Effectiveness of school water fluoridation and dietary fluoride supplements in school-aged children.
School water fluoridation and school-based fluoride tablet programs both have been shown in many studies to be effective in preventing dental caries. These studies indicate that school water fluoridation reduces dental decay by approximately 40 percent and school-based fluoride tablet programs by about 30 percent. However, nearly all the studies were done when the prevalence of caries among US schoolchildren was greater than it is today, which makes it difficult to assess their current effectiveness. Data from dental surveys of school-aged children conducted during the past 30 years indicate that overall caries prevalence has declined by more than 75 percent and that of approximal tooth surfaces by more than 90 percent. Recent national data indicate the difference in caries prevalence between children with lifetime residence in either fluoridated or nonfluoridated areas has also diminished, which raises questions about the cost effectiveness of initiating school-based fluoride programs for all areas. There are still groups of children, however, seriously affected by dental caries. It is safe to assume that implementation of school water fluoridation or fluoride tablet programs will result in traditionally reported benefits among these children. Ongoing school-based fluoride programs should not be discontinued until it is known what impact their cessation will have on dental disease.


Mercury exposure and risks from dental amalgam in the US population, post-2000.
Dental amalgam is 50% metallic mercury (Hg) by weight and Hg vapour continuously evolves from in-place dental amalgam, causing increased Hg content with increasing amalgam load in urine, faeces, exhaled breath, saliva, blood, and various organs and tissues including the kidney, pituitary gland, liver, and brain. The Hg content also increases with maternal amalgam load in amniotic fluid, placenta, cord blood, meconium, various foetal tissues including liver, kidney and brain, in colostrum and breast milk. Based on 2001 to 2004 population statistics, 181.1 million Americans carry a grand total of 1.46 billion restored teeth. Children as young as 26 months were recorded as having restored teeth. Past dental practice and recently available data indicate that the majority of these restorations are composed of dental amalgam. Employing recent US population-based statistics on body weight and the frequency of dentally restored tooth surfaces, and recent research on the incremental increase in urinary Hg concentration per amalgam-filled tooth surface, estimates of Hg exposure from amalgam fillings were determined for 5 age groups of the US population. Three specific exposure scenarios were considered, each scenario incrementally reducing the number of tooth surfaces assumed to be restored with amalgam. Based on the least conservative of the scenarios evaluated, it was estimated that some 67.2 million Americans would exceed the Hg dose associated with the reference exposure level (REL) of 0.3 μg/m(3) established by the US Environmental Protection Agency; and 122.3 million Americans would exceed the dose associated with the REL of 0.03 μg/m(3) established by the California Environmental Protection Agency. Exposure estimates are consistent with previous estimates presented by Health Canada in 1995, and amount to 0.2 to 0.4 μg/day per amalgam-filled tooth surface, or 0.5 to 1 μg/day/amalgam-filled tooth, depending on age and other factors.


Phorbol ester inhibition of Na-H exchange in rabbit proximal colon.
In rabbit proximal colon, in vitro addition of phorbol 12,13-dibutyrate (PDB, 10(-7) M) to the serosal bathing medium inhibits mucosal (m)-to-serosal (s) unidirectional Na flux (JsmNa) without altering JsmNa or unidirectional Cl fluxes. Similar results were obtained when amiloride (2 X 10(-4) M) was added to the mucosal bathing medium. No additivity of effect was seen when tissues were exposed to both agents. Measurements with carboxyfluorescein reveal that the two agents cause equal decreases of intracellular pH (pHi), an effect that is dependent on the presence of extracellular Na (Na replacement also decreases pHi). No additivity of pHi effects is seen when both agents are added together. To determine the membrane site of this PDB-inhibitable Na-H exchange, Na influx across the luminal border of proximal colon was measured and was found to be inhibited equally by PDB and amiloride. We conclude that PDB, by activation of protein kinase C, inhibits electro-neutral amiloride-sensitive Na-H exchange in the luminal membrane of proximal colon.


Rapid Diagnosis of Central Nervous System Scedosporiosis by Specific Quantitative Polymerase Chain Reaction Applied to Formalin-Fixed, Paraffin-Embedded Tissue.
Scedosporium (S.) apiospermum is a typical mold causing cerebral abscesses, often after near-drowning. Infections are associated with high morbidity and mortality due to diagnostic challenges including the need for prolonged incubation of cultures. In addition, histopathological differentiation from other filamentous fungi, including Aspergillus fumigatus, may not be possible, excluding early specific diagnosis and targeted therapy. Polymerase chain reaction (PCR) on tissue samples can rapidly identify fungi, leading to an earlier adequate treatment. Due to an extensive spectrum of causative fungi, broad-range PCRs with amplicon sequencing have been endorsed as the best DNA amplification strategy. We herein describe a case with brain abscesses due to S. apiospermum in a 66-year-old immunocompromised female patient. While broad-range PCR failed to identify a fungal pathogen from a cerebral biopsy demonstrating hyaline mold hyphae, specific quantitative PCR (qPCR) identified Scedosporium and ruled out Aspergillus, the most prevalent agent of central nervous system mold infection. A panel of specific qPCR assays, guided by the morphology of fungal elements in tissue or as a multiplex assay, may be a successful molecular approach to identify fungal agents of brain abscesses. This also applies in the presence of negative broad-range fungal PCR, therefore providing diagnostic and therapeutic potential for early specific management and improvement of patient clinical outcome.


ENFIN a network to enhance integrative systems biology.
Integration of biological data of various types and development of adapted bioinformatics tools represent critical objectives to enable research at the systems level. The European Network of Excellence ENFIN is engaged in developing both an adapted infrastructure to connect databases and platforms to enable the generation of new bioinformatics tools as well as the experimental validation of computational predictions. We will give an overview of the projects tackled within ENFIN and discuss the challenges associated with integration for systems biology.


Paracrine regulation of the renal microcirculation.
There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.


Patient Self-Management of Asthma Using Mobile Health Applications: A Systematic Review of the Functionalities and Effects.
Objective The aim of this systematic review was to summarize the evidence regarding the effects of mobile health applications (mHealth apps) for self-management outcomes in patients with asthma and to assess the functionalities of effective interventions. Methods We systematically searched Medline, Scopus, and the Cochrane Central Register of Controlled Trials. We included English-language studies that evaluated the effects of smartphone or tablet computer apps on self-management outcomes in asthmatic patients. The characteristics of these studies, effects of interventions, and features of mHealth apps were extracted. Results A total of 10 studies met all the inclusion criteria. Outcomes that were assessed in the included studies were categorized into three groups (clinical, patient-reported, and economic). mHealth apps improved asthma control (five studies) and lung function (two studies) from the clinical outcomes. From the patient-reported outcomes, quality of life (three studies) was statistically significantly improved, while there was no significant impact on self-efficacy scores (two studies). Effects on economic outcomes were equivocal, so that the number of visits (in two studies) and admission and hospitalization-relevant outcomes (in one study) statistically significantly improved; and in four other studies, these outcomes did not improve significantly. mHealth apps features were categorized into seven categories (inform, instruct, record, display, guide, remind/alert, and communicate). Eight of the 10 mHealth apps included more than one functionality. Nearly all interventions had the functionality of recording user-entered data and half of them had the functionality of providing educational information and reminders to patients. Conclusion Multifunctional mHealth apps have good potential in the control of asthma and in improving the quality of life in such patients compared with traditional interventions. Further studies are needed to identify the effectiveness of these interventions on outcomes related to medication adherence and costs.


Capsid-like particles decorated with the SARS-CoV-2 receptor-binding domain elicit strong virus neutralization activity.
The rapid development of a SARS-CoV-2 vaccine is a global priority. Here, we develop two capsid-like particle (CLP)-based vaccines displaying the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. RBD antigens are displayed on AP205 CLPs through a split-protein Tag/Catcher, ensuring unidirectional and high-density display of RBD. Both soluble recombinant RBD and RBD displayed on CLPs bind the ACE2 receptor with nanomolar affinity. Mice are vaccinated with soluble RBD or CLP-displayed RBD, formulated in Squalene-Water-Emulsion. The RBD-CLP vaccines induce higher levels of serum anti-spike antibodies than the soluble RBD vaccines. Remarkably, one injection with our lead RBD-CLP vaccine in mice elicits virus neutralization antibody titers comparable to those found in patients that had recovered from COVID-19. Following booster vaccinations, the virus neutralization titers exceed those measured after natural infection, at serum dilutions above 1:10,000. Thus, the RBD-CLP vaccine is a highly promising candidate for preventing COVID-19.


Physical, Physiological and Perceptual Match Demands of Amateur Mixed Gender Touch Players.
The purpose of this study was to provide a position specific (middle, link [male], link [female], wing) analysis of mixed gender touch on the physical physiological and perceptual demands of amateur players during match-play across a season. Distance and speed measures were obtained through the use of 10-Hz global positioning system devices, whilst telemetric heart rate devices were used determine a range of physiological measures. Players also provided a rating of perceived exertion following each match. The greatest physical demand was associated with the middle playing position by comparison to all others (Distance travelled ≥5.00 m·s-1 effect size [ES]: 0.01-0.13; average distance ≥5.00 m·s-1 ES: 0.11-0.38). Those playing as a middle also displayed a greater physiological (Mean heart rate ES: 0.05-0.13) and perceptual demand (rating of perceived exertion ES: 0.01-0.04). However, most measures reported only a trivial effect between each playing position. The findings provide an insight into the differing demands associated with the different playing positions within mixed gender touch which practitioners can use to provide more position-specific conditioning programs.


sPIF promotes myoblast differentiation and utrophin expression while inhibiting fibrosis in Duchenne muscular dystrophy via the H19/miR-675/let-7 and miR-21 pathways.
Duchenne muscular dystrophy (DMD) is a progressive, lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Loss of dystrophin leads to muscle fiber damage and impairment of satellite cell asymmetric division, which are essential for muscle regeneration. These processes ultimately result in muscle wasting and the replacement of the degenerating muscles by fibrogenic cells, a process that leads to the generation of fibrotic tissues. Preimplantation factor (PIF) is an evolutionary conserved 15-amino acid peptide secreted by viable mammalian embryos. Synthetic PIF (sPIF) reproduces the protective/regenerative effects of the endogenous peptide in immune disorders and transplantation models. In this study, we demonstrated that sPIF treatment promoted mouse and human myoblast differentiation and inhibited the expression of collagen 1A1, collagen 1A2, and TGF-β in DMD patient-derived myoblasts. Additionally, sPIF increased the expression of utrophin, a homolog of dystrophin protein. sPIF effects were mediated via the upregulation of lncRNA H19 and miR-675 and downregulation of let-7. sPIF also inhibited the expression of miR-21, a major fibrosis regulator. The administration of sPIF in mdx mice significantly decreased serum creatine kinase and collagen I and collagen IV expression in the diaphragm, whereas it increased utrophin expression in the diaphragm, heart and quadriceps muscles. In conclusion, sPIF promoted the differentiation of DMD myoblasts, increased utrophin expression via the H19/miRNA-675/let-7 pathway, and reduced muscle fibrosis possibly via the upregulation of miR-675 and inhibition of miR-21 expression. These findings strongly support pursuing sPIF as a potential therapeutic agent for DMD. Moreover, the completion of an sPIF phase I safety trial will further promote the use of sPIF for the treatment of muscular dystrophies.


The Neurotransmitters Involved in Drosophila Alcohol-Induced Behaviors.
Alcohol is a widely used and abused substance with numerous negative consequences for human health and safety. Historically, alcohol's widespread, non-specific neurobiological effects have made it a challenge to study in humans. Therefore, model organisms are a critical tool for unraveling the mechanisms of alcohol action and subsequent effects on behavior. Drosophila melanogaster is genetically tractable and displays a vast behavioral repertoire, making it a particularly good candidate for examining the neurobiology of alcohol responses. In addition to being experimentally amenable, Drosophila have high face and mechanistic validity: their alcohol-related behaviors are remarkably consistent with humans and other mammalian species, and they share numerous conserved neurotransmitters and signaling pathways. Flies have a long history in alcohol research, which has been enhanced in recent years by the development of tools that allow for manipulating individual Drosophila neurotransmitters. Through advancements such as the GAL4/UAS system and CRISPR/Cas9 mutagenesis, investigation of specific neurotransmitters in small subsets of neurons has become ever more achievable. In this review, we describe recent progress in understanding the contribution of seven neurotransmitters to fly behavior, focusing on their roles in alcohol response: dopamine, octopamine, tyramine, serotonin, glutamate, GABA, and acetylcholine. We chose these small-molecule neurotransmitters due to their conservation in mammals and their importance for behavior. While neurotransmitters like dopamine and octopamine have received significant research emphasis regarding their contributions to behavior, others, like glutamate, GABA, and acetylcholine, remain relatively unexplored. Here, we summarize recent genetic and behavioral findings concerning these seven neurotransmitters and their roles in the behavioral response to alcohol, highlighting the fitness of the fly as a model for human alcohol use.


Protein complex formation: computational clarification of the sequential versus probabilistic recruitment puzzle.
Our current view on how protein complexes assemble and disassemble at promoter sites is based on experimental data. For instance this data is provided by biochemical methods (e.g. ChIP-on-chip assays) or GFP-based assays. These two approaches suggest very different characteristics for protein recruitment processes that regulate and initiate gene transcription. Biochemical methods suggest a strictly ordered and consecutive protein recruitment while GFP-based assays draw a picture much closer to chaotic or stochastic recruitment. To understand the reason for these conflicting results, we design a generalized recruitment model (GRM) that allows to simulate all possible scenarios between strictly sequential recruitment and completely probabilistic recruitment. With this model we show that probabilistic, transient binding events that are visible in GFP experiments can not be detected by ChIP experiments. We demonstrate that sequential recruitment processes and probabilistic recruitment processes that contain "shortcuts" exhibit periodic dynamics and are hard to distinguish with standard ChIP measurements. Therefore we propose a simple experimental method that can be used to discriminate sequential from probabilistic recruitment processes. We discuss the limitations of this method.


Effect of aerobic exercise intensity on glycemic control in type 2 diabetes: a meta-analysis of head-to-head randomized trials.
To conduct a meta-analysis of head-to-head trials comparing aerobic exercise training of different intensities on glycemic control in type 2 diabetes. Databases, including MEDLINE and EMBASE, were searched up to January 2016. Randomized trials of at least 12 weeks in duration that compared two exercise interventions of different intensities were identified. Two reviewers independently extracted data from eligible trials. Using fixed effect model, weighted mean differences (WMD) between different exercise intensities were calculated for changes in glycated hemoglobin (HbA1c) and secondary outcomes, such as fasting glucose and fasting insulin. Eight studies with a total of 235 participants were eligible. The exercise interventions lasted from 12 weeks to 6 months. The prescribed exercise intensities varied among studies. Four studies utilized vigorous exercise intensities for short durations by performing interval training. Overall, higher-intensity exercise resulted in a greater reduction in HbA1c compared to lower-intensity exercise (WMD = -0.22 %; 95 % confidence interval [-0.38, -0.06]; or -2.4 mmol/mol [-4.15, -0.66], I (2) = 0). Adherence to exercise and proportion of dropouts did not differ within trials. No adverse events were reported in these small trials with selected inclusion criteria. Although our meta-analysis had a limited sample size, increasing exercise intensity safely accentuated reductions in HbA1c in some people with type 2 diabetes. Different approaches have been used to increase exercise intensity (i.e., some used interval training, whereas others used higher-intensity continuous exercise). However, at this time, it is unclear which form, if any, leads to the most favorable results.


Polyphenol-rich blackcurrant extract exerts hypocholesterolaemic and hypoglycaemic effects in mice fed a diet containing high fat and cholesterol.
Obesity is associated with an increased risk of metabolic abnormalities, such as hyperlipidaemia and hyperglycaemia. We investigated whether polyphenol-rich blackcurrant extract (BCE) can prevent high fat/high cholesterol (HF/HC) diet-induced metabolic disturbances in mice. Male C57BL/6J mice were fed a modified AIN-93M diet containing HF/HC (16% fat, 0·25% cholesterol, w/w) or the same diet supplemented with 0·1% BCE (w/w) for 12 weeks. There were no differences in total body weight and liver weight between groups. Plasma total cholesterol (TC) and glucose levels were significantly lower in BCE group than in controls, while plasma TAG levels were not significantly different. There was a decreasing trend in hepatic TAG levels, and histological evaluation of steatosis grade was markedly lower in the livers of mice fed BCE. Although the mRNA levels of major regulators of hepatic cholesterol metabolism, i.e. 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) and LDL receptor (LDLR), were not significantly altered by BCE supplementation, protein expression of mature sterol-regulatory element-binding protein and LDLR was significantly increased with no change in HMGR protein. The expression of proprotein convertase subtilisin/kexin type 9 that facilitates LDLR protein degradation, as well as one of its transcriptional regulators, i.e. hepatocyte nuclear factor 4α, was significantly decreased in the livers of mice fed BCE. Taken together, BCE supplementation decreased plasma TC and glucose, and inhibited liver steatosis, suggesting that this berry may be consumed to prevent metabolic dysfunctions induced by diets high in fat and cholesterol.


Determination of relative rate of spectral events by novel modification of two-dimensional correlation spectroscopy.
Sign of two-dimensional (2D) correlation peaks provides information on sequence of spectral events. This information is related to molecular mechanism of changes in a given system. Recently, few papers addressing the problems with interpretation of the sign of 2D correlation peaks have been published. To overcome these problems, a modification of the generalized 2D correlation method has been proposed. This method compares variations in the dynamic spectrum with a linear change at a reference point. The rates of spectral responses at individual wavenumbers are proportional to magnitudes of the peaks in the slice of asynchronous spectrum at the reference point. This way, analysis of complex 2D contour plots is replaced by a simple examination of one-dimensional (1D) slice spectrum. In spite of reduced ability of the resolution enhancement, in special cases the proposed method provides information not accessible from the classical 2D correlation analysis. At first, the principles of this method are shown with the synthetic data. Next, the influence of spectral separation, band width and position changes on the slice spectrum is evaluated. Finally, the proposed approach is applied to the experimental spectra of two hydrogen-bonded systems.


The ecology of Diplostomum phoxini infections in two minnow (Phoxinus phoxinus) populations in Scotland.
Data are presented on the infection dynamics of the brain-dwelling metacercariae of Diplostomum phoxini (Digenea: Trematoda) parasitizing European minnow (Phoxinus phoxinus) populations in a lowland river (River Endrick) and a highland loch (Loch Maragan) in central Scotland. Prevalence of the parasite approached 100% in all samples taken from both populations over a 12-month period, and within each population the intensity of infection increased with increasing host fork length. However, the two relationships differed, and size-matched minnows from the Endrick exhibited significantly higher intensities than those from Loch Maragan, suggesting that metacercarial acquisition occurred at different rates in the two populations. Data regarding seasonal trends in the acquisition of D. phoxini indicated that fish in both populations become infected with the parasites mainly during the spring and summer, with negligible infection occurring during winter months. Analysis of size-matched fish from individual samples revealed apparent differences in the distribution of D. phoxini within the two host populations. Whereas D. phoxini metacercariae appeared to be overdispersed amongst length-matched fish from Loch Maragan samples, the parasite was distributed normally amongst fish from the Endrick. Possible reasons for the observed differences in the infection characteristics of D. phoxini in the two minnow populations are discussed, with reference to the parasite's transmission dynamics and local environmental conditions.


Demographics of a large paediatric Postural Orthostatic Tachycardia Syndrome Program.
The aim of this study was to identify and evaluate demographic and clinical features of paediatric patients with postural orthostatic tachycardia syndrome in a tertiary hospital speciality clinic. This is a retrospective review of clinical data obtained during initial outpatient evaluation. A total of 708 patients met the evaluation criteria. Female patients outnumbered males, 3.45:1. Caucasians were over-represented at 94.1% of patients. Median age at diagnosis was 15.7 years. Joint hypermobility occurred in 57.3% of patients; 22.4% had hypermobile Ehlers-Danlos syndrome; and 34.9% had hypermobility spectrum disorder. Median age of onset of symptoms was 12.6 years in patients with hypermobility versus 13.7 years in those without (p=0.0001). Median duration of symptoms was 3.3 years with hypermobility versus 1.5 years without (p<0.00001). Putative triggers included infection in 23.6% of patients, concussion in 11.4%, and surgery/trauma in 2.8%. Concurrent inflammatory disorders were noted in 5.2% of patients. Six symptoms comprised 80% of initial patient complaints. Overall, 66% of patients subsequently had at least 10 symptoms, 50% had at least 14 symptoms, and 30% reported at least 26 symptoms. Symptoms were largely cardiovascular, gastrointestinal, and neurological. Paediatric patients with postural orthostatic tachycardia syndrome seen in a large speciality clinic are predominantly female, are mostly Caucasian, have onset of symptoms in early adolescence, and have symptoms for over two years before diagnosis. Over half of patients have joint hypermobility. More than one-third of patients have a possible autoimmune or inflammatory trigger, including infection, concussion, or surgery/trauma. Patients experience symptoms that are highly variable and multi-system in origin over the course of illness.


Pharmacologic neuroimaging of the ontogeny of dopamine receptor function.
Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.


Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children.
Organophosphate (OP) pesticides are widely used in agriculture and homes. Animal studies suggest that even moderate doses are neurodevelopmental toxicants, but there are few studies in humans. We investigated the relationship of prenatal and child OP urinary metabolite levels with children's neurodevelopment. Participating children were from a longitudinal birth cohort of primarily Latino farm-worker families in California. We measured six nonspecific dialkylphosphate (DAP) metabolites in maternal and child urine as well as metabolites specific to malathion (MDA) and chlorpyrifos (TCPy) in maternal urine. We examined their association with children's performance at 6 (n = 396), 12 (n = 395), and 24 (n = 372) months of age on the Bayley Scales of Infant Development [Mental Development (MDI) and Psychomotor Development (PDI) Indices] and mother's report on the Child Behavior Checklist (CBCL) (n = 356). Generally, pregnancy DAP levels were negatively associated with MDI, but child measures were positively associated. At 24 months of age, these associations reached statistical significance [per 10-fold increase in prenatal DAPs: beta = -3.5 points; 95% confidence interval (CI), -6.6 to -0.5; child DAPs: beta = 2.4 points; 95% CI, 0.5 to 4.2]. Neither prenatal nor child DAPs were associated with PDI or CBCL attention problems, but both prenatal and postnatal DAPs were associated with risk of pervasive developmental disorder [per 10-fold increase in prenatal DAPs: odds ratio (OR) = 2.3, p = 0.05; child DAPs OR = 1.7, p = 0.04]. MDA and TCPy were not associated with any outcome. We report adverse associations of prenatal DAPs with mental development and pervasive developmental problems at 24 months of age. Results should be interpreted with caution given the observed positive relationship with postnatal DAPs.


Elemental Analysis of Chinese Black Inks on Xuan Paper by ArF Laser-Excited Plume Fluorescence.
Chemical analysis of Chinese black ink on xuan paper is useful for the authentication of Asian artwork. The analysis has to be nondestructive and has to accommodate artworks of all sizes. We apply three analytical techniques, ArF laser-induced plume fluorescence, Fourier transform infrared (FTIR) spectroscopy, and portable X-ray fluorescence (pXRF) to analyze five commercial Chinese black inks on two kinds of xuan paper. The FTIR signal is found to be interfered by the substrate which is inevitable because the pigments diffuse extensively into the xuan fiber network. The XRF signal is shown to be feeble and no signal can be registered until the samples are stacked and when the analytes are present at tens of percent. In contrast, the plume fluorescence technique can detect the minor and trace signature elements. The method is based on a two-laser-pulse scheme performed on a high precision optical setup: the first 355 nm laser pulse ablates a thin layer of the ink to create a plume; the second 193 nm laser pulse induces multi analytes in the plume to fluoresce. Partial-least-squares discriminant analysis of the fluorescence spectra unambiguously sorts the ink-xuan combinations while the sampled area is not visibly damaged even under the microscope. The laser probe can handle samples of arbitrary size and shape, is air compatible, and no sample pretreatment is necessary.


Presumed uremic optic neuropathy in a patient with Senior-Loken syndrome.
A patient who had been diagnosed with infantile retinal dystrophy developed renal failure in his twenties, at which time the diagnosis was revised to Senior-Loken syndrome. He was poorly compliant. At 36 years old, he experienced a sudden drop in visual acuity in the setting of cramping and fatigue and was found to be in uremic crisis. Six months after the event and its treatment, his vision failed to improved. Optic nerve pallor was out of proportion to the retinal dystrophy, and the presumed reason for his new visual loss was uremic optic neuropathy. The patient's younger sister also had been diagnosed with infantile retinal dystrophy, and metabolic screening confirmed subclinical renal dysfunction that was to be carefully followed going forward. Infantile retinal dystrophy can be associated with later systemic disease. Early detection of such disease can potentially decrease morbidity. Patients with retinal dystrophy can develop new visual loss from causes other than the retinopathy itself.


Clinical presentation, management, and short-term outcome of patients with type A acute dissection complicated by mesenteric malperfusion: observations from the International Registry of Acute Aortic Dissection.
Few data exist on clinical/imaging characteristics, management, and outcomes of patients with type A acute dissection and mesenteric malperfusion. Patients with type A acute dissection enrolled in the International Registry for Acute Dissection (IRAD) were evaluated to assess differences in clinical features, management, and in-hospital outcomes according to the presence/absence of mesenteric malperfusion. A mortality model was used to identify predictors of in-hospital mortality in patients with mesenteric malperfusion. Mesenteric malperfusion was detected in 68 (3.7%) of 1809 patients with type A acute dissection. Patients with mesenteric malperfusion were more likely to be older and to have coma, cerebrovascular accident, spinal cord ischemia, acute renal failure, limb ischemia, and any pulse deficit. They were less likely to undergo surgical/hybrid treatment (52.9% vs 87.9%) and more likely to receive only medical (30.9% vs 11.6%) or endovascular (16.2% vs 0.5%) management (P < .001). Overall in-hospital mortality was 63.2% and 23.8% in patients with and without mesenteric malperfusion, respectively (P < .001). In-hospital mortality of patients with mesenteric malperfusion receiving medical, endovascular, and surgical/hybrid therapy was 95.2%, 72.7%, and 41.7%, respectively (P < .001). At multivariate analysis, male gender (odds ratio [OR], 1.7; P = .002), age (OR, 1.1/y; P = .002), and renal failure (OR, 5.9; P = .020) were predictors of mortality whereas surgical/hybrid management (OR, 0.1; P = .005) was associated with better outcome. Type A acute aortic dissection complicated by mesenteric malperfusion is a rare but ominous complication carrying a high risk of hospital mortality. Surgical/hybrid therapy, although associated with 2-fold hospital mortality, appears to be associated with better long-term outcomes in the management of type A acute aortic dissection in this setting.


Spirulina platensis versus silymarin in the treatment of chronic hepatitis C virus infection. A pilot randomized, comparative clinical trial.
Spirulina platensis, a cynobacterium used frequently as a dietary supplement had been found to exhibit many immune-stimulating and antiviral activities. It had been found to activate macrophages, NK cells, T cells, B cells, and to stimulate the production of Interferon gamma (IFN-γ) and other cytokines. Natural substances isolated from Spirulina platensis had been found to be potent inhibitors against several enveloped viruses by blocking viral absorption/penetration and some replication stages of progeny viruses after penetration into cells. We aimed to study whether this dietary supplement possesses any therapeutically feasible activity worthy of further larger controlled clinical evaluation. Sixty six patients with chronic hepatitis C virus infection and eligible for inclusion had been randomized to either Spirulina or Silymarin treated groups for a period of six months treatment.The two groups were followed up and blindly compared for early (after 3 months) and end of 6 months treatment virological response. The effects of both treatments on each of alanine aminotransferase (ALT), Chronic Liver Disease Questionnaire scores (CLDQ), Arizona Sexual Experience Scale scores (ASEX) and the occurrence of any attributable adverse events were also compared. Among the 30 patients who had been treated with Spirulina and completed the 6 months protocol, 4 patients (13.3%) had a complete end of treatment virological response and 2 patients (6.7%) had a partial end of treatment response defined as significant decrease of virus load of at least 2-logs10. Though the proportion of responders in Spirulina group was greater than in the Silymarin group, the difference was not statistically significant at the end of both 6 months (p = 0.12) and 3 months treatment (p = 0.22) by Exact test. Alanine aminotransferase as well as CLDQ and ASEX scores were found to be more significantly improved in Spirulina than in Silymarin treated group. Our results could suggest a therapeutically feasible potential for Spirulina platensis in chronic HCV patients, worthy to conduct a larger sized and longer study to confirm these safety and efficacy encouraging results. WHO Clinical Trial Registration ID: ACTRN12610000958088http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12610000958088.


Electrophysiological insights into language processing in schizophrenia.
Deficits in language comprehension in schizophrenia were examined using event-related potentials (ERPs). Schizophrenic and healthy participants read sentences in which the first clause ended with a homograph, and the second clause started with a target word that was semantically related to the homograph's dominant meaning (e.g., 1. Diving was forbidden from the bridge because the river had rocks in it. or 2. The guests played bridge because the river had rocks in it.). Processing of the targets (e.g., "river") was expected to be primarily influenced by the preceding overall sentence context (congruent in 1; incongruent in 2) in healthy participants, but to be inappropriately affected by the dominant meaning of homographs (e.g., the "structure" meaning of "bridge") in sentences like 2 in schizophrenic patients. The N400 ERP component that is known to be sensitive to contextual effects during language processing confirmed these predictions. This showed that language abnormalities in schizophrenia may be related to deficient processing of context-irrelevant semantic representations of words from the discourse.


Thickness-Independent Vibrational Thermal Conductance across Confined Solid-Solution Thin Films.
We experimentally show that the thermal conductance across confined solid-solution crystalline thin films between parent materials does not necessarily lead to an increase in thermal resistances across the thin-film geometries with increasing film thicknesses, which is counterintuitive to the notion that adding a material serves to increase the total thermal resistance. Confined thin epitaxial Ca0.5Sr0.5TiO3 solid-solution films with systematically varying thicknesses in between two parent perovskite materials of calcium titanate and (001)-oriented strontium titanate are grown, and thermoreflectance techniques are used to accurately measure the thermal boundary conductance across the confined solid-solution films, showing that the thermal resistance does not substantially increase with the addition of solid-solution films with increasing thicknesses from ∼1 to ∼10 nm. Contrary to the macroscopic understanding of thermal transport where adding more material along the heat propagation direction leads to larger thermal resistances, our results potentially offer experimental support to the computationally predicted concept of vibrational matching across interfaces. This concept is based on the fact that a better match in the available heat-carrying vibrations due to an interfacial layer can lead to lower thermal boundary resistances, thus leading to an enhancement in thermal boundary conductance across interfaces driven by the addition of a thin "vibrational bridge" layer between two solids.


Impact of the multiplex molecular FilmArray Respiratory Panel on antibiotic prescription and clinical management of immunocompromised adults with suspected acute respiratory tract infections: A retrospective before-after study.
This study aimed to assess the impact of the implementation of a rapid multiplex molecular FilmArray Respiratory Panel (FRP) on the medical management of immunocompromised patients from a community general hospital. We conducted a single-center, retrospective, and before-after study. Two periods were evaluated: before the implementation of the FRP (pre-FRP) from April 2017 to May 2018 and after the implementation of the FRP (post-FRP) from January to July 2019. The inclusion criteria were immunocompromised patients over 18 years of age with suspected acute respiratory illness tested by conventional diagnostic methods (pre-FRP) or the FilmArray™ Respiratory Panel v1.7 (post-FRP). A total of 142 patients were included, 64 patients in the pre-FRP and 78 patients in the post-FRP. The positive detection rate was significantly higher in the post-FRP (63% vs. 10%, p<0.01). There were more patients receiving antimicrobial treatment in the pre-FRP compared with the post-FRP period (94% vs. 68%, p<0.01). A decrease in beta-lactam (89% vs. 61%, p<0.01) and macrolide (44% vs. 13%, p<0.01) prescriptions were observed in the post-FRP. No differences were observed in oseltamivir use (22% vs. 13%, p=0.14), changes in antimicrobial treatment, hospital admission rate, days-reduction in droplet isolation precautions, hospital length of stay (LOS), admission to intensive care unit (ICU), LOS in ICU, treatment failure and 30-day mortality. The implementation of the FRP impacted patient care by improving diagnostic yield and optimizing antimicrobial treatment in immunocompromised adult patients.


Predicting the Need for Desmopressin Treatment During Inpatient and After Discharge Following Endoscopic Sellar Surgery.
Postoperative diabetes insipidus (DI) is a common complication following endoscopic sellar surgery. However, the requirement of desmopressin treatment for patients with DI are heterogenous. Although the predictors of postoperative DI have been reported, whether these patients required desmopressin treatment remained uninvestigated. Predicting the need of desmopressin can benefit clinical decision making more directly than predicting the occurence of postoperative DI. This study aimed to identify variables that predict the need for desmopressin treatment following sellar surgery. Patients undergoing endoscopic sellar surgery between 2016 and 2019 were retrospectively reviewed. Twenty-three variables, characterized as potential predictors for requiring desmopressin treatment, were analyzed. To assess the capability to generalize the identified predictors, external validation with receiver operating characteristic (ROC) analysis was performed using a second series from 2019 to 2020. Postoperative DI occurred in 40 of 159 included patients. Twelve patients required inpatient desmopressin treatment and 20 patients needed desmopressin prescription after discharge. The potential predictors of requiring any desmopressin use included higher peak sodium (Na) level (p = 0.007), lower minimum Na level (p = 0.043), and higher peak urine output (p = 0.006), but these were not supported by external validation. The predictors of requiring desmopressin after discharge included higher peak Na (p = 0.040) and minimum Na levels (p = 0.048), which were supported by external ROC validation showing areas under curve of 0.787, 0.611, and 0.898 for peak Na (p = 0.036), minimum Na (p = 0.460), and peak Na - minimum Na levels (p < 0.001), respectively. A criterion of peak Na ≥ 150 mmol/L or peak Na - minimum Na ≥ 10 predicted the need of desmopressin prescription after discharge. A postoperative management algorithm was proposed. The required treatments for patients with postoperative DI following endoscopic sellar surgery are heterogenous. Elevated peak Na and large peak Na-minimum Na levels in the perioperative period predicted requiring desmopressin after hospital discharge. Patients with peak Na <150 mmol/L and peak Na-minimum Na <10 can be safely discharged without desmopressin prescription.


Thermodynamic modelling of a membrane distillation crystallisation process for the treatment of mining wastewater.
Membrane distillation (MD) could be applicable in zero liquid discharge applications. This is due to the fact that MD is applicable at high salinity ranges which are generally outside the scope of reverse osmosis (RO) applications, although this requires proper management of precipitating salts to avoid membrane fouling. One way of managing these salts is with MD crystallisation (MDC). This paper focuses on the applicability of MDC for the treatment of mining wastewater by thermodynamically modelling the aqueous chemistry of the process at different temperatures. The paper is based on the typical brine generated from an RO process in the South African coal mining industry and investigates the effect water recovery and operating temperature have on the salts that are predicted to crystallise out, the sequence in which they will crystallise out and purities as a function of the water recovery. The study confirmed the efficacy of using thermodynamic modelling as a tool for investigating and predicting the crystallisation aspects of the MDC process. The key finding from this work was that, for an MDC process, a purer product can be obtained at higher operating temperatures and recoveries because of the inverse solubility of calcium sulphate.


Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.
Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.


Health effects of informal caregiving across Europe: A longitudinal approach.
Due to an expected increase of people in need of care, sound knowledge about health effects of informal care provision is becoming more and more important. Theoretically, there might be positive as well as negative health effects due to caregiving to relatives. Moreover, we suppose that such health effects differ by national context - since care is differently organized in Europe - and depend on the social setting in which the care relationship takes place. Using data from the Survey of Health, Ageing and Retirement (SHARE, waves 1, 2, 3, and 5) and from the English Longitudinal Study of Ageing (ELSA, waves 2-5) we examined the connection between informal caregiving and self-perceived as well as mental health in a country comparative perspective. Taking advantage of the longitudinal structure of the data, pooled ordinary least squares (OLS) and fixed-effects models (FEM) were estimated. Our results show distinct differences in the relationship between reported health and the provision of informal care depending on whether individuals give care to someone inside or outside the household. Caregivers inside the household reported worse health, caregivers from outside the household reported better health than non-caregivers. We find that this correlation is largely due to selection into caregiving: people in worse health took up care inside while people in better health took up care outside the household. However, in most countries people who started caregiving inside the household experienced a decline in their mental health. This suggests that caregiving inside the household results in psychological stress irrespective of the type of welfare state. The results regarding self-perceived health and caregiving outside the household are less distinct. All in all our results show that health consequences of caregiving vary not only between different welfare regimes but also between countries of similar welfare state types.


Fetal breathing and generalized fetal movements in normal antenatal patients.
Fetal breathing movements (FBM) and generalized fetal movements (GFM) were recorded for 30 minutes using a real time B-scan instrument in 46 women with uncomplicated pregnancies. FBM occurred for 10.9+/-0.9 (SE) per cent of the recording time. The time occupied by FBM was not significantly related to smoking, meal times or plasma glucose concentrations. FBM were absent during the observation period in 15 per cent of patients and present for less than 10 per cent of the time in 33 per cent of patients.


Transient down-regulation of beta1 integrin subtypes on kidney carcinoma cells is induced by mechanical contact with endothelial cell membranes.
Adhesion molecules of the integrin beta1 family are thought to be involved in the malignant progression renal cell carcinoma (RCC). Still, it is not clear how they contribute to this process. Since the hematogenous phase of tumour dissemination is the rate-limiting step in the metastatic process, we explored beta1 integrin alterations on several RCC cell lines (A498, Caki1, KTC26) before and after contacting vascular endothelium in a tumour-endothelium (HUVEC) co-culture assay. Notably, alpha2, alpha3 and alpha5 integrins became down-regulated immediately after the tumour cells attached to HUVEC, followed by re-expression shortly thereafter. Integrin down-regulation on RCC cells was caused by direct contact with endothelial cells, since the isolated endothelial membrane fragments but not the cell culture supernatant contributed to the observed effects. Integrin loss was accompanied by a reduced focal adhesion kinase (FAK) expression, FAK activity and diminished binding of tumour cells to matrix proteins. Furthermore, intracellular signalling proteins RCC cells were altered in the presence of HUVEC membrane fragments, in particular 14-3-3 epsilon, ERK2, PKCdelta, PKCepsilon and RACK1, which are involved in regulating tumour cell motility. We, therefore, speculate that contact of RCC cells with the vascular endothelium converts integrin-dependent adhesion to integrin-independent cell movement. The process of dynamic integrin regulation may be an important part in tumour cell migration strategy, switching the cells from being adhesive to becoming motile and invasive.


Allelopathic effects of volatile organic compounds released from Pinus halepensis needles and roots.
The Mediterranean region is recognized as a global biodiversity hotspot. However, over the last decades, the cessation of traditional farming in the north part of the Mediterranean basin has given way to strong afforestation leading to occurrence of abandoned agricultural lands colonized by pioneer expansionist species like Pinus halepensis. This pine species is known to synthesize a wide range of secondary metabolites, and previous studies have demonstrated strong allelopathic potentialities of its needle and root leachates. Pinus halepensis is also recognized to release significant amounts of volatile organic compounds (VOC) with potential allelopathic effects that have never been investigated. In this context, the objectives of the present study were to improve our knowledge about the VOC released from P. halepensis needles and roots, determine if these VOC affect the seed germination and root growth of two herbaceous target species (Lactuca sativa and Linum strictum), and evaluate if soil microorganisms modulate the potential allelopathic effects of these VOC. Thirty terpenes were detected from both, needle and root emissions with β-caryophyllene as the major volatile. Numerous terpenes, such as β-caryophyllene, δ-terpinene, or α-pinene, showed higher headspace concentrations according to the gradient green needles < senescent needles < needle litter. Seed germination and root growth of the two target species were mainly reduced in presence of P. halepensis VOC. In strong contrast with the trend reported with needle leachates in literature, we observed an increasing inhibitory effect of P. halepensis VOC with the progress of needle physiological stages (i.e., green needle < senescent needle < needle litter). Surprisingly, several inhibitory effects observed on filter paper were also found or even amplified when natural soil was used as a substrate, highlighting that soil microorganisms do not necessarily limit the negative effects of VOC released by P. halepensis on herbaceous target species.


Forensic Mental Health Nurses' Experiences of Clinical Supervision.
Clinical supervision may support forensic mental health nurses with personal and professional growth in a work environment characterized by therapeutic, ethical, and practical challenges. The aim of this study was to describe the experiences of forensic mental health nurses participating in a clinical supervision program. Seven forensic mental health nurses and two allied health professionals, working in a high-security forensic mental health hospital, were interviewed regarding their experiences of participating in a clinical supervision program. Participants expressed a need for clinical supervision and were motivated to participate in the program. Benefits of clinical supervision experienced by participants included improved communication with their colleagues, being supported in their career development, and developing habits and techniques to reflect on practice issues. Participants described being able to connect with their supervisor, enabled by both trust and confidence in the supervisor's expertise. Staff showed engagement in the clinical supervision process and expressed experiencing positive outcomes related to personal and professional growth and development. To support nurses with the forensic mental health context-specific challenges they face, organizations should enable and promote access to clinical supervision. Considerations for forensic mental health organizations to increase uptake and effectiveness of clinical supervision include use of externally based clinical supervisors with adequate skills and experience with providing clinical supervision to clinical staff who work in a secure environment.


The relative ages of ectomycorrhizal mushrooms and their plant hosts estimated using Bayesian relaxed molecular clock analyses.
Ectomycorrhizae (ECM) are symbioses formed by polyphyletic assemblages of fungi (mostly Agaricomycetes) and plants (mostly Pinaceae and angiosperms in the rosid clade). Efforts to reconstruct the evolution of the ECM habit in Agaricomycetes have yielded vastly different results, ranging from scenarios with many relatively recent origins of the symbiosis and no reversals to the free-living condition; a single ancient origin of ECM and many subsequent transitions to the free-living condition; or multiple gains and losses of the association. To test the plausibility of these scenarios, we performed Bayesian relaxed molecular clock analyses including fungi, plants, and other eukaryotes, based on the principle that a symbiosis cannot evolve prior to the origin of both partners. As we were primarily interested in the relative ages of the plants and fungi, we did not attempt to calibrate the molecular clock using the very limited fossil record of Agaricomycetes. Topologically constrained and unconstrained analyses suggest that the root node of the Agaricomycetes is much older than either the rosids or Pinaceae. The Agaricomycetidae, a large clade containing the Agaricales and Boletales (collectively representing 70% of Agaricomycetes), is also significantly older than the rosids. The relative age of Agaricomycetidae and Pinaceae, however, is sensitive to tree topology, and the inclusion or exclusion of the gnetophyte Welwitschia mirabilis. The ancestor of the Agaricomycetes could not have been an ECM species because it existed long before any of its potential hosts. Within more derived clades of Agaricomycetes, there have been at least eight independent origins of ECM associations involving angiosperms, and at least six to eight origins of associations with gymnosperms. The first ECM symbioses may have involved Pinaceae, which are older than rosids, but several major clades of Agaricomycetes, such as the Boletales and Russulales, are young enough to have been plesiomorphically associated with either rosids or Pinaceae, suggesting that some contemporary ECM partnerships could be of very ancient origin.


Meat intake and mortality: a prospective study of over half a million people.
High intakes of red or processed meat may increase the risk of mortality. Our objective was to determine the relations of red, white, and processed meat intakes to risk for total and cause-specific mortality. The study population included the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study cohort of half a million people aged 50 to 71 years at baseline. Meat intake was estimated from a food frequency questionnaire administered at baseline. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of meat intake. The covariates included in the models were age, education, marital status, family history of cancer (yes/no) (cancer mortality only), race, body mass index, 31-level smoking history, physical activity, energy intake, alcohol intake, vitamin supplement use, fruit consumption, vegetable consumption, and menopausal hormone therapy among women. Main outcome measures included total mortality and deaths due to cancer, cardiovascular disease, injuries and sudden deaths, and all other causes. There were 47 976 male deaths and 23 276 female deaths during 10 years of follow-up. Men and women in the highest vs lowest quintile of red (HR, 1.31 [95% CI, 1.27-1.35], and HR, 1.36 [95% CI, 1.30-1.43], respectively) and processed meat (HR, 1.16 [95% CI, 1.12-1.20], and HR, 1.25 [95% CI, 1.20-1.31], respectively) intakes had elevated risks for overall mortality. Regarding cause-specific mortality, men and women had elevated risks for cancer mortality for red (HR, 1.22 [95% CI, 1.16-1.29], and HR, 1.20 [95% CI, 1.12-1.30], respectively) and processed meat (HR, 1.12 [95% CI, 1.06-1.19], and HR, 1.11 [95% CI 1.04-1.19], respectively) intakes. Furthermore, cardiovascular disease risk was elevated for men and women in the highest quintile of red (HR, 1.27 [95% CI, 1.20-1.35], and HR, 1.50 [95% CI, 1.37-1.65], respectively) and processed meat (HR, 1.09 [95% CI, 1.03-1.15], and HR, 1.38 [95% CI, 1.26-1.51], respectively) intakes. When comparing the highest with the lowest quintile of white meat intake, there was an inverse association for total mortality and cancer mortality, as well as all other deaths for both men and women. Red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality.


PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation.
It is well known that prostaglandin E2 (PGE2) both inhibits arginine vasopressin (AVP)-stimulated water permeability (hydraulic conductivity, Lp) in the cortical collecting duct (CCD) or, if administered alone, modestly increases Lp in the CCD. These bifunctional effects on Lp correspond to PGE2's capacity to inhibit AVP-stimulated adenylate cyclase (AC) activity, or to singularly stimulate AC activity in the collecting duct. The present studies suggest that the inhibitory effect of PGE2 on Lp may also be mediated by phosphatidylinositol (PI) hydrolysis. Using in vitro microperfused rabbit CCDs, we show that PGE2 releases Ca from intracellular stores. We also demonstrate that the inhibitory effect of PGE2 on AVP-stimulated Lp in the CCD is significantly reversed by the protein kinase C (PKC) inhibitor, staurosporine (SSP). Although PGE2 does not reduce an established water flow response to 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPTcAMP), when the sequence of addition is reversed and PGE2 is added first, marked inhibition of 8-CPTcAMP-induced Lp is observed. This provides independent evidence that PGE2 can act through a mechanism separate from modulating AC activity. PGE2 inhibition of 8-CPTcAMP-induced Lp is reversed by SSP pretreatment. Finally, SSP pretreatment also markedly potentiates the capacity of PGE2 itself to increase Lp. We conclude that PGE2 releases Ca from intracellular stores and, by activating PKC, inhibits AVP-induced osmotic water flow. This suggests an important role for PI hydrolysis in mediating PGE2's effects on the CCD.


pH electrode performance under automated management conditions.
pH is frequently measured in laboratories, but to have confidence in the results it is necessary to know that it was measured properly. For an electrode to give accurate results it must be treated well and calibrated correctly. In this paper, an automated system for pH measurement is described; the system uses the operational pH scale and calibrates using two or three buffer solutions, taking proper account of the effects of temperature on the system. The system can be programmed with standard methods and procedures to ensure that the electrode gives the best possible performance. Calibrations and measurements within the system are reproducible, and the automated system is more robust than the manual pH meter, and requires less operator time.


ApoER2 and Reelin are expressed in regenerating peripheral nerve and regulate Schwann cell migration by activating the Rac1 GEF protein, Tiam1.
ApoER2 and its ligand Reelin participate in neuronal migration during development. Upon receptor binding, Reelin induces the proteolytic processing of ApoER2 as well as the activation of signaling pathway, including small Rho GTPases. Besides its presence in the central nervous system (CNS), Reelin is also secreted by Schwann cells (SCs), the glial cells of the peripheral nervous system (PNS). Reelin deficient mice (reeler) show decreased axonal regeneration in the PNS; however neither the presence of ApoER2 nor the role of the Reelin signaling pathway in the PNS have been evaluated. Interestingly SC migration occurs during PNS development and during injury-induced regeneration and involves activation of small Rho GTPases. Thus, Reelin-ApoER2 might regulate SC migration during axon regeneration in the PNS. Here we demonstrate the presence of ApoER2 in PNS. After sciatic nerve injury Reelin was induced and its receptor ApoER2 was proteolytically processed. In vitro, SCs express both Reelin and ApoER2 and Reelin induces SC migration. To elucidate the molecular mechanism underlying Reelin-dependent SC migration, we examined the involvement of Rac1, a conspicuous small GTPase family member. FRET experiments revealed that Reelin activates Rac1 at the leading edge of SCs. In addition, Tiam1, a major Rac1-specific GEF was required for Reelin-induced SC migration. Moreover, Reelin-induced SC migration was decreased after suppression of the polarity protein PAR3, consistent with its association to Tiam1. Even more interesting, we demonstrated that PAR3 binds preferentially to the full-length cytoplasmic tail of ApoER2 corresponding to the splice-variant containing the exon 19 that encodes a proline-rich insert and that ApoER2 was required for SC migration. Our study reveals a novel function for Reelin/ApoER2 in PNS, inducing cell migration of SCs, a process relevant for PNS development and regeneration.


Transcriptional regulation and structural modeling of the FutC subunit of an ABC-type iron transporter in Synechocystis sp. strain PCC 6803.
The futC gene encodes a subunit of an ATP-binding cassette (ABC)-type iron transporter in Synechocystis sp. strain PCC 6803. In the present study, we have focused on the environmental regulation of futC transcription in the model organism Synechocystis sp. strain PCC 6803 and, moreover, studied the transcriptional regulation of the other transporter subunits, futA1, futA2 and futB. The steady-state amounts of the futA1, futA2, futB and futC transcripts were regulated under several conditions studied including darkness, temperature, alternative nitrogen source, salt and osmotic stresses and iron deficiency. Transcription of all subunits of the FutABC-iron transporter seems to be under similar regulation, which, according to our results, may also apply to genes encoding subunits of other transporters in Synechocystis. The sequence alignment, including sequences from six different organisms, revealed the conserved nature of FutC. Based on the sequence alignment and the structural model of FutC, the monomer consists of a nucleotide-binding domain (NBD) and a regulatory domain. The NBD is well conserved indicating completely functional ATP binding.


Validation of the NeuroImaging Radiological Interpretation System for Acute Traumatic Brain Injury.
The aim of the study was to refine and validate the NeuroImaging Radiological Interpretation System (NIRIS), which was developed to predict management and clinical outcome based on noncontrast head computerized tomography findings in patients suspected of acute traumatic brain injury (TBI). We assessed the performance of the NIRIS score in a prospective, single-center cohort of patients suspected of TBI (n = 648) and compared the performance of NIRIS with that of the Marshall and Rotterdam scoring systems. We also revised components of the NIRIS scoring system using decision tree methodologies implemented on pooled data from the retrospective and prospective studies (N = 1190). The NIRIS performed similarly to the Marshall and Rotterdam scoring systems in predicting mortality and markedly better in terms of predicting more granular elements of disposition and management of TBI patients, such as admission, follow-up imaging, intensive care unit stay, and neurosurgical procedures. The revised NIRIS classification correctly predicted disposition and outcome in 91.2% (331/363) after excluding patients with other major extracranial traumatic injuries or intracranial nontraumatic injuries. The present study further demonstrates the predictive value of NIRIS in guiding standardized clinical management and decision-making regarding treatment options for TBI patients.


Diagnosis of carcinoma and benign cysts of the breast. The value of needle aspiration.
Diagnosis of solid breast masses by needle aspiration with cytological examination of the aspirate has been practiced for some time in several centers in this country and abroad. It has been proposed as an alternative to the conventional excisional biopsy for the diagnosis of carcinoma of the breast. At the same time, simple needle aspiration of benign cysts as an office procedure has gained new favor as a means of proving the presence of benign disease at the first office visit and thus avoiding the loss of time, and the expense and worry of surgical excision in a hospital. From a review of the reliability and practical usefulness of both methods, it is concluded that aspiration biopsy for the diagnosis of carcinoma is less reliable than conventional excisional biopsy and offers very little practical advantage. Simple aspiration of cysts, on the other hand, appears to offer a true saving of time, expense and worry, and to be a reliable method, if used properly.


Historic Overview of Genetic Engineering Technologies for Human Gene Therapy.
The concepts of gene therapy were initially introduced during the 1960s. Since the early 1990s, more than 1900 clinical trials have been conducted for the treatment of genetic diseases and cancers mainly using viral vectors. Although a variety of methods have also been performed for the treatment of malignant gliomas, it has been difficult to target invasive glioma cells. To overcome this problem, immortalized neural stem cell (NSC) and a nonlytic, amphotropic retroviral replicating vector (RRV) have attracted attention for gene delivery to invasive glioma. Recently, genome editing technology targeting insertions at site-specific locations has advanced; in particular, the clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) has been developed. Since 2015, more than 30 clinical trials have been conducted using genome editing technologies, and the results have shown the potential to achieve positive patient outcomes. Gene therapy using CRISPR technologies for the treatment of a wide range of diseases is expected to continuously advance well into the future.


Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant.
The treatment of a patient with an invasive bladder tumor is based on the original urologic assessment. The global recommendation of a single treatment plan such as radical surgery, chemotherapy, radiation, or variations thereof, for all patients is clearly an antiquated approach. Case selection criteria for each single or multimodality approach need to be defined. Neoadjuvant therapy has the advantage of an in vivo response evaluation and the potential for bladder preservation. However, before treatment, the therapeutic goal--bladder preservation, treatment of micrometastases, or both--should be outlined. Patients with T2 or T3a tumors can be considered for bladder salvage by chemotherapy alone, chemotherapy plus radiation therapy or, chemotherapy followed by partial cystectomy. For those with higher stage tumors, therapy is directed more to the treatment of micrometastases, with bladder preservation as a secondary goal. In most cases additional therapy directed at the primary is required and clinical understaging remains significant. For some patients, initial surgery with the definition of the prognosis on firm pathologic grounds, may represent a better strategy. Those with positive nodes should be offered chemotherapy in the postoperative setting. Refinements in the techniques of ileo neo-bladders are of importance in improving quality of life, but when used alone will not alter the natural history of the disease. Drug resistance remains a major therapeutic obstacle. More effective agents, and the prospective identification of intrinsic or acquired resistance, invasion, and metastatic potential are required to optimize therapy for an individual patient. Ultimately, large scale randomized trials will be required to negate the heterogeneity of this patient population. Only then will individualization of treatment be possible.


Variation in reproductive isolation across a species range.
Reproductive isolation is often variable within species, a phenomenon that while largely ignored by speciation studies, can be leveraged to gain insight into the potential mechanisms driving the evolution of genetic incompatibilities. We used experimental greenhouse crosses to characterize patterns of reproductive isolation among three divergent genetic lineages of Campanulastrum americanum that occur in close geographic proximity in the Appalachian Mountains. Substantial, asymmetrical reproductive isolation for survival due to cytonuclear incompatibility was found among the lineages (up to 94% reduction). Moderate reductions in pollen viability, as well as cytoplasmic male sterility, were also found between some Mountain populations. We then compared these results to previously established patterns of reproductive isolation between these Mountain lineages and a fourth, widespread Western lineage to fully characterize reproductive isolation across the complete geographic and genetic range of C. americanum. Reproductive isolation for survival and pollen viability was consistent across studies, indicating the evolution of the underlying genetic incompatibilities is primarily determined by intrinsic factors. In contrast, reproductive isolation for germination was only found when crossing Mountain populations with the Western lineage, suggesting the underlying genetic incompatibility is likely influenced by environmental or demographic differences between the two lineages. Cytoplasmic male sterility was also limited in occurrence, being restricted to a handful of Mountain populations in a narrow geographic range. These findings illustrate the complexity of speciation by demonstrating multiple, independent genetic incompatibilities that lead to a mosaic of genetic divergence and reproductive isolation across a species range.


The socio-ecology of zoonotic infections.
The resurgence of infectious diseases of zoonotic origin observed in recent years imposes a major morbidity/mortality burden worldwide, and also a major economic burden that extends beyond pure medical costs. The resurgence and epidemiology of zoonoses are complex and dynamic, being influenced by varying parameters that can roughly be categorized as human-related, pathogen-related, and climate/environment-related; however, there is significant interplay between these factors. Human-related factors include modern life trends such as ecotourism, increased exposure through hunting or pet owning, and culinary habits, industrialization sequelae such as farming/food chain intensification, globalization of trade, human intrusion into ecosystems and urbanization, significant alterations in political regimes, conflict with accompanying breakdown of public health and surveillance infrastructure, voluntary or involuntary immigration, loosening of border controls, and hierarchy issues in related decision-making, and scientific advances that allow easier detection of zoonotic infections and evolution of novel susceptible immunocompromised populations. Pathogen-related factors include alterations in ecosystems and biodiversity that influence local fauna synthesis, favouring expansion of disease hosts or vectors, pressure for virulence/resistance selection, and genomic variability. Climate/environment-related factors, either localized or extended, such as El Niño southern oscillation or global warming, may affect host-vector life cycles through varying mechanisms. Emerging issues needing clarification include the development of predictive models for the infectious disease impact of environmental projects, awareness of the risk imposed on immunocompromised populations, recognition of the chronicity burden for certain zoonoses, and the development of different evaluations of the overall stress imposed by a zoonotic infection on a household, and not strictly a person.


Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice.
Piceatannol (3,5,3',4'-trans-tetrahydroxystilbene) is a natural analog and a metabolite of resveratrol present in grapes and red wine. Previous studies have reported that piceatannol exerts a broad spectrum of health benefits including antioxidant, anti-inflammatory, chemopreventive, and neuroprotective effects. However, little is known about the hepatoprotective effect of piceatannol against toxin-induced liver fibrosis. Therefore, the objective of this study is to evaluate the protective effect of piceatannol in a mouse model of CCl4-induced hepatic fibrosis. Oral administration of piceatannol significantly improved the hepatic functions of CCl4-treated mice in both therapeutic and preventive models. Additionally, the immunohistochemical staining results revealed that collagen deposition in CCl4-injected mice was significantly reduced by treatment with piceatannol. Moreover, piceatannol remarkably suppressed the expressions of collagen I, α-smooth muscle protein (α-SMA), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) induced by CCl4. The anti-fibrotic mechanism of piceatannol was associated with the regulation of the transforming growth factor-β (TGF-β)/Smad signaling pathway. Finally, piceatannol also profoundly alleviated CCl4-induced hepatic oxidative damage by elevating the level of glutathione and catalase activity. Altogether, our current findings suggest that piceatannol may serve as a bioactive agent that inhibits or alleviates toxic-induced fibroproliferative diseases, especially in the prevention of liver fibrosis.


Sequential immunohistochemical expression of IGF-I and the transferrin receptor in regenerating rat muscle in vivo.
The immunohistochemical expression of insulin-like growth factor I and the transferrin receptor was investigated in regenerating rat skeletal muscle. Muscle injury was induced in the extensor digitorum longus muscle in one hind limb by tourniquet ischemia. The regenerating muscles were investigated 3 to 7 days after the injury. Expression of IGF-I and the transferrin receptor was demonstrated in cryostat sections by a double-staining method. It was found that both markers were transiently expressed by the regenerating muscle cells. Expression of IGF-I immunoreactivity preceded that of the transferrin receptor and the staining for IGF-I disappeared 1 to 2 days before the staining for the transferrin receptor. The data are compatible with a regulatory role of IGF-I on the transferrin receptor.


Regulation of extracellular matrix degradation and metastatic spread by IQGAP1 through endothelin-1 receptor signalling in ovarian cancer.
The invasive phenotype of serous ovarian cancer (SOC) cells is linked to the formation of actin-based protrusions, invadopodia, operating extracellular matrix (ECM) degradation and metastatic spread. Growth factor receptors might cause engagement of integrin-related proteins, like the polarity protein IQ-domain GTPase-activating protein 1 (IQGAP1), to F-actin core needed for invadopodia functions. Here, we investigated whether IQGAP1 forms a signalosome with endothelin-1 (ET-1)/β-arrestin1 (β-arr1) network, as signal-integrating module for adhesion components, cytoskeletal remodelling and ECM degradation. In SOC cells, ET-1 receptor (ET-1R) activation, besides altering IQGAP1 expression and localization, coordinates the binding of IQGAP1 with β-arr1, representing a "hotspot" for ET-1R-induced invasive signalling. We demonstrated that the molecular interaction of IQGAP1 with β-arr1 affects relocalization of focal adhesion components, as vinculin, and cytoskeleton dynamics, through the regulation of invadopodia-related pathways. In particular, ET-1R deactivates Rac1 thereby promoting RhoA/C activation for the correct functions of invasive structures. Silencing of either IQGAP1 or β-arr1, or blocking ET-1R activation with a dual antagonist macitentan, prevents matrix metalloproteinase (MMP) activity, invadopodial function, transendothelial migration and cell invasion. In vivo, targeting ET-1R/β-arr1 signalling controls the process of SOC metastasis, associated with reduced levels of IQGAP1, as well as other invadopodia effectors, such as vinculin, phospho-cortactin and membrane type 1-MMP. High expression of ETAR/β-arr1/IQGAP1 positively correlates with poor prognosis, validating the clinical implication of this signature in early prognosis of SOC. These data establish the ET-1R-driven β-arr1/IQGAP1 interaction as a prerequisite for the dynamic integration of pathways in fostering invadopodia and metastatic process in human SOC.


Managed care: controlling costs and changing practice.
The emergence of cost control and managed care stem from economic realities. While managed care is built on economic principles, it promises to change the way Americans consume health services. As one of the largest single groups providing services to acutely and chronically-ill adults, medical-surgical nurses must understand the key aspects of managed care and how its implementation may change practice.


Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non-insulin-dependent diabetes mellitus albino rats.
Punica granatum L., (Family: Punicaceae) is used in Indian Unani medicine for treatment of diabetes mellitus. Therefore, the present study was done to evaluate the antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of P. granatum in alloxan-induced diabetic rats. Healthy Wistar albino rats (100-150 g) were divided into four groups of six animals each. Groups A and B received normal saline [(10 ml/kg/day/per oral (p.o.)]; group C received ethanolic extract of leaves of P. granatum (500 mg/kg/p.o.); and group D received glibenclamide (0.5 mg/kg/day/p.o.). The extracts were given for 1 week in all groups. To induce diabetes, alloxan 150 mg/kg, intraperitoneal (i.p.) single dose was administered to groups B, C, and D. Blood glucose and serum lipids [Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoproteins (LDL), and High Density Lipoproteins (HDL)] and the atherogenic index were estimated after one week. For mechanism of antidiabetic action glycogen estimation on the liver, cardiac and skeletal muscle, and intestinal glucose absorption was done. Group B showed a significant (P<0.01) increase in blood glucose as compared to group A. Groups C and D showed significant decrease (P<0.01) in blood glucose level in comparison to group B. The test drug showed a significant (P<0.01) increase in glycogen content in the liver, cardiac, and skeletal muscle; it significantly (P<0.01) reduced intestinal glucose absorption. Groups C and D showed significant (P<0.01) decrease in serum TC, TG, LDL, and AI as compared to Group B, which showed a significant (P<0.01) increase. Groups C and D showed significant (P<0.01) increase in serum HDL as compared to Group B, which showed a significant (P<0.01) decrease in all values. P. granatum leaves possess significant antidiabetic and antihyperlipidemic activity.


Cognitive aid in telecommunication information handover - prospective field experimental open-label study.
Health care providers are paying more and more attention to clinical handovers. Previous studies have found that poor handovers resulted in adverse effects for patients. This study aims to determine the effectiveness of the standardized pre-notification process, from emergency medical services (EMS) to in-hospital care, with specific cognitive aid based on ATMIST. In February 2018, a prospective field test of the effectiveness of a standardized handover tool based on the ATMIST acronym was conducted in 11 Prague hospitals. The Emergency Medical Dispatch Centre used the form to record the information from the Crews (Protocol 1). The hospital dispatch centre (Protocol 2) used the same form to record the information from the EMS Dispatching. Both protocols were then compared and monitored to determine whether the information from the field was correctly transferred to the hospital. Signature items from the ATMIST form in different groups were empirically set to find out if the level of awareness of the personnel differs between groups. Two hundred and sixty-nine Protocols 1 and 2 (37.41% of all pre-notifications) were analysed. There were 7,262 possible pieces of information to be transferred in total. 82.78% (n=6012) of all information was transferred correctly. The group analyses show no differences between the clinical condition of the patient and the awareness of the health care providers. This is first study evaluating the use of a standardized handover tool for telecommunication handover. The clinical condition of patients did not play any role in how the information was transferred.


Hallucinating Face Image by Regularization Models in High-Resolution Feature Space.
In this paper, we propose two novel regularization models in patch-wise and pixel-wise respectively, which are efficient to reconstruct high-resolution (HR) face image from low-resolution (LR) input. Unlike the conventional patch-based models which depend on the assumption of local geometry consistency in LR and HR spaces, the proposed method directly regularizes the relationship between the target patch and corresponding training set in the HR space. It avoids to deal with the tough problem of preserving local geometry in various resolutions. Taking advantage of kernel function in efficiently describing intrinsic features, we further conduct the patch-based reconstruction model in the high-dimensional kernel space for capturing nonlinear characteristics. Meanwhile, a pixel-based model is proposed to regularize the relationship of pixels in the local neighborhood, which can be employed to enhance the fuzzy details in the target HR face image. It privileges the reconstruction of pixels along the dominant orientation of structure, which is useful for preserving high-frequency information on complex edges. Finally, we combine the two reconstruction models into a unified framework. The output HR face image can be finally optimized by performing an iterative procedure. Experimental results demonstrate that the proposed face hallucination method produces superior performance than the state-of-the-art methods.


NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis.
Tumor-associated macrophages (TAMs) play substantial roles in tumor growth, invasion, and metastasis. Nuclear factor of activated T cell (NFAT1) has been shown to promote melanoma growth and metastasis in vivo We herein aim to investigate whether NFAT1 is capable to promote melanoma growth and metastasis by influencing TAM properties. Melanoma-conditioned TAMs were obtained from human monocytes after incubation with conditioned medium from A375 cell culture. The phenotype of the macrophages was detected. Cell proliferation, migration, and invasion were evaluated. Human malignant melanoma tissues exhibited increased CD68+-macrophage infiltration and NFAT1 expression compared with the normal pigmented nevus tissues. Melanoma-conditioned TAMs displayed M2-like phenotype. Melanoma-conditioned TAMs also promoted proliferation, migration, and invasion of human malignant melanoma cell lines A375 and WM451. Furthermore, NFAT1 expression in TAMs was significantly increased compared with the M0 group. NFAT1 overexpression significantly strengthened the melanoma-conditioned TAM-mediated promotion of cell migration and invasion in A375 and WM451 cells, whereas NFAT1 knockdown exerted the opposite effects. Moreover, NFAT1 overexpression in melanoma-conditioned TAMs promoted CD68+-macrophage infiltration, tumor growth, and metastasis in vivo NFAT1 may play a critical role in enhancing the TAM-mediated promotion of growth and metastasis in malignant melanoma.


Comparison of the optical image quality in the periphery of phakic and pseudophakic eyes.
The natural lens may provide some compensatory optical effect in the periphery. When it is substituted by an IOL during cataract surgery, the quality of the peripheral optics will be modified. We compared the peripheral image quality in the eyes of patients with one eye implanted with a monofocal IOL and the fellow eye still with the natural precataract lens. We used a scanning peripheral Hartmann-Shack wavefront sensor to measure the central 80° of visual angle along the horizontal meridian. Twelve patients with ages ranging between 65 to 81 years were evaluated. The results of the phakic and pseudophakic eyes were compared using the spherical equivalent, astigmatism, higher order aberrations, and the Strehl ratio. The statistical differences at each angle between the two eyes were evaluated. In the eyes implanted with IOLs, the peripheral mean spherical equivalent was slightly more myopic than in the phakic eyes, although the differences were only significant for some angles. Astigmatism increased much faster in the periphery for the pseudophakic eyes as compared with the phakic eyes. The mean values were significantly different from 9° and 17° outwards at the temporal and nasal retina, respectively. As an example, at 30°, eyes implanted with IOLs presented 1.5 diopters (D) of additional astigmatism. The higher order aberrations were not significantly different between the two groups. Eyes implanted with monofocal IOLs present more astigmatism in the periphery than the healthy older eyes. This suggests that the crystalline lens provides a beneficial effect to partially compensate off-axis astigmatism. The degradation of the peripheral retinal image may reduce the pseudophakic patient's performance in common visual tasks.


Antioxidant activity of 5-aminosalicylic acid against peroxidation of phosphatidylcholine liposomes in the presence of alpha-tocopherol: a synergistic interaction?
Oxidative damage has been implicated in the pathogenesis of inflammatory bowel diseases. 5-Aminosalicylic acid (5-ASA), the anti-inflammatory drug commonly used in the treatment of this condition, has been shown to possess antioxidant properties considered to be of particular importance in the pathologic context of these diseases. However, its action mechanisms are far from being completely elucidated, especially regarding its antioxidant properties in the presence of endogenous antioxidants such as alpha-tocopherol (alpha-T), the major defence system of biomembranes against lipid peroxidation. In this study we investigated the scavenging activity of 5-ASA toward peroxyl radicals generated at different sites of soybean PC liposomes, used as model membranes, either alone or in combination with alpha-T. 5-ASA, separately, shows strong scavenging activity toward peroxyl radicals generated in the aqueous phase by thermal decomposition of 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), inducing a clear concentration-dependent inhibition period, either of oxygen consumption or of conjugated diene hydroperoxides production. HPLC analysis indicates that 5-ASA is consumed, at a constant rate, throughout the reaction, and when the inhibition period is over, the oxidation rate is resumed. On the other hand, apart from a slight decrease in the rate of oxidation, 5-ASA is unable to suppress efficiently lipid peroxidation, when the reaction starts inside the lipid membranes, by thermal decomposition of 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). When 5-ASA is combined with alpha-T, and the oxidation starts in the aqueous phase, an additive inhibitory effect occurs between both compounds. 5-ASA protects efficiently alpha-T against initial attack from AAPH-peroxyl radicals, delaying its consumption. On the other hand, if the reaction starts inside the lipid bilayer, 5-ASA prolongs significantly the inhibitory period produced by alpha-T on the initial rate of oxidation, as measured by oxygen consumption and conjugated diene hydroperoxides. This inhibitory effect points to a synergistic interaction between 5-ASA and alpha-T, since 5-ASA, by itself, is unable to suppress the oxidation reaction. Therefore, 5-ASA reveals an important cooperative effect with alpha-T, either affording an efficient protection to this antioxidant compound, when free radicals are generated in the aqueous site, or potentiating its activity when oxidation is initiated inside the lipid bilayer. Taking into account that the ascorbic acid content decreases significantly in the inflamed mucosa of patients with inflammatory bowel diseases, our data are, certainly, a very important contribution to the knowledge of the anti-inflammatory action of 5-ASA.


Self-Advocacy Services for People With Intellectual and Developmental Disabilities: A National Analysis.
Self-advocacy plays an important role in facilitating the empowerment of people with intellectual and developmental disabilities (IDD), and helps people with IDD develop the skills necessary for the participant direction of services. The purpose of this study was to examine Medicaid Home and Community Based Services (HCBS) 1915(c) waivers across the nation to determine how states were utilizing self-advocacy services for people with IDD. Findings revealed approximately half of waivers provided self-advocacy services; however, less than .01% of waiver spending was projected for stand-alone self-advocacy services. States need to expand the provision of self-advocacy services for people with IDD in order to strengthen their ability to direct their waiver services and exercise their rights.


Beyond genomics-technological advances improving the molecular characterization and precision treatment of heart failure.
Dilated cardiomyopathy (DCM) is a major cause of heart failure and cardiovascular mortality. In the past 20 years, there has been an overwhelming focus on developing therapeutics that target common downstream disease pathways thought to be involved in all forms of heart failure independent of the initial etiology. While this strategy is effective at the population level, individual responses vary tremendously and only approximately one third of patients receive benefit from modern heart failure treatments. In this perspective, we propose that DCM should be considered as a collection of diseases with a common phenotype of left ventricular dilation and systolic dysfunction rather than a single disease entity, and that mechanism-based classification of disease subtypes will revolutionize our understanding and clinical approach towards DCM. We discuss how these efforts are central to realizing the potential of precision medicine and how they are empowered by the development of new tools that allow investigators to strategically employ genomic and transcriptomic information. Finally, we outline an investigational strategy to (1) define DCM at the patient level, (2) develop new tools to model and mechanistically dissect subtypes of human heart failure, and (3) harness these insights for the development of precision therapeutics.


Enteropathogenic Escherichia coli Uses NleA to Inhibit NLRP3 Inflammasome Activation.
Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are related strains capable of inducing severe gastrointestinal disease. For optimal infection, these pathogens actively modulate cellular functions through the deployment of effector proteins in a type three secretion system (T3SS)-dependent manner. In response to enteric pathogen invasion, the Nod-like receptor pyrin domain containing (NLRP) inflammasome has been increasingly recognized as an important cytoplasmic sensor against microbial infection by activating caspase-1 and releasing IL-1β. EPEC and EHEC are known to elicit inflammasome activation in macrophages and epithelial cells; however, whether the pathogens actively counteract such innate immune responses is unknown. Using a series of compound effector-gene deletion strains of EPEC, we screened and identified NleA, which could subdue host IL-1β secretion. It was found that the reduction is not because of blocked NF-κB activity; instead, the reduction results from inhibited caspase-1 activation by NleA. Immunostaining of human macrophage-like cells following infection revealed limited formation of inflammasome foci with constituents of total caspase-1, ASC and NLRP3 in the presence of NleA. Pulldown of PMA-induced differentiated THP-1 lysate with purified MBP-NleA reveals that NLRP3 is a target of NleA. The interaction was verified by an immunoprecipitation assay and direct interaction assay in which purified MBP-NleA and GST-NLRP3 were used. We further showed that the effector interacts with regions of NLRP3 containing the PYD and LRR domains. Additionally, NleA was found to associate with non-ubiquitinated and ubiquitinated NLRP3 and to interrupt de-ubiquitination of NLRP3, which is a required process for inflammasome activation. Cumulatively, our findings provide the first example of EPEC-mediated suppression of inflammasome activity in which NieA plays a novel role in controlling the host immune response through targeting of NLRP3.