonstrated task-specific asymmetry in bimanual force control. Specifically, the paretic hand contributed less force than the non-paretic hand in finger extension whereas this relationship was reversed in power grip. Importantly, regardless of the nature of the task, reduction in motor impairments was associated with increased symmetry and coordination in bimanual tasks. Further, bimanual submaximal grip force control revealed asymmetry and coordination deficits that are not identified by investigating bimanual maximal force production alone. The motor control strategy adopted to optimize performance on bimanual tasks revealed the altered force production of the paretic hand due to the combined effect of extensor weakness and enhanced flexor bias following stroke. Bimanual asymmetries in stroke survivors highlight the need for identifying and treating the task-specific impairments for maximizing motor recovery post stroke.


Growth Charting of Brain Connectivity Networks and the Identification of Attention Impairment in Youth.
Intrinsic connectivity networks (ICNs), important units of brain functional organization, demonstrate substantial maturation during youth. In addition, interrelationships between ICNs have been reliably implicated in attention performance. It is unknown whether alterations in ICN maturational profiles can reliably detect impaired attention functioning in youth. To use a network growth charting approach to investigate the association between alterations in ICN maturation and attention performance. Data were obtained from the publicly available Philadelphia Neurodevelopmental Cohort, a prospective, population-based sample of 9498 youths who underwent genomic testing, neurocognitive assessment, and neuroimaging. Data collection was conducted at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011, and data analysis was conducted between February 1, 2015, and January 15, 2016. Statistical associations between deviations from normative network growth were assessed as well as 2 main outcome measures: accuracy during the Penn Continuous Performance Test and diagnosis with attention-deficit/hyperactivity disorder. Of the 9498 individuals identified, 1000 youths aged 8 to 22 years underwent brain imaging. A sample of 519 youths who met quality control criteria entered analysis, of whom 25 (4.8%) met criteria for attention-deficit/hyperactivity disorder. The mean (SD) age of the youth was 15.7 (3.1) years, and 223 (43.0%) were male. Participants' patterns of deviations from normative maturational trajectories were indicative of sustained attention functioning (R2 = 24%; F6,512 = 26.89; P < 2.2 × 10-16). Moreover, these patterns were found to be a reliable biomarker of severe attention impairment (peak receiver operating characteristic curve measured by area under the curve, 79.3%). In particular, a down-shifted pattern of ICN maturation (shallow maturation), rather than a right-shifted pattern (lagged maturation), was implicated in reduced attention performance (Akaike information criterion relative likelihood, 3.22 × 1026). Finally, parallel associations between ICN dysmaturation and diagnosis of attention-deficit/hyperactivity disorder were identified. Growth charting methods are widely used to assess the development of physical or other biometric characteristics, such as weight and head circumference. To date, this is the first demonstration that this method can be extended to development of functional brain networks to identify clinically relevant conditions, such as dysfunction of sustained attention.


An autoreactive gamma delta TCR derived from a polymyositis lesion.
To investigate the role of gammadelta T cells in human autoimmune disease we expressed and characterized a gammadelta TCR from an autoimmune tissue lesion. The TCR was first identified in a rare form of polymyositis characterized by a monoclonal infiltrate of gammadelta T cells which invaded and destroyed skeletal muscle fibers. The Vgamma1.3-Jgamma1-Cgamma1/Vdelta2-Jdelta3 TCR cDNA of the original muscle invasive gammadelta T cell clone was reconstructed from unrelated cDNA and transfected into the mouse hybridoma BW58alpha(-)beta(-). Appropriate anti-human gammadelta TCR Abs stimulated the TCR transfectants to produce IL-2, thus demonstrating that the human gammadelta TCR functionally interacted with murine signaling components. The transfected Vgamma1.3/Vdelta2 TCR recognized a cytosolic protein expressed in cultured human myoblasts and TE671 rhabdomyosarcoma cells. The Ag was recognized in the absence of presenting cells. Using a panel of control gammadelta TCR transfectants with defined exchanges in different positions of both TCR chains, we showed that the gammadelta TCR recognized its Ag in a TCR complementarity-determining region 3-dependent way. To our knowledge, this is the first example of a molecularly defined gammadelta TCR directly derived from an autoimmune tissue lesion. The strategy used in this study may be applicable to other autoimmune diseases.


Role of fine needle aspiration cytology in head and neck lesions of paediatric age group.
Fine Needle Aspiration Cytology [FNAC] of the head and neck region is well accepted as a diagnostic procedure. Various studies in the context of FNAC in the head and neck region are available for the adult population, but only few studies are available for the paediatric age group. To study the role of fine needle aspiration cytology and its utility in paediatric head and neck lesions. This was a hospital based, prospective study. Hundred cases of head and neck lesions of the paediatric age group [0-15 years] were studied for cytomorphology through fine needle aspiration cytology and the results were correlated with the histomorphology. There was a male predominance in the case distribution among both the sexes in children [55%]. The head and neck lesions were most frequent in the age group of 10-15 years, followed by the age group of 5-10 years than the age group of 0-5 years. Lesions in the cervical lymph nodes constituted 81% of the head and neck lesions and 87% of the adequate smears, followed by those in the skin and subcutaneous tissues [3 cases (3.2%)], the thyroid [4 cases (4.3%)] and the salivary gland [1 case (1%)]. 88.17% cases of head and neck lesions in children were diagnosed as benign on their smears and 11.83% cases were diagnosed as malignant, of which 8 cases of malignant lesions were located in the cervical lymph nodes, 1 case was located in the thyroid and 2 cases of malignant lesions were located in the orbits. FNAC is an important and a non-invasive, investigational tool in children for identifying and planning the medical management of inflammatory and infectious conditions. It helped us in indicating the diagnosis of the lesions in congenital or aquired malformations, cystic lesions and benign neoplastic lesions, in which surgical management were needed and we got confirmations on histological examinations. For the malignant lesions, FNAC was a more important investigation tool than an accurate investigation tool, which suggested about the lesions and guided us to do more advanced specific investigations for obtaining the diagnosis.


Follow-up of mild cognitive impairment and related disorders over four years in adults in their sixties: the PATH Through Life Study.
The study aimed to estimate incidence rates of mild cognitive impairment and related disorders, and conversion to dementia. The data are drawn from the PATH Through Life Study. Baseline assessment in 2001-2002 included 2,551 participants 60-64 years old with 2,222 participating in a 4-year follow-up. Those screened positive with a cognitive assessment received clinical assessment for diagnoses of mild cognitive disorders (MCD) or dementia using established clinical criteria. Prevalence and incidence rates for the cohort were estimated with predictive regression models. Annual incidence of dementia was 0.25%. Prevalence of mild cognitive impairment was 4.2%, age-associated memory impairment was 2.4%, age-associated cognitive decline was 7.6%, mild neurocognitive disorders occurred in 12.9% and other cognitive disorders in 7.3%. Prevalence of any diagnosis of any MCD (Any-MCD) was 29.5% and the annual incidence rate for Any-MCD was 5.7%. Agreement for specific diagnoses between waves 1 and 2 was fair to poor (0-47.0%), but agreement for Any-MCD over 4 years was 89.0%. MCD diagnoses do not predict dementia at a 4-year follow-up in young-old adults. Prevalence rates for MCD vary greatly depending on the criteria and time of assessment.


Large delay-bandwidth product and tuning of slow light pulse in photonic crystal coupled waveguide.
This paper reports two advances in a slow light device consisting of chirped photonic crystal slab coupled waveguide on SOI substrate. One is concerning the delay-bandwidth product, indicating the buffering capacity of the device. We experimentally evaluated a record high value of 57 (a 40 ps delay and a 1.4 THz bandwidth). We also observed ~1 ps wide optical pulse transmission in the cross-correlation measurement. Regarding the pulse as a signal and considering the broadening of the pulse width due to the imperfect dispersion compensation in the device, storage of more than 12 signal bits was confirmed. The other is a wide-range tuning of the pulse delay. We propose a technique for externally controlling the chirping to permit variable delay. We demonstrate tuning of the pulse delay up to 23 ps, corresponding to a ~7 mm extension of the free space length.


Magnetic resonance imaging osteonecrosis pattern within an osteochondral dowel allograft.
A 22-year-old male with a history of a previously debrided large posttraumatic osteochondral lesion of the lateral femoral condyle presented to our institution for further treatment due to persistent pain and instability. He was treated with a large cryopreserved osteochondral dowel allograft and remained clinically asymptomatic with no pain, locking, or instability at his 12-month, 18-month, and 42-month follow-up appointments. However, his 12-month magnetic resonance imaging (MRI) examination demonstrated an osteonecrosis pattern within the osseous component of the allograft. Six months later, the osteonecrosis pattern decreased in size, and 30 months later had completely resolved. The allograft was otherwise stable in appearance. The MRI appearance was most likely due to a normal maturation process of bone healing within osteochondral allograft dowel, referred to as "creeping substitution".


Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes.
We report an infant with intrauterine growth retardation and transient neonatal diabetes who has paternal uniparental disomy for chromosome 6. The infant was not dysmorphic and had no congenital anomalies. To our knowledge, this is the third case of paternal uniparental disomy occurring in an infant with transient neonatal diabetes, thus confirming the association.


Distraction osteogenesis of costocartilaginous rib grafts and treatment algorithm for severely hypoplastic mandibles.
In craniofacial microsomia, patients with severely hypoplastic mandibles (Pruzansky type III) require replacement of the ramus and condyle unit. Autogenous costocartilaginous rib graft and distraction osteogenesis are the most important techniques used, but long-term results need to be looked at to determine optimal management. Of the 485 patients with craniofacial microsomia and mandibular abnormality identified by the authors' craniofacial multidisciplinary clinic, 31 patients were identified with Pruzansky type III mandibles who underwent treatment and were available for study. Patients primarily had either costocartilaginous grafts or mandibular distraction after molar extraction. Outcomes assessed rib failure, undergrowth, or overgrowth. Reoperation included regrafting for graft failure, rib distraction for undergrowth, and mandibular setback for overgrowth. Details surrounding complications for each modality including osteotomy site were recorded. For primary mandibular reconstruction, 27 patients underwent costocartilaginous rib graft surgery (30 grafts, three bilateral) at 9.9 ± 4.1 years; four patients underwent mandibular distraction at 7.4 ± 2.3 years. Rib graft failure in seven of 30 cases (23 percent) required regrafting. Undergrowth in 17 cases (57 percent) required rib distraction. Overgrowth in three cases (10 percent) required correction at the time of orthognathic correction. For rib graft distraction, osteotomy site locations included native mandible (25 percent), rib-mandible junction (19 percent), and rib graft (56 percent). The rib-mandible junction site had graft-related complications (100 percent) that the other sites did not. For the severely hypoplastic mandibles (Pruzansky type III), costocartilaginous grafts are an accepted modality. However, when rib graft growth is insufficient, secondary distraction should be performed within the native mandible or rib graft and not at the rib graft-mandible junction site.


The power to detect artificial selection acting on single loci in recently domesticated species.
An increasing number of aquaculture species are subjected to artificial selection in systematic breeding programs. Rapid improvements of important commercial traits are reported, but little is known about the effects of the strong directional selection applied, on gene level variation. Large numbers of genetic markers are becoming available, making it feasible to detect and estimate these effects. Here a simulation tool was developed in order to explore the power by which single genetic loci subjected to uni-directional selection in parallel breeding populations may be detected. Two simulation models were pursued: 1) screening for loci displaying higher genetic differentiation than expected (high-FST outliers), from neutral evolution between a pool of domesticated populations and a pool of wild populations; 2) screening for loci displaying lower genetic differentiation (low-FST outliers) between domesticated strains than expected from neutral evolution. The premise for both approaches was that the isolated domesticated strains are subjected to the same breeding goals. The power to detect outlier loci was calculated under the following parameter values: number of populations, effective population size per population, number of generations since onset of selection, initial FST, and the selection coefficient acting on the locus. Among the parameters investigated, selection coefficient, the number of generation since onset of selection, and number of populations, had the largest impact on power. The power to detect loci subjected to directional in breeding programmes was high when applying the between farmed and wild population approach, and low for the between farmed populations approach. A simulation tool was developed for estimating the power to detect artificial selection acting directly on single loci. The simulation tool should be applicable to most species subject to domestication, as long as a reasonable high accuracy in input parameters such as effective population size, number of generations since the initiation of selection, and initial differentiation (FST) can be obtained. Identification of genetic loci under artificial selection would be highly valuable, since such loci could be used to monitor maintenance of genetic variation in the breeding populations and monitoring possible genetic changes in wild populations from genetic interaction between escapees and their wild counterpart.


Treatment of menstrual migraine with prostaglandin synthesis inhibitor mefenamic acid: double-blind study with placebo.
The therapeutic effect of mefenamic acid, prostaglandin synthesis inhibitor, on pain of acute menstrual migraine and at the following days during menstrual bleeding period was studied and compared with placebo. 24 patients, 18 to 35 years old, with menstrual migraine were entered for study. They had regular menstrual cycles and they had been diagnosed as experiencing menstrual migraine without aura for more than one year. The patients were treated for 2 consecutive menstrual cycles, one cycle with 500 mg mefenamic acid and one cycle with placebo. Each drug was given at beginning of complaint and similar dose was repeated 8 hourly at following days during the menstrual bleeding period (Total dosage used 1500 mg per day). The use of medication was double blind. Pain intensity was rated by means of a 4 points scale and functional disability was rated from 0 to 3. Results showed that 79.16% of the patients showed significant pain relief with mefenamic acid as compared to 16.6% with placebo. The mean pain score of the mefenamic acid treated attacks decreased significantly from 2.46 +/- 0.5 to 0.62 +/- 1.0 at 2hr postdose. 83.3% of patients treated with mefenamic acid was able to function with or without little effort whereas 12.4% restored their activities with placebo. All the patients (100%) who showed significant initial responses to placebo experienced headache recurrence as compared to 26.3% with mefenamic acid. When considering mean pain scores, percentage of patients with pain free at 2h postdose, percentage of patients required rescue treatment, percentage of patients with headache recurrence and percentages of patients restored full activities, mefenamic acid is significantly superior to placebo in treatment of acute menstrual migraine. It might be concluded that mefenamic acid is safe and effective for treatment of acute menstrual migraine.


Hypertension among adults in a deprived urban area of Peru - undiagnosed and uncontrolled?
In Peru, cardiovascular disease was the second most common cause of death in those aged 65 years or more in 2000. Hypertension is a major modifiable risk factor for cardiovascular disease, and if treated can significantly reduce cardiovascular disease risk. The objectives of this study were to investigate the prevalence of hypertension and levels of awareness, treatment and control in a deprived urban area of Peru. A cross-sectional study was completed. Blood pressure measurements were recorded in triplicate. Hypertension was defined as systolic blood pressure >/= 140 mmHg or diastolic blood pressure >/= 90 mmHg, or self report of receiving antihypertensive medication at the time of interview. The study sample was 584 adults (29.1% male, mean age 35.3 years). Age standardized prevalence of hypertension was 19.5% (95% CI 9.9%, 29.1%) in men, 11.4% (95% CI 3.7%, 19.1%) in women, and 13.2% (95% CI 5.0%, 21.5%) overall. Among those with hypertension 38.3% (95% CI 22.7%, 53.9%, n = 18/47) were aware of their condition with greater awareness among women than men. Of those aware, 61.1% (n = 11/18) were treated, equating to 23.4% (95% CI 10.1%, 36.7%, n = 11/47) of all adults with hypertension. Of those treated 63.6% (n = 7/11) had controlled hypertension, equating to 14.9% (95% CI 3.0%, 26.8%, n = 7/47) of all adults with hypertension. Levels of awareness and control in this population were low. Lack of control is likely to be due to both a failure to diagnose hypertension, especially among men, and initiate or comply with treatment, especially among women. These results suggest a considerable burden of undiagnosed hypertension, and poor levels of control in those treated, in a deprived urban area of Lima, Peru.


Practical implementation of globally priced episodes of care: lessons learned from Oxford's specialty management program.
Globally priced episodes of care afford payers a more efficient method of allocating risk and simultaneously accommodating the now permanent demand for choice and access at the point of service. Foreseeing the trend away from capitated delivery systems, in April of 1996. Oxford Health Plans began to invest considerable resources to implement global fees. When Oxford ran afoul of Wall Street and New York State insurance regulators (for reasons unrelated to the subject of this article), it was forced to abandon the new program. For the growing number of payers interested in pursuing similar contracting strategies, this article may serve as a useful source of information.


Recent advances in viral hepatitis.
In the space of one decade we have come to understand the mode of replication of the hepatitis B virus and something of the mechanisms by which it produces liver cell damage and primary liver cell cancer. Although several drugs have been shown to be effective in inhibiting the replication of this virus, none are completely satisfactory. Our knowledge of the mode of replication of the virus now enables us to design new trials to selectively inhibit the enzymes involved in the replication of the virus. Although these advances will be of great benefit to the individual patient, clearly the problem is best dealt with, world-wide, by effective prophylaxis and the availability of a safe and effective vaccine now makes this possible. However, although the problems of Type B hepatitis infection are being overcome the problem of non-A, non-B hepatitis remains.


TCR signaling induces selective exclusion of CD43 from the T cell-antigen-presenting cell contact site.
CD43, a large highly glycosylated molecule, is arguably the most abundant molecule on the surface of T cells. Nevertheless, the function of CD43 remains unclear. Utilizing fluorescence microscopy, we find that CD43 is excluded from the T cell-APC contact site. This exclusion is Ag dependent since optimal CD43 exclusion requires Ag-pulsed APC, and since signaling through CD3, in the absence of any other receptor ligand interactions, can induce the modulation of CD43. These data suggest that CD43 may function as a barrier to nonspecific T cell-APC interactions that is removed as a result of T cell activation. Exclusion from the interaction site is a unique feature of CD43 and not universally found for all large highly glycosylated molecules since CD45 is not excluded. Thus, CD43 may represent a novel regulatory molecule on the T cell surface that can direct T cell interactions by changing its location on the cell surface.


The Ultimate Outlier: Transitional Care for Persons with Dementia and BPSD.
Transitional care units aim to assist caregivers who cannot manage the care for persons with dementia who manifest behavioral and psychological symptoms of dementia (BPSD). However, there is a dearth of research on such care units. The current study reviewed one specialized transitional unit to better understand the characteristics of the persons with dementia and behavioral symptoms entering such unit. The study also looked at the change in terms of (a) BPSD, (b) use of psychotropic medications and (c) function of the patients in this unit. A retrospective chart review of 73 residents of a transitional care unit was conducted. Background and outcome information were collected on electronic data entry sheets. Patients had an average age of 75.0 years, 74.0% were men. Mean Cognitive Performance Scale score was 4.7. Comparing admission to discharge, there was a significant decrease in BPSD, and a significant increase in number of central nervous system medications. There were no significant changes in cognition or ability to perform activities of daily living. Patient characteristics differed from those of other long term care settings. This unique population requires further study to optimize the outcomes.


Relationship between nerve blood flow and intercapillary distance in peripheral nerve edema.
Some human and experimental neuropathies are characterized by endoneurial edema and increased intercapillary distance (ICD). This may potentially produce chronic endoneurial ischemia. To examine the relationship between nerve blood flow (NBF) and ICD we measured NBF in rats with experimental galactose neuropathy (EGN), a model where ICD is known to be increased. Simultaneous measurements of NBF in the center and subperineurial region were made in normal and edematous tibial nerves using hydrogen-sensitive microelectrodes and hydrogen polarography. NBF was significantly reduced in rats with EGN when compared with controls. A second finding was that in half the rats with EGN there was a greater reduction in NBF in the subperineurial region, a site of maximal ICD increase. In contrast, NBF was similar in central and peripheral regions in control rats. These findings support the hypothesis that an increase in ICD produces a reduction in NBF. Further support for the hypothesis is derived from a computer model of the effect of changes in ICD on endoneurial oxygen tension. We conclude that a chronic reduction in NBF may participate in the pathogenesis of edematous neuropathies.


Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex.
At face value, the Sin3 histone deacetylase (HDAC) complex appears to be a prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression. While this is almost certainly part of its role, Sin3 stubbornly refuses to be pigeon-holed in quite this way. Genome-wide mapping studies have found that Sin3 localises predominantly to the promoters of actively transcribed genes. While Sin3 knockout studies in various species result in a combination of both up- and down-regulated genes. Furthermore, genes such as the stem cell factor, Nanog, are dependent on the direct association of Sin3 for active transcription to occur. Sin3 appears to have properties of a co-repressor, co-activator and general transcription factor, and has thus been termed a co-regulator complex. Through a series of unique domains, Sin3 is able to assemble HDAC1/2, chromatin adaptors and transcription factors in a series of functionally and compositionally distinct complexes to modify chromatin at both gene-specific and global levels. Unsurprisingly, therefore, Sin3/HDAC1 have been implicated in the regulation of numerous cellular processes, including mammalian development, maintenance of pluripotency, cell cycle regulation and diseases such as cancer.