Timing of archaic hominin occupation of Denisova Cave in southern Siberia.
The Altai region of Siberia was inhabited for parts of the Pleistocene by at least two groups of archaic hominins-Denisovans and Neanderthals. Denisova Cave, uniquely, contains stratified deposits that preserve skeletal and genetic evidence of both hominins, artefacts made from stone and other materials, and a range of animal and plant remains. The previous site chronology is based largely on radiocarbon ages for fragments of bone and charcoal that are up to 50,000 years old; older ages of equivocal reliability have been estimated from thermoluminescence and palaeomagnetic analyses of sediments, and genetic analyses of hominin DNA. Here we describe the stratigraphic sequences in Denisova Cave, establish a chronology for the Pleistocene deposits and associated remains from optical dating of the cave sediments, and reconstruct the environmental context of hominin occupation of the site from around 300,000 to 20,000 years ago.


Sustainable sources need reliable standards.
This review discusses the challenges within the research area of modern biomass fractionation and valorization. The current pulping industry focuses on pulp production and the resulting cellulose fiber. Hemicellulose and lignin are handled as low value streams for process heat and the regeneration of process chemicals. The paper and pulp industry have therefore developed analytical techniques to evaluate the cellulose fiber, while the other fractions are given a low priority. In a strive to also use the hemicellulose and lignin fractions of lignocellulosic biomass, moving towards a biorefining concept, there are severe shortcomings with the current pulping techniques and also in the analysis of the biomass. Lately, new fractionation techniques have emerged which valorize a larger extent of the lignocellulosic biomass. This progress has disclosed the shortcomings in the analysis of mainly the hemicellulose and lignin structure and properties. To move the research field forward, analytical tools for both the raw material, targeting all the wood components, and the generated fractions, as well as standardized methods for evaluating and reporting yields are desired. At the end of this review, a discourse on how such standardizations can be implemented is given.


Recalibrating intellectual property rights to enhance translational research collaborations.
Multisectoral collaborative models for drug and therapeutic research and development (R&D) are emerging, requiring a recalibration of how intellectual property rights (IPRs) are used. Although these models appear promising, little study has been conducted on the optimal blend of sharing and exclusion as mediated through the proactive use or nonuse of IPRs. This Commentary is a call for a combination of theoretical and empirical analyses to build a comprehensive understanding of the interplay between formal IP laws, institutions that administer and manage IPRs, and the use of IPRs in practice to better construct and manage collaborations. Such analyses require outcome metrics formulated to measure the success of therapeutic outcomes and to capture the complexity of a highly networked R&D environment.


Characterization of B-cell and monocyte antibodies in recipient sera and in eluates from rejected kidney allografts.
The specificity of B-cell antibodies developing in kidney transplant recipients was investigated by blocking with monoclonal anti-DR and chicken anti-human IA antibody. Among 34 recipients who ultimately rejected their kidney allograft, 35% displayed antibodies against B cells before transplantation, most of which were blocked by the anti-DR reagents. Thirty-three of 34 recipients developed B-cell lymphocytotoxins after nephrectomy, and over half of these were not blocked by monoclonal anti-DR. B-cell antibodies were found also in the majority of the kidney eluates, and most of them were shown to be directed against HLA-DR antigens, Monocyte-specific antibodies, which were not blocked by chicken anti-human IA serum, were frequently found in eluates from kidney allografts undergoing rejection. The methods described appear to be useful for the characterization of B-cell and monocyte antibodies developing in kidney transplant recipients. The possibility of correlation with allograft outcome is currently being investigated.


Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier.
Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aβ) from brain are thought to contribute to Alzheimer's disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood-brain barrier. CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aβ1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells. These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aβ transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease.


Current status of cadmium as an environmental health problem.
Cadmium is a toxic metal occurring in the environment naturally and as a pollutant emanating from industrial and agricultural sources. Food is the main source of cadmium intake in the non-smoking population. The bioavailability, retention and toxicity are affected by several factors including nutritional status such as low iron status. Cadmium is efficiently retained in the kidney (half-time 10-30 years) and the concentration is proportional to that in urine (U-Cd). Cadmium is nephrotoxic, initially causing kidney tubular damage. Cadmium can also cause bone damage, either via a direct effect on bone tissue or indirectly as a result of renal dysfunction. After prolonged and/or high exposure the tubular injury may progress to glomerular damage with decreased glomerular filtration rate, and eventually to renal failure. Furthermore, recent data also suggest increased cancer risks and increased mortality in environmentally exposed populations. Dose-response assessment using a variety of early markers of kidney damage has identified U-Cd points of departure for early kidney effects between 0.5 and 3 microg Cd/g creatinine, similar to the points of departure for effects on bone. It can be anticipated that a considerable proportion of the non-smoking adult population has urinary cadmium concentrations of 0.5 microg/g creatinine or higher in non-exposed areas. For smokers this proportion is considerably higher. This implies no margin of safety between the point of departure and the exposure levels in the general population. Therefore, measures should be put in place to reduce exposure to a minimum, and the tolerably daily intake should be set in accordance with recent findings.


Sequence and structure of a human glucose transporter.
The amino acid sequence of the glucose transport protein from human HepG2 hepatoma cells was deduced from analysis of a complementary DNA clone. Structural analysis of the purified human erythrocyte glucose transporter by fast atom bombardment mapping and gas phase Edman degradation confirmed the identity of the clone and demonstrated that the HepG2 and erythrocyte transporters are highly homologous and may be identical. The protein lacks a cleavable amino-terminal signal sequence. Analysis of the primary structure suggests the presence of 12 membrane-spanning domains. Several of these may form amphipathic alpha helices and contain abundant hydroxyl and amide side chains that could participate in glucose binding or line a transmembrane pore through which the sugar moves. The amino terminus, carboxyl terminus, and a highly hydrophilic domain in the center of the protein are all predicted to lie on the cytoplasmic face. Messenger RNA species homologous to HepG2 glucose transporter messenger RNA were detected in K562 leukemic cells, HT29 colon adenocarcinoma cells, and human kidney tissue.


Examining Provisions Related to Consent in the Revised Common Rule.
The long-standing overarching policy governing research with human subjects conducted and supported by most federal agencies and departments in the United States, known as the Common Rule, has recently been revised, with most requirements slated to become effective in 2018. Although there are multiple alterations to the current regulations, some of the most significant changes aim to enhance consent for research. While some of the particular provisions in this regard will be easy to apply and promise to help meet this goal, others may be more challenging to implement despite their intuitive appeal. In this article, I examine some of the provisions in the revised Common Rule that relate to consent: (1) new required consent elements; (2) the goal of comprehension in the consent process; (3) consent forms; and (4) broad consent. By raising issues about these provisions now and suggesting possible ways to overcome their potential shortfalls, the hope is that future efforts can be taken to help clarify and appropriately implement them.


Feasibility Study of Human Corneal Endothelial Cell Transplantation Using an In Vitro Human Corneal Model.
To test the feasibility of a cell therapy approach to treat corneal endothelial (CE) disorders using an in vitro model of human corneal decompensation. A CE decompensation model was established by removal of the Descemet membrane/endothelium complex from cadaveric human corneas in an air interface organ culture system (group 2) and compared with normal corneas (group 1). The posterior stroma of decompensated corneas was seeded with immortalized human corneal endothelial cells (HCEC-12) in group 3 and passage 0 primary human CE cells in group 4 corneas. Functional effects on stromal thickness were determined with histological analysis 3 to 10 days after cell therapy treatment. Removal of the Descemet membrane/endothelium complex in group 2 corneas resulted in a stromal thickness of 903 ± 86 μm at 12 hours compared with 557 ± 72 μm in group 1 corneas. Stromal thickness reduced from 1218 ± 153 μm to 458 ± 90 μm (63% ± 6%, P = 0.001) after cell transplantation in group 3 and from 1100 ± 86 μm to 489 ± 94 μm (55% ± 7%, P = 0.00004) in group 4. Posttransplantation histology demonstrated formation of a monolayer of corneal endothelium attached to the posterior stromal surface. Direct transplantation of cultured human CE cells and immortalized HCEC-12 to bare posterior corneal stroma resulted in formation of an endothelial monolayer and restoration of stromal hydration to physiological thickness, demonstrating the feasibility of cell therapy in treatment of CE decompensation in a human in vitro model.


Fluorinated Thiophene-Phenylene Co-Oligomers for Optoelectronic Devices.
Organic optoelectronics requires materials combining bright luminescence and efficient ambipolar charge transport. Thiophene-phenylene co-oligomers (TPCOs) are promising highly emissive materials with decent charge-carrier mobility; however, they typically show poor electron injection in devices, which is usually assigned to high energies of their lowest unoccupied molecular orbitals (LUMOs). A widely used approach to lower the frontier orbitals energy levels of a conjugated molecule is its fluorination. In this study, we synthesized three new fluorinated derivatives of one of the most popular TPCOs, 2,2'-(1,4-phenylene)bis[5-phenylthiophene] (PTPTP) and studied them by cyclic voltammetry, absorption, photoluminescence, and Raman spectroscopies. The obtained data reveal a positive effect of fluorination on the optoelectronic properties of PTPTP: LUMO levels are finely tuned, and photoluminescence quantum yield and absorbance are increased. We then grew crystals from fluorinated PTPTPs, resolved their structures, and showed that fluorination dramatically affects the packing motif and facilitates π-stacking. Finally, we fabricated thin-film organic field-effect transistors (OFETs) and demonstrated a strong impact of fluorination on charge injection/transport for both types of charge carriers, namely, electrons and holes. Specifically, balanced ambipolar charge transport and electroluminescence were observed only in the OFET active channel based on the partially fluorinated PTPTP. The obtained results can be extended to other families of conjugated oligomers and highlight the efficiency of fluorination for rational design of organic semiconductors for optoelectronic devices.


Monomodal Ultrahigh-Molar-Mass Polycarbonate Homopolymers and Diblock Copolymers by Anionic Copolymerization of Epoxides with CO2.
Whatever the chemistry used for the synthesis of aliphatic polycarbonates, in particular, those of high molar mass, the adventitious presence of water leads to bimodal GPC traces and affords polycarbonate samples of uncontrolled and unpredictable molar masses. It appears that among all reagents used in the copolymerization of CO2 and epoxides, CO2 is the most difficult one to dry. To address this issue, triisobutylaluminum (TiBA) was employed in this work to dry CO2 through a bubbling method; its drying capability was investigated in the context of the copolymerization of CO2 with epoxides initiated by onium chloride in the presence of triethylborane (TEB). It was then compared to the efficiency of other already reported drying agents such as phosphorus pentoxide, molecular sieves and commercially available CO2 purifiers. With TiBA-dried CO2, its copolymerizations respectively with propylene oxide (PO) and cyclohexene oxide (CHO) could be successfully achieved in a wide range of degrees of polymerization (DP), with the value of DP as high as 16000. Diblock copolymers poly(propylene carbonate-b-cyclohexene carbonate) (PPC-b-PCHC) could also be prepared through sequential addition of epoxide monomers. The polycarbonates obtained under the conditions were all well-defined as characterized by NMR, GPC, triple detector-GPC, and differential scanning calorimetry (DSC).


Identification of G1 kinase activity for cdk6, a novel cyclin D partner.
A family of vertebrate cdc2-related kinases has been identified, and these kinases are candidates for roles in cell cycle regulation. Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. Furthermore, we demonstrate that endogenous cdk6 from human cell extracts is an active kinase which can phosphorylate pRB, the product of the retinoblastoma tumor suppressor gene. The activation of cdk6 kinase occurs during mid-G1 in phytohemagglutinin-stimulated T cells, well prior to the activation of cdk2 kinase. This timing suggests that cdk6, and by analogy its homolog cdk4, links growth factor stimulation with the onset of cell cycle progression.


A tale of two papers.
Two papers published in HEREDITAS between 1921 and 1939 show how the attitude towards race biology changed in the course of the interwar period in the Nordic countries. In the early 1920s race biology was seen to constitute a legitimate science. Ordinary human genetics prevailed, however, over race biology already in the very beginning on the pages of HEREDITAS. Population thinking was introduced into the study of human heredity around the year 1930. It effectively contradicted the concept of the race. Interestingly, HEREDITAS does not carry a single paper on eugenics and sterilization. In 1939 we see a final repudiation of the doctrines on race. Times had changed and the National Socialists had usurped the doctrines of race in Germany.


Topography of neuron loss in the retinal ganglion cell layer in human glaucoma.
To determine if retinal ganglion cell (RGC) loss influences the loss of surrounding RGCs to generate clustered patterns of cell death in human glaucoma. It is hypothesised that retinal ganglion cell loss accelerates the loss of surrounding cells to generate, at a local, cellular scale, clustered patterns of retinal of RGC death. The absence of these interactions would result in a diffuse pattern RGC loss. Six glaucomatous retinas (67-83 years old) and six age-matched control retinas (61-89 years old) were prepared as wholemounts and stained by 4',6-diamidino-2-phenylindole (DAPI) solution (3 microg/ml in PBS). An area corresponding to central 14 degrees of the visual field was imaged. The nearest-neighbour distribution was determined for cells in both normal and glaucomatous RGCL. Clustered RGC loss in human glaucoma was observed on a background of diffuse loss. The mean nearest-neighbour distance (NND) of the glaucomatous retinas was significantly higher than with controls (p<0.001). The distribution of NND in glaucomatous retinas was skewed to the higher values with a higher positive kurtosis relative to controls. The quantitative analysis of the pattern of cell loss is supported by the visual inspection of the patterns of cell loss. The nearest-neighbour analysis is consistent with the presence of two patterns of cell loss in the RGCL in glaucoma. While the diffuse of cell loss can account for an overall reduction in the RGC population, an additional non-random pattern is consistent with the hypothesis that RGC loss has a local influence on the viability of surrounding cells.


A combination of ascorbic acid and α-tocopherol or a combination of Mg and Zn are both able to reduce the adverse effects of lindane-poisoning on rat brain and liver.
The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of supplementation with ascorbic acid (Vit C) and α-tocopherol (Vit E) or with Mg and Zn upon lindane-induced damages in liver and brain. Under our experimental conditions, lindane poisoning (5mg/kg body weight per day for 3 days) resulted in (1) an increased level of plasma glucose, cholesterol and triglycerides, (2) an increased activity of LDH, ALP, AST, ALT, (3) an oxidative stress in liver and brain as revealed by an increased level of lipids peroxidation (TBARS) and a decrease of glutathione-peroxidase, superoxide dismutase and catalase activities in liver and brain. In conclusion, both Vit C+E or Mg+Zn treatments display beneficial effects upon oxidative stress induced by lindane treatment in liver and brain.


High-dose fish oil and antioxidants in Crohn's disease and the response of bone turnover: a randomised controlled trial.
Crohn's disease is associated with altered bone turnover that may be influenced by nutritional status, the systemic inflammatory response, cytokine production by circulating (peripheral blood) mononuclear cells (PBMC) and antioxidant micronutrient intake. High-dose fish oil is associated with reductions in disease relapse and inflammatory markers, and modulates PBMC function. The effect of fish oil plus antioxidants on bone turnover and PBMC function (the production of interferon-gamma and prostaglandin E2) in Crohn's disease was investigated in a randomised-controlled trial. Patients with currently or recently raised biochemical markers of inflammation (C-reactive protein > or = 6.9 mg/l or erythrocyte sedimentation rate > or =18 mm/h) received fish oil (providing 2.7 g/d EPA and DHA) and antioxidants (vitamins A, C and E, and Se) (n 31) or placebo (n 30) for 24 weeks. Bone turnover was assessed by measuring the concentrations of urinary deoxypyridinoline (bone resorption) and serum osteocalcin (bone formation). Fish oil plus antioxidants were associated with increases in EPA, DHA Se in plasma (all P < 0.01), and with a reduction in interferon-gamma production by mitogen-stimulated PBMC, which demonstrated a negative correlation with deoxypyridinoline/creatinine:osteocalcin ratio (r - 0.33, P = 0.009). There were no differences between the groups at 24 weeks in the response of deoxypyridinoline or osteocalcin or their ratio, or in nutritional status. Dietary supplementation in Crohn's disease with high intakes of EPA and DHA, as fish oil, plus antioxidants was associated with a modulated production of interferon-gamma by PBMC but not altered indices of bone turnover.


The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells.
We demonstrate that the presentation of LRP and the subsequent uptake of its ligands by malignant cells are both strongly regulated by MT1-MMP. Because LRP is essential for the clearance of multiple ligands, these findings have important implications for many pathophysiological processes including the pericellular proteolysis in neoplastic cells as well as the fate of the soluble matrix-degrading proteases such as MMP-2. MT1-MMP is a key protease in cell invasion and a physiological activator of MMP-2. Cellular LRP consists of a non-covalently associated 515-kDa extracellular alpha-chain (LRP-515) and an 85-kDa membrane-spanning beta-chain, and plays a dual role as a multifunctional endocytic receptor and a signaling molecule. Through the capture and uptake of several soluble proteases, LRP is involved in the regulation of matrix proteolysis. LRP-515 associates with the MT1-MMP catalytic domain and is highly susceptible to MT1-MMP proteolysis in vitro. Similar to MT1-MMP, the metalloproteinases MT2-MMP, MT3-MMP and MT4-MMP also degrade LRP. The N-terminal and C-terminal parts of the LRP-515 subunit are resistant and susceptible, respectively, to MT1-MMP proteolysis. In cells co-expressing LRP and MT1-MMP, the proteolytically competent protease decreases the levels of cellular LRP and releases its N-terminal portion in the extracellular milieu while the catalytically inert protease co-precipitates with LRP. These events implicate MT1-MMP, not only in the activation of MMP-2, but also in the mechanisms that control the subsequent fate of MMP-2 in cells and tissues.


Antiviral Responses and Biological Concequences of Piscine orthoreovirus Infection in Salmonid Erythrocytes.
Salmonid red blood cells are the main target cells for Piscine orthoreovirus (PRV). Three genotypes of PRV (PRV-1,2,3) infect Atlantic salmon (Salmo salar), Chinook salmon (Onchorhynchus tshawytscha), Coho salmon (Oncorhynchus kisutch), rainbow trout (Onchorhynchus mykiss) and brown trout (Salmo trutta), and can cause diseases like heart and skeletal muscle inflammation (HSMI), jaundice syndrome, erythrocyte inclusion body syndrome (EIBS) and proliferative darkening syndrome (PDS). Purified PRV administrated to fish has proven the causality for HSMI and EIBS. During the early peak phase of infection, salmonid erythrocytes are the main virus-replicating cells. In this initial phase, cytoplasmic inclusions called "virus factories" can be observed in the erythrocytes, and are the primary sites for the formation of new virus particles. The PRV-infected erythrocytes in Atlantic salmon mount a strong long-lasting innate antiviral response lasting for many weeks after the onset of infection. The antiviral response of Atlantic salmon erythrocytes involves upregulation of potential inhibitors of translation. In accordance with this, PRV-1 protein production in erythrocytes halts while virus RNA can persist for months. Furthermore, PRV infection in Coho salmon and rainbow trout are associated with anemia, and in Atlantic salmon lower hemoglobin levels are observed. Here we summarize and discuss the recently published findings on PRV infection, replication and effects on salmonid erythrocytes, and discuss how PRV can be a useful tool for the study of innate immune responses in erythrocytes, and help reveal novel immune functions of the red blood cells in fish.


Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia.
The effects of chlorogenic acid (CA) on hepatic glucose output, blood glucose levels and on glucose tolerance were analysed. Hepatic uptake of CA and its effects on hepatic catabolism of L-alanine and glucose-6-phosphatase (G-6-Pase) activity were also evaluated. CA (1 mM) inhibited about 40% of G-6-Pase activity (p < 0.05) in the microsomal fraction of hepatocytes, but no effect was observed on production of glucose from gluconeogenesis or on L-alanine catabolism, at various concentrations of CA (0.33, 0.5 and 1 mM), in liver perfusion experiments. Since there were indications of a lack of uptake of CA by the liver, it is possible that this compound did not reach sufficiently high intracellular levels to inhibit the target enzyme. Accordingly, intravenous administration of CA also failed to provoke a reduction in blood glucose levels. However, CA did promote a significant reduction (p < 0.05) in the plasma glucose peak at 10 and 15 min during the oral glucose tolerance test, probably by attenuating intestinal glucose absorption, suggesting a possible role for it as a glycaemic index lowering agent and highlighting it as a compound of interest for reducing the risk of developing type 2 diabetes.


Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries.
Stress ulcer prophylaxis (SUP) may decrease the incidence of gastrointestinal bleeding in patients in the intensive care unit (ICU), but the risk of infection may be increased. In this study, we aimed to describe SUP practices in adult ICUs. We hypothesised that patient selection for SUP varies both within and between countries. Adult ICUs were invited to participate in the survey. We registered country, type of hospital, type and size of ICU, preferred SUP agent, presence of local guideline, reported indications for SUP, criteria for discontinuing SUP, and concerns about adverse effects. Fisher's exact test was used to assess differences between groups. Ninety-seven adult ICUs in 11 countries participated (eight European). All but one ICU used SUP, and 64% (62/97) reported having a guideline for the use of SUP. Proton pump inhibitors were the most common SUP agent, used in 66% of ICUs (64/97), and H2-receptor antagonists were used 31% (30/97) of the units. Twenty-three different indications for SUP were reported, the most frequent being mechanical ventilation. All patients were prescribed SUP in 26% (25/97) of the ICUs. Adequate enteral feeding was the most frequent reason for discontinuing SUP, but 19% (18/97) continued SUP upon ICU discharge. The majority expressed concern about nosocomial pneumonia and Clostridium difficile infection with the use of SUP. In this international survey, most participating ICUs reported using SUP, primarily proton pump inhibitors, but many did not have a guideline; indications varied considerably and concern existed about infectious complications.


Supplementing healthy women with up to 5.0 g/d of L-tryptophan has no adverse effects.
Because of the frequent use of L-tryptophan (L-Trp) in dietary supplements, determination of the no-observed-adverse-effect-level is desirable for public health purposes. We therefore assessed the no-observed-adverse-effect-level for L-Trp and attempted to identify a surrogate biomarker for excess L-Trp in healthy humans. A randomized, double-blind, placebo-controlled, crossover intervention study was performed in 17 apparently healthy Japanese women aged 18-26 y with a BMI of ≈ 20 kg/m(2). The participants were randomly assigned to receive placebo (0 g/d) or 1.0, 2.0, 3.0, 4.0, or 5.0 g/d of L-Trp for 21 d each with a 5-wk washout period between trials. Food intake, body weight, general biomarkers in blood and urine, and amino acid composition in blood and urine were not affected by any dose of L-Trp. Administration of up to 5.0 g/d L-Trp had no effect on a profile of mood states category measurement. The urinary excretion of nicotinamide and its catabolites increased in proportion to the ingested amounts of L-Trp, indicating that participants could normally metabolize this amino acid. The urinary excretion of L-tryptophan metabolites, including kynurenine (Kyn), anthranilic acid, kynurenic acid, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and quinolinic acid (QA), all of which are intermediates of the L-TRP→Kyn→QA pathway, was in proportion to L-Trp loading. The response of 3-HK was the most characteristic of these L-Trp metabolites. This finding suggests that the urinary excretion of 3-HK is a good surrogate biomarker for excess L-Trp ingestion.


Engagement of visual fixation suppresses sensory responsiveness and multisensory integration in the primate superior colliculus.
Neurons in the intermediate and deep layers of the superior colliculus (SC) often exhibit sensory-related activity in addition to discharging for saccadic eye movements. These two patterns of activity can combine so that modifications of the sensory response can lead to changes in orienting behaviour. Can behavioural factors, however, influence sensory activity? In this study of rhesus monkeys, we isolate one behavioural factor, the state of visual fixation, and examine its influences on sensory processing and multisensory integration in the primate SC. Two interleaved fixation conditions were used: a FIX condition requiring exogenous fixation of a visible fixation point; and a FIX-BLINK condition, requiring endogenous fixation in the absence of a visible fixation point. Neurons of the SC were influenced by fixation state, exhibiting both lower levels of sensory activity and reduced multisensory interactions when fixation was exogenously engaged on a visible fixation point. These results are consistent with active visual fixation suppressing responses to extraneous stimuli, and thus demonstrate that sensory processing and multisensory responses in the SC are not dependent solely on the physical properties of the sensory environment, but are also dynamically influenced by the behavioural state of the animal.


Behavioural awareness, interaction and counselling education in audiological rehabilitation: development of methods and application in a pilot study.
In conventional audiological rehabilitation, the hearing therapist interacts with the hearing-impaired person and with significant others. In order to strengthen the personality and self-confidence of the hearing-impaired individual, a different strategy was designed and implemented whereby the pedagogic interaction was directed only towards the hearing-impaired individual, who in turn worked as a tutor/aid/counsellor to the communication partner. On the basis of an interactive communication model, new methods for rehabilitation of subjects with moderate hearing impairment were developed and evaluated in a pilot study on 13 men with noise-induced hearing loss. A course programme was developed with three main active components: (1) increased insight and knowledge; (2) education as counsellors with the ability to focus on the problems of the communication partner; and (3) motivation to change through group discussion and reflexive conversation. Increased insight and knowledge were obtained through test and training experiences in a sound environmental chamber, tutorials and discussions. The pedagogic training focused on helping the hearing-impaired subjects to become able communication counsellors in relation to their interlocutors. An act-react, offensive-defensive paradigm was used in conjunction with transactional analysis. Results of the pilot study were evaluated using questionnaires, interviews and a method of dialogue analysis. The results were evaluated for the hearing-impaired and the partner and in recordings of conversations in the home environment. There were clearly positive cognitive and emotional effects seen in the inquiries and interviews. The observations from the dialogue analysis indicated only small effects, with the exception of the two individuals with the most pronounced functional impairment, for whom dialogue was improved after the course. It was concluded that these new methods could contribute new possibilities in rehabilitation programmes, emphasizing the shared responsibility for communication and the unique competence and abilities of the hearing-impaired person.


Pain management and satisfaction in postsurgical patients.
To examine the relationship between patient satisfaction and the incidence of severe and enduring pain through a health board wide hospital satisfaction questionnaire. The incidence and management of acute postoperative pain and its relationship to patient satisfaction have been of great interest to clinicians over the last 20 years. Evidence suggests that despite many moves to address this problem with the advent of acute pain nurse specialists and dedicated pain teams, severe and enduring pain continues to be a problem. However, patients appear to report high satisfaction levels. The study design was a postal questionnaire the results of which were analysed statistically. The postal questionnaire was sent to patients who had been discharged from acute hospitals in one health board in the previous two weeks. A total of three large acute hospitals were included. The data were analysed to produce descriptive statistics for all patients on the pain questions and then for patients with severe and enduring pain on the variables of age, gender, ethnic group, responses to pain questions and type of admission. Twenty-six percent of patients reported having pain all or most of the time. Patients suffering from severe and enduring pain were younger females. Acute postoperative pain continues to be a problem, although patients continue reporting moderate satisfaction levels. Acute postoperative pain is an ongoing issue for postsurgical patients. It is crucial to understand and recognise issues that can adversely contribute to increased pain severity.


Whole-grain intake as a marker of healthy body weight and adiposity.
To review evidence relating to the consumption of whole grains and healthy body weight (BW). Systematic review and analysis of observational studies reporting whole-grain consumption and measures of BW and adiposity, including the effect on macronutrient intakes and lifestyle factors. Medline and other databases were searched for the period 1990 to 2006 to produce a full reference list; observational studies were retained for further analysis if they included an appropriate control group and reported whole-grain intake and body mass index (BMI) or a measure of adiposity. Fifteen trials were identified which included data from 119 829 male and female subjects aged 13 years and over. The combined and weighted mean difference in BMI from 15 studies representing 20 treatment groups (n = 119 829) using a random-effects model was 0.630 kg/m2 lower when high versus low whole-grain intake was compared, P < 0.0001 (95 % confidence interval (CI) 0.460, 0.800 kg/m2). In high consumers, adiposity assessed as waist circumference was reduced by 2.7 (95 % CI 0.2, 5.2) cm, P = 0.03 (six data sets, n = 4178) or as waist:hip ratio by 0.023 (95 % CI 0.016, 0.030), P < 0.0001 (four data sets, n = 20 147). Higher intake of whole grains led to increased dietary fibre intake (9 g, P < 0.01), while total and saturated fat intakes decreased by 11 g and 3.9 g, respectively. A higher intake of whole grains (about three servings per day) was associated with lower BMI and central adiposity. In addition, people who consume more whole grains are likely to have a healthier lifestyle as fewer of them smoke, they exercise more frequently and they tend to have lower fat and higher fibre intakes.


The mismatch negativity as an index of cognitive decline for the early detection of Alzheimer's disease.
Evidence suggests that Alzheimer's disease (AD) is part of a continuum, characterized by long preclinical phases before the onset of clinical symptoms. In several cases, this continuum starts with a syndrome, defined as mild cognitive impairment (MCI), in which daily activities are preserved despite the presence of cognitive decline. The possibility of having a reliable and sensitive neurophysiological marker that can be used for early detection of AD is extremely valuable because of the incidence of this type of dementia. In this study, we aimed to investigate the reliability of auditory mismatch negativity (aMMN) as a marker of cognitive decline from normal ageing progressing from MCI to AD. We compared aMMN elicited in the frontal and temporal locations by duration deviant sounds in short (400 ms) and long (4000 ms) inter-trial intervals (ITI) in three groups. We found that at a short ITI, MCI showed only the temporal component of aMMN and AD the frontal component compared to healthy elderly who presented both. At a longer ITI, aMMN was elicited only in normal ageing subjects at the temporal locations. Our study provides empirical evidence for the possibility to adopt aMMN as an index for assessing cognitive decline in pathological ageing.


Breastfeeding Practices in Georgia: Rural-Urban Comparison and Trend Analyses Based on 2004-2013 PRAMS Data.
The Centers for Disease Control and Prevention identified rural mothers as a priority population for targeted breastfeeding promotion programs. In Georgia, breastfeeding rates lag behind the national ones. This study examines rural-urban differences and trends over time in breastfeeding initiation and continuation (breastfeeding for at least 8 weeks) among women with a live birth from 2004 to 2013 in Georgia. This observational study is based on the Pregnancy Risk Assessment Monitoring System data. The National Center for Health Statistics urban-rural continuum codes were used to operationalize mother's county of residence. Prevalence of breastfeeding was estimated from the logistic regression models, unadjusted and adjusted for sociodemographic and health-related characteristics. In both unadjusted and adjusted analyses, significantly fewer rural (60.2%, 95% CI: 57.5-62.9 and 64.5%, 95% CI: 61.3-67.6, respectively) than urban (74.9%, 95% CI: 73.4-76.4 and 72.9%, 95% CI: 71.1-74.6, respectively) mothers initiated breastfeeding (P < .001). Similar rural-urban differences persisted throughout the 10-year study period-approximately 15 percentage points (pps) in unadjusted and over 8 pps in adjusted analyses (Ps < .001). Fewer rural (35.9%, CI: 32.4-39.3) than urban (44.7%, CI: 42.7-46.7) mothers continued breastfeeding, but this difference was significant overall and over time in unadjusted analyses only (P < .001). Interventions increasing breastfeeding initiation in rural mothers can be expected to lead to cumulative increase in breastfeeding practices among Georgia women. Equally important, however, is to increase the rates of breastfeeding initiation in all women and support for all women to continue breastfeeding for longer duration.


Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis.
The initiation of mammalian puberty and the maintenance of female reproductive cycles are events controlled by hypothalamic neurons that secrete the decapeptide gonadotropin-releasing hormone (GnRH). GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The hierarchical control of the process is unknown, but it requires coordinated regulation of these cell-cell interactions. Here we report the functional characterization of a gene (termed enhanced at puberty 1 [EAP1]) that appears to act as an upstream transcriptional regulator of neuronal networks controlling female reproductive function. EAP1 expression increased selectively at puberty in both the nonhuman primate and rodent hypothalamus. EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity. Inhibition of EAP1 expression, targeted to the rodent hypothalamus via lentivirus-mediated delivery of EAP1 siRNAs, delayed puberty, disrupted estrous cyclicity, and resulted in ovarian abnormalities. These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.


Dispersion of barium gallogermanate glass.
Gallogermanate glasses are the subject of intense study as a result of their unique combination of physical and optical properties, including transmission from 0.4 to beyond 5.0 microm. These glasses can be easily made into large optics with high-index homogeneity for numerous U.S. Department of Defense and commercial visible-IR window applications such as reconnaissance, missile domes, IR countermeasures, avionics, and collision avoidance on automobiles. These applications require a knowledge of the refractive index of glass throughout the region of transmission. Consequently, we have measured the refractive index of BaO-Ga2O3-GeO2 glass from 0.4 to 5.0 microm and calculated the Sellmeier coefficients required for optical device design.


Variations of melatonin and stress hormones under extended shifts and radiofrequency electromagnetic radiation.
We studied the time-of-day variations in urinary levels of 6-sulphatoxy-melatonin and three stress hormones in operators working fast-rotating extended shifts under radiofrequency electromagnetic radiation (EMR). The excretion rate of the hormones was monitored by radioimmunoassay and spectrofluorimetry at 4-hour intervals in a group of 36 male operators comprising 12 broadcasting station operators, 12 TV station operators, and a control group of 12 satellite station operators. Measuring the time-weighted average (TWA) of EMR exposure revealed a high-level of exposure in broadcasting station operators (TWAmean= 3.10 microW/ cm2, TWAmax = 137.00 microW/cm2), a low-level in TV station operators (TWAmean = 1.89 microW/cm2, TWAmax = 5.24 microW/cm2), and a very low level in satellite station operators. The differences among the groups remained the same after confounding factors were taken into account. Radiofrequency EMR had no effect on the typical diurnal pattern of 6-sulphatoxymelatonin. High-level radiofrequency EMR exposure significantly increased the excretion rates of cortisol (p < 0.001), adrenaline (p = 0.028), and noradrenaline (p < 0.000), whereas changes under low-level exposure did not reach significance. The 24-hour excretion of cortisol and noradrenaline correlated with TWAmean and TWAmax. In conclusion, the excretion of 6-sulphatoxymelatonin retained a typical diurnal pattern under fast-rotating extended shifts and radiofrequency EMR, but showed an exposure-effect relation with stress hormones.


Curcumin attenuates murine lupus via inhibiting NLRP3 inflammasome.
Despite rapid progress in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for novel and more effective interventions. Curcumin, a natural polyphenol compound, has been shown to be anti-inflammatory in various disorders. In this study, we investigated the potential therapeutic value of curcumin in SLE. Lupus-prone female MRL/lpr mice were treated with curcumin. The development and extent of nephritis were assessed by monitoring proteinuria and by histologic analysis. Serum anti-dsDNA levels were measured by enzyme-linked immunosorbent assay. Kidney samples were analyzed by Western blot. In vitro, mouse podocytes were used for investigation in the presence of mouse anti-dsDNA antibody-positive (anti-dsDNA+) serum. Curcumin treatment dramatically decreased proteinuria and renal inflammation. Serum anti-dsDNA levels and spleen size were also reduced by curcumin. In addition, curcumin reduced NLRP3 inflammasome activation in lupus-prone mice. In vitro, curcumin significantly inhibited anti-dsDNA+ serum induced expression of NLRP3 inflammasome in podocytes. Overall, these data demonstrate the potential use of curcumin in SLE treatment.


Recommendations for sepsis management in resource-limited settings.
To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis. The medical literature on sepsis management was reviewed. Specific attention was paid to identify clinical evidence on sepsis management from resource-limited settings. Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, normal heart rate and arterial blood pressure, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, frequent measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation >90%, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, timely administration of adequate antimicrobials, thorough clinical investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. Specific considerations for malaria, puerperal sepsis and HIV/AIDS patients with sepsis are included. Only scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. The presented recommendations may help to improve sepsis management in middle- and low-income countries.


Resveratrol in the management of human cancer: how strong is the clinical evidence?
Among the plethora of biochemical mechanisms engaged by resveratrol in preclinical systems, its anticarcinogenic effects represent some of the most convincing and intriguing. As outlined in this review, there is considerable interest in developing resveratrol for cancer prevention and treatment. The plasma pharmacokinetics of resveratrol in humans are now reasonably well defined, and studies have shown that repeated daily doses up to 1 g are safe and well tolerated, although gastrointestinal toxicity is observed at higher intakes. However, care is needed regarding underlying conditions in specific patient groups, and there is potential for drug interactions at doses greater than 1 gram. Little is known regarding the pharmacodynamic effects of resveratrol in humans, but the observation that it modulates components of the insulin-like growth factor system in the plasma of volunteers is encouraging. While the knowledge base that helps determine whether resveratrol may be useful in cancer management has increased substantially in recent years, important questions remain.


Breast cancer risk in relation to adipose concentrations of organochlorine pesticides and polychlorinated biphenyls in Long Island, New York.
To assess a possible etiological role of organochlorine compounds in breast cancer development on Long Island, a high-risk region of New York State, concentrations of organochlorine pesticides and polychlorinated biphenyls (PCBs) were measured in the adipose tissue of 232 women with breast cancer and 323 hospital controls admitted to surgery for benign breast disease or non-breast-related conditions. Seven pesticide residues and 14 PCB congeners were assayed via a supercritical fluid extraction method followed by gas chromatography with electron capture detection. After adjustment for age and body mass index, which were strongly correlated with organochlorine levels, adipose concentrations of 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, and total polychlorinated biphenyls (PCBs) did not differ significantly between cases and controls. The relative abundance of individual pesticide species and PCB congeners was similar in cases and controls. Odds ratios adjusted for age, BMI, hospital, and race gave no evidence of a dose-response for 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, or total PCBs, whether stratified by estrogen receptor status or not. Breast cancer risk among Long Island residents was not elevated compared with residents of the adjacent New York City borough of Queens. We did not confirm a previously reported association between breast cancer risk and levels of PCB congener 118 (2,3',4,4',5-pentachlorobiphenyl), nor did we observe an association with the most abundant congener 153 (2,2',4,4',5,5'-hexachlorobiphenyl), a strong inducer of phase I enzymes that was reported recently to have estrogenic properties. Only PCB congener 183 (2,2',3,4,4',5',6-heptachlorobiphenyl), which is also an inducer, was significantly associated with risk, with an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.4) in women with adipose levels >5.67 ng/g; the biological importance of this observation is unclear without confirmation in additional studies. Although neither the present nor other studies have provided convincing evidence of an association between body burden of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane and PCBs with cancer of the breast, these compounds are rated as "possible" and "probable" human carcinogens, respectively, by the International Agency for Research on Cancer. Investigations of associations with cancer at other sites should be carried out.


Localization and signaling of G(beta) subunit Ste4p are controlled by a-factor receptor and the a-specific protein Asg7p.
Haploid yeast cells initiate pheromone signaling upon the binding of pheromone to its receptor and activation of the coupled G protein. A regulatory process termed receptor inhibition blocks pheromone signaling when the a-factor receptor is inappropriately expressed in MATa cells. Receptor inhibition blocks signaling by inhibiting the activity of the G protein beta subunit, Ste4p. To investigate how Ste4p activity is inhibited, its subcellular location was examined. In wild-type cells, alpha-factor treatment resulted in localization of Ste4p to the plasma membrane of mating projections. In cells expressing the a-factor receptor, alpha-factor treatment resulted in localization of Ste4p away from the plasma membrane to an internal compartment. An altered version of Ste4p that is largely insensitive to receptor inhibition retained its association with the membrane in cells expressing the a-factor receptor. The inhibitory function of the a-factor receptor required ASG7, an a-specific gene of previously unknown function. ASG7 RNA was induced by pheromone, consistent with increased inhibition as the pheromone response progresses. The a-factor receptor inhibited signaling in its liganded state, demonstrating that the receptor can block the signal that it initiates. ASG7 was required for the altered localization of Ste4p that occurs during receptor inhibition, and the subcellular location of Asg7p was consistent with its having a direct effect on Ste4p localization. These results demonstrate that Asg7p mediates a regulatory process that blocks signaling from a G protein beta subunit and causes its relocalization within the cell.


Stochastic modeling of T cell receptor gamma gene rearrangement.
The mechanisms controlling the recombination process of the gamma genes that encode the gamma chain of the antigen receptor of the gammadelta T lymphocytes are unclear. Based on experimental data on the recombination status of the two major TCR gamma genes expressed in V(gamma)4+ and V(gamma)1+ thymocytes, we tested the plausibility of three possible rearrangement mechanisms: (1) a time window mechanism according to which the two chromosomes are accessible to the recombination machinery during a defined period of time; (2) a feedback mechanism in which recombination stops shortly after the first in-frame rearrangement event anywhere in both chromosomes; and (3) a feedback mechanism with asynchronous chromosome accessibility, in which there is a first period when only one chromosome is accessible for recombination, followed by a second period when both chromosomes are accessible; shortly after the first in-frame rearrangement event, during any of these two periods, recombination will definitely stop. We model the time window mechanism using a pure probabilistic approach and the two feedback mechanisms using a continuous-time Markov chain formalism. We used maximum likelihood methodology to infer the goodness-of-fit of the models showing evidence for the last model, which best fits the data. Further analysis of this model suggests an evolutionary tradeoff between allelic and isotypic exclusion and the probability that a precursor differentiates into a mature gammadelta T lymphocyte.


A Mycobacterium bovis mycotic abdominal aortic aneurysm resulting from bladder cancer treatment, resection, and reconstruction with a cryopreserved aortic graft.
Mycotic abdominal aortic aneurysms (AAAs) are a clinical challenge for vascular surgeons due to their critical location, surrounding inflammation, risk of rupture, and danger of reinfection following treatment. We present a case of Mycobacterium bovis AAA in a 69-year-old male after treatment with intravesicular bacillus Calmette-Guérin (BCG) therapy for bladder carcinoma. The classical approach for mycotic AAA entails extra-anatomic reconstruction followed by resection with oversewing of the proximal and distal aortic stumps. Alternative in-line reconstruction options have also been advocated. This case illustrates a technically straightforward, durable, in-line repair within an infected field utilizing cryopreserved aortic allograft.


Relationship between baseline haemoglobin and major bleeding complications in acute coronary syndromes.
In patients with acute coronary syndromes (ACS), the negative impact of baseline haemoglobin levels on ischaemic events, particularly death, is well established, but the association with bleeding risk is less well studied. The aim of this study was to assess the impact of baseline haemoglobin levels on major bleeding complications. Pooled analysis of OASIS 5 and 6 data involving 32 170 patients with ACS with and without ST-segment elevation was performed. The association between baseline haemoglobin and major bleeding or ischaemic events was examined using multiple regression model. were 30-day rates of major bleeding, death, and death/myocardial infarction (MI) analysed according to baseline haemoglobin levels. Baseline haemoglobin level independently predicted the risk of overall, procedure-related, and non-procedure-related major bleedings at 30 days [odds ratio (OR) 0.94, 95% CI 0.90-0.98; OR 0.94, 95% CI 0.90-0.99; and OR 0.89, 95% CI 0.83-0.95, respectively, per 1 g/dL haemoglobin increment above 10 g/dL]. In addition, a curvilinear relationship between baseline haemoglobin levels and death at 30 days was observed with a 6% decrease in the risk for every 1 g/dL haemoglobin increment above 10 g/dL up to 15.9 g/dL (OR 0.94, 95% CI 0.90-0.98) and a 19% increase above this value (OR 1.19, 95% CI, 0.98-1.43). A similar relationship for the composite outcome of death/MI was observed. A low baseline haemoglobin level is an independent predictor of the risk of major bleeding in ACS as well as of the risk of death and death and MI. Among other predictors of bleeding risk, baseline haemoglobin should be taken into account in patients presenting with ACS. ClinicalTrials.gov number, NCT00139815. http://clinicaltrials.gov/ct2/show/NCT00139815?term=NCT00139815&rank=1.


The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy.
This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.


Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.


Sequences of wild-type and mutant ampD genes of Citrobacter freundii and Enterobacter cloacae.
The ampD gene product regulates the expression of AmpC beta-lactamase in gram-negative bacteria and is proposed to be involved in peptidoglycan metabolism. In this study, we sequenced the ampD wild type and three mutant genes of Enterobacter cloacae and Citrobacter freundii. They exhibited a high degree of homology with the corresponding gene of Escherichia coli except in the carboxy termini, where, in the wild-type genes of E. cloacae and C. freundii, four additional amino acids yielding the Ser-X-X-Lys motif were found. Evidence that this C-terminal region of the ampD gene product is necessary for activity was shown by constructing a deletion of the last 16 amino acids. The spontaneous mutation of ampD02 is an out-of-frame insertion and yields an inactive AmpD protein. The single-base-pair substitution of Gly for Asp-121 in ampD05 is responsible for a hyperinducible phenotype. These results demonstrate regions of the ampD gene and the corresponding protein which have functional importance for the induction of AmpC beta-lactamase in E. cloacae.


[Decreases in Japanese adolescent drinking in 1996, 2000 and 2004 national surveys of Japanese junior and senior high school students].
We conducted three national surveys to clarify the drinking status of Japanese junior and senior high school students in 1996, 2000 and 2004. The total numbers of subjects in each survey were about 50 thousands junior high school students and 70 thousands senior high school students. The present study compares drinking status and alcohol related problems of the subjects of the three surveys. The results were as follows. First, drinking experiences of the subjects decreased over the three surveys. Those of junior high school students dropped from 60% to 40%, and those of senior high school students from 75% to 60%. Second, drinking behavior of the subjects has changed, e.g., the amount of drinking on each occasion has decreased, failures due to drunkenness have also decreased, compliance with the Law Prohibiting Minors Drinking has increased, their buying alcoholic drinks has decreased and experiences of being offered alcohol by parents have decreased. Third, male problem drinkers among the subjects decreased slightly but female problem drinkers did not decrease. We discussed the reasons why Japanese adolescent drinking has decreased. Over the past 10 years, Japanese society started to prohibit adolescent drinking, by revising the Law Prohibiting Minors Drinking, penalties for driving while intoxicated became more severe and Japanese alcohol consumption started to decrease.


Challenges in maintaining medicine quality while aiming for universal health coverage: a qualitative analysis from Indonesia.
Indonesia, the world's fourth most populous nation, is close to achieving universal health coverage (UHC). A widely-publicised falsified vaccine case in 2016, coupled with a significant financial deficit in the national insurance system, has contributed to concern that the rapid scale-up of UHC might undermine medicine quality. We investigated the political and economic factors that drive production and trade of poor-quality medicines in Indonesia. We reviewed academic publications, government regulations, technical agency documents and news reports to develop a semi-structured questionnaire. We interviewed healthcare providers, policy-makers, medicine regulators, pharmaceutical manufacturers, patients and academics (n=31). We included those with in-depth knowledge about the falsified vaccine case or the pharmaceutical business, medicine regulation, prescribing practice and the implementation of UHC. We coded data using NVivo software and analysed by constant comparative method. The scale-up of UHC has cut revenues for physicians and pharmaceutical manufacturers. In the vaccine case, free, quality-assured vaccines were available but some physicians, seeking extra revenue, promoted expensive alternatives. Taking advantage of poor governance in private hospitals, they purchased cut-price 'vaccines' from freelance salespeople.A single-winner public procurement system which does not explicitly consider quality has slashed the price paid for covered medicines. Trade, industrial and religious policies simultaneously increased production costs, pressuring profit margins for manufacturers and distributors. They reacted by cutting costs (potentially threatening quality) or by market withdrawal (leading to shortages which provide a market for falsifiers). Shortages and physician-promoted irrational demand push patients to buy medicines in unregulated channels, increasing exposure to falsified medicines. Market factors, including political pressure to reduce medicine prices and healthcare provider incentives, can drive markets for substandard and falsified medicines. To protect progress towards UHC, policy-makers must consider the potential impact on medicine quality when formulating rules governing health financing, procurement, taxation and industry.


Inotropes do not increase cardiac output or cerebral blood flow in preterm piglets.
The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions. At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope. In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn.


Enhancing Risk Assessment in Patients Receiving Chronic Opioid Analgesic Therapy Using Natural Language Processing.
Clinical guidelines for the use of opioids in chronic noncancer pain recommend assessing risk for aberrant drug-related behaviors prior to initiating opioid therapy. Despite recent dramatic increases in prescription opioid misuse and abuse, use of screening tools by clinicians continues to be underutilized. This research evaluated natural language processing (NLP) together with other data extraction techniques for risk assessment of patients considered for opioid therapy as a means of predicting opioid abuse. Using a retrospective cohort of 3,668 chronic noncancer pain patients with at least one opioid agreement between January 1, 2007, and December 31, 2012, we examined the availability of electronic health record structured and unstructured data to populate the Opioid Risk Tool (ORT) and other selected outcomes. Clinician-documented opioid agreement violations in the clinical notes were determined using NLP techniques followed by manual review of the notes. Confirmed through manual review, the NLP algorithm had 96.1% sensitivity, 92.8% specificity, and 92.6% positive predictive value in identifying opioid agreement violation. At the time of most recent opioid agreement, automated ORT identified 42.8% of patients as at low risk, 28.2% as at moderate risk, and 29.0% as at high risk for opioid abuse. During a year following the agreement, 22.5% of patients had opioid agreement violations. Patients classified as high risk were three times more likely to violate opioid agreements compared with those with low/moderate risk. Our findings suggest that NLP techniques have potential utility to support clinicians in screening chronic noncancer pain patients considered for long-term opioid therapy.


Nanoplasma Formation by High Intensity Hard X-rays.
Using electron spectroscopy, we have investigated nanoplasma formation from noble gas clusters exposed to high-intensity hard-x-ray pulses at ~5 keV. Our experiment was carried out at the SPring-8 Angstrom Compact free electron LAser (SACLA) facility in Japan. Dedicated theoretical simulations were performed with the molecular dynamics tool XMDYN. We found that in this unprecedented wavelength regime nanoplasma formation is a highly indirect process. In the argon clusters investigated, nanoplasma is mainly formed through secondary electron cascading initiated by slow Auger electrons. Energy is distributed within the sample entirely through Auger processes and secondary electron cascading following photoabsorption, as in the hard x-ray regime there is no direct energy transfer from the field to the plasma. This plasma formation mechanism is specific to the hard-x-ray regime and may, thus, also be important for XFEL-based molecular imaging studies. In xenon clusters, photo- and Auger electrons contribute more significantly to the nanoplasma formation. Good agreement between experiment and simulations validates our modelling approach. This has wide-ranging implications for our ability to quantitatively predict the behavior of complex molecular systems irradiated by high-intensity hard x-rays.


Fluctuations in perceived energy and mood among patients with chronic fatigue syndrome.
Patients currently suffering or recently recovered from chronic fatigue syndrome (CFS) were compared with each other and with a group of well-matched controls in a study of diurnal variation in levels of perceived mental and physical energy and positive and negative affect. Patients who were currently ill showed diurnal variation in patterns of energy, with maximum levels being recorded between 10.00 h and 12.00 h which were significantly higher (P < 0.05) than energy levels recorded on rising or retiring. This pattern was similar to the controls but average energy levels at each time point were lower (P < 0.05) among the ill patients. Recovered patients showed the same pattern, with mean energy levels falling between those of the ill patients and controls. Similar diurnal patterns were found for perceptions of positive, though not negative affect. Correlations between physical and mental energy and between both of these energy variables and positive affect were high (r = 0.75 to 0.85) in both controls and CFS patients. However, correlations with negative affect were low (eg r = -0.10) and non-significant. Total scores on the Hospital Anxiety and Depression Scale (HAD) were significantly higher (P < 0.05) among patients who were still ill than those who had recovered. Scores on the HAD Depression (but not Anxiety) subscale were also significantly higher among those who were still ill (P < 0.01). These findings may be of value in facilitating programmes of cognitive-behavioural modification intended to aid the recovery of patients with CFS.


Electron transfer within self-assembling cyclic tetramers using chlorophyll-based donor-acceptor building blocks.
The synthesis and photoinduced charge transfer properties of a series of Chl-based donor-acceptor triad building blocks that self-assemble into cyclic tetramers are reported. Chlorophyll a was converted into zinc methyl 3-ethylpyrochlorophyllide a (Chl) and then further modified at its 20-position to covalently attach a pyromellitimide (PI) acceptor bearing a pyridine ligand and one or two naphthalene-1,8:4,5-bis(dicarboximide) (NDI) secondary electron acceptors to give Chl-PI-NDI and Chl-PI-NDI(2). The pyridine ligand within each ambident triad enables intermolecular Chl metal-ligand coordination in dry toluene, which results in the formation of cyclic tetramers in solution, as determined using small- and wide-angle X-ray scattering at a synchrotron source. Femtosecond and nanosecond transient absorption spectroscopy of the monomers in toluene-1% pyridine and the cyclic tetramers in toluene shows that the selective photoexcitation of Chl results in intramolecular electron transfer from (1*)Chl to PI to form Chl(+•)-PI(-•)-NDI and Chl(+•)-PI(-•)-NDI(2). This initial charge separation is followed by a rapid charge shift from PI(-•) to NDI and subsequent charge recombination of Chl(+•)-PI-NDI(-•) and Chl(+•)-PI-(NDI)NDI(-•) on a 5-30 ns time scale. Charge recombination in the Chl-PI-NDI(2) cyclic tetramer (τ(CR) = 30 ± 1 ns in toluene) is slower by a factor of 3 relative to the monomeric building blocks (τ(CR) = 10 ± 1 ns in toluene-1% pyridine). This indicates that the self-assembly of these building blocks into the cyclic tetramers alters their structures in a way that lengthens their charge separation lifetimes, which is an advantageous strategy for artificial photosynthetic systems.


Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study.
Paracetamol (acetaminophen) is generally considered a safe medication, but is associated with hepatotoxicity at doses above doses of 4.0 g/day, and even below this daily dose in certain populations. The Nova Scotia Prescription Monitoring Program (NSPMP) in the Canadian province of Nova Scotia is a legislated organization that collects dispensing information on all out-of-hospital prescription controlled drugs dispensed for all Nova Scotia residents. The NSPMP provided data to track all paracetamol/opioids redeemed by adults in Nova Scotia, from July 1, 2005 to June 30, 2010. Trends in the number of adults dispensed these prescriptions and the numbers of prescriptions and tablets dispensed over this period were determined. The numbers and proportions of adults who filled prescriptions exceeding 4.0 g/day and 3.25 g/day were determined for the one-year period July 1, 2009 to June 30, 2010. Data were stratified by sex and age (<65 versus 65+). Both the number of prescriptions filled and the number of tablets dispensed increased over the study period, although the proportion of the adult population who filled at least one paracetamol/opioid prescription was lower in each successive one-year period. From July 2009 to June 2010, one in 12 adults (n = 59,197) filled prescriptions for over 13 million paracetamol/opioid tablets. Six percent (n = 3,786) filled prescriptions that exceeded 4.0 g/day and 18.6% (n = 11,008) exceeded 3.25 g/day of paracetamol at least once. These findings exclude non-prescription paracetamol and paracetamol-only prescribed medications. A substantial number of individuals who redeem prescriptions for paracetamol/opioid combinations may be at risk of paracetamol-related hepatotoxicity. Healthcare professionals must be vigilant when prescribing and dispensing these medications in order to reduce the associated risks.


The influence of mutation, recombination, population history, and selection on patterns of genetic diversity in Neisseria meningitidis.
Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of host-microbe interactions, contain important information about the epidemiological history of infectious disease. Exploiting this information, however, requires a systematic approach that distinguishes the genetic signal generated by epidemiological processes from the effects of other forces, such as recombination, mutation, and population history. Here, a variety of quantitative techniques were employed to investigate multilocus sequence information from isolate collections of Neisseria meningitidis, a major cause of meningitis and septicemia world wide. This allowed quantitative evaluation of alternative explanations for the observed population structure. A coalescent-based approach was employed to estimate the rate of mutation, the rate of recombination, and the size distribution of recombination fragments from samples from disease-associated and carried meningococci obtained in the Czech Republic in 1993 and a global collection of disease-associated isolates collected globally from 1937 to 1996. The parameter estimates were used to reject a model in which genetic structure arose by chance in small populations, and analysis of molecular variation showed that geographically restricted gene flow was unlikely to be the cause of the genetic structure. The genetic differentiation between disease and carriage isolate collections indicated that, whereas certain genotypes were overrepresented among the disease-isolate collections (the "hyperinvasive" lineages), disease-associated and carried meningococci exhibited remarkably little differentiation at the level of individual nucleotide polymorphisms. In combination, these results indicated the repeated action of natural selection on meningococcal populations, possibly arising from the coevolutionary dynamic of host-pathogen interactions.


Autosomal dominant nonsyndromic cleft lip and palate: significant evidence of linkage at 18q21.1.
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital facial defects, with an incidence of 1 in 700-1,000 live births among individuals of European descent. Several linkage and association studies of NSCL/P have suggested numerous candidate genes and genomic regions. A genomewide linkage analysis of a large multigenerational family (UR410) with NSCL/P was performed using a single-nucleotide-polymorphism array. Nonparametric linkage (NPL) analysis provided significant evidence of linkage for marker rs728683 on chromosome 18q21.1 (NPL=43.33 and P=.000061; nonparametric LOD=3.97 and P=.00001). Parametric linkage analysis with a dominant mode of inheritance and reduced penetrance resulted in a maximum LOD score of 3.61 at position 47.4 Mb on chromosome 18q21.1. Haplotype analysis with informative crossovers defined a 5.7-Mb genomic region spanned by proximal marker rs1824683 (42,403,918 bp) and distal marker rs768206 (48,132,862 bp). Thus, a novel genomic region on 18q21.1 was identified that most likely harbors a high-risk variant for NSCL/P in this family; we propose to name this locus "OFC11" (orofacial cleft 11).


[Clinical evaluation of faropenem against infections in pediatric fields].
The recent increases in the prevalence of penicillin-resistant Streptococcus pneumoniae becomes a point at issue clinically. We carried out a clinical study in 40 cases in the pediatrics department, as faropenem (FRPM) was proved to have an excellent antimicrobial activity against penicillin-resistant Streptococcus pneumoniae. The study was planned to investigate in detail the movement of stools that had been a problem in a clinical development studies out before. In this study, an observation of the daily movement of stools was one of the principal evaluation items, hence the patients were divided into two groups. One group (S-group) were administered FRPM only, the other group (E-group) were administered FRPM in combination with a medicine for intestinal disorders (Enteronon-R). An observed frequencies of any loose bowel movements were 94.7% in S-group, and 63.2% in E-group, hence the study suggested that the combination drug was effective. The patients observed higher frequencies of development of the movement of stools, all of them were recovered from in the course of administration or within 4 days after administration, however whether or not being treated symptomatic therapy. Clinical efficacy rates of FRPM on mainly respiratory infections were 94.6%. In this study, 4 strains (patients) of penicillin-resistant Streptococcus pneumoniae were isolated. Against penicillin-resistant Streptococcus pneumoniae, FRPM demonstrated more potent antibacterial activity than the oral penicillins and cephems tested here except cefditoren. Clinical efficacies was deemed effective in all of the 4 cases, and bacteriologically, 3 organisms were eradicated. As for side effects including diarrhea and loose stool, no serious side effects were observed. Based on the above results, FRPM is effective against most infections in the pediatric field which Streptococcus pneumoniae are isolated at high frequencies highly, and is considered to cases in be useful an attention will have to be paid to stool movement, however.


Physical fitness percentiles for Portuguese children and adolescents aged 10-18 years.
This study aimed to produce age- and sex-specific physical fitness reference data for Portuguese youth; to report the prevalence of youth in the healthy zone of physical fitness according to the FITNESSGRAM(®) criteria; to verify the agreement between the Portuguese physical fitness percentiles and the FITNESSGRAM(®) healthy zones. In 2008, 22,048 Portuguese children and adolescents (10-18 years) were evaluated. Physical fitness (curl-ups, push-ups, 20-m shuttle run and modified-back-saver-sit-and-reach tests) was evaluated using the FITNESSGRAM(®) Test Battery 8.0. Smoothed percentile curves were estimated using Cole's LMS method. Boys consistently outperformed girls in every physical fitness test, except for the modified-back-saver-sit-and-reach tests. In both sexes and for all physical fitness tests, higher percentile values were observed at older ages. The 50th percentile of all physical fitness tests had the highest accuracy to discriminate between under healthy zone and healthy zone of the FITNESSGRAM(®). Portuguese schools and physical education teachers may considerer the 50th percentile for age and sex or the FITNESSGRAM(®) criteria for classifying participants in the healthy zone as acceptable cut-offs, above which youth should be considered fit. These reference values can be used as normative data and for baseline values for subsequent surveillance of the physical fitness of Portuguese youth.


Thymus size and its relationship to perinatal events.
A retrospective study was conducted to assess radiographically the thymus size in well and sick neonates and to search for a possible relationship to perinatal events. Thymus size was expressed as cardiothymic:thoracic ratio (CT/T) by measuring the width of the cardiothymic shadow at the level of carina and dividing it by the width of the thorax at the costophrenic angles. The CT/T was measured on chest radiographs obtained on day 1 in well term neonates consecutively born in our nursery and sick neonates with meconium staining of the amniotic fluid, meconium aspiration syndrome or respiratory distress syndrome (RDS). Neonates with congenital anomalies, congenital heart disease or intrauterine growth retardation were excluded. There were no significant relationships between CT/T and sex, birth route, birthweight or gestational age in well and sick term neonates. The CT/T were comparable among well and sick term neonates and were significantly greater in the preterm neonates with RDS than in the preterm neonates without RDS. The CT/T was correlated to the birth route only in the preterm neonates. We conclude that thymus involution in the perinatal period is a complex process and the response is different between term and preterm neonates.


Three-dimensional electromagnetic articulography: a measurement principle.
A measurement principle of the three-dimensional electromagnetic articulographic device is presented. The state of the miniature receiver coil is described by five variables representing the position in the three-dimensional coordinate system and the rotation angles relative to it. When the receiver coil is placed in the magnetic field produced from the distributed transmitter coils, its state can be optimally estimated by minimizing the difference between the measured strength of the received signal and the predicted one using the known spatial pattern of the magnetic field. Therefore, the design and calibration of the field function inherently determine the accuracy in estimating the state of the receiver coil. The field function in our method is expressed in the form of a multivariate B spline as a function of position in the three-dimensional space. Because of the piecewise property of the basis function and the freedom in the selection of the rank and the number of basis functions, the spline field function has a superior ability to flexibly and accurately represent the actual magnetic field. Given a set of calibration data, the spline function is designed to form a smooth curved surface interpolating all of these data samples. Then, an iterative procedure is employed to solve the nonlinear estimation problem of the receiver state variables. Because the spline basis function is a polynomial, it is also shown that the calculation of the Jacobian or Hessian required to obtain updated quantities for the state variables can be efficiently performed. Finally, experimental results reveal that the measurement accuracy is about 0.2 mm for a preliminary condition, indicating that the method can achieve the degree of precision required for observing articulatory movements in a three-dimensional space. It is also experimentally shown that the Marquardt method is a better nonlinear programming technique than the Gauss-Newton or Newton-Raphson method for solving the receiver state problem.


A Low Level of NaCl Stimulates Plant Growth by Improving Carbon and Sulfur Assimilation in Arabidopsis thaliana.
High-salinity stress represses plant growth by inhibiting various metabolic processes. In contrast to the well-studied mechanisms mediating tolerance to high levels of salt, the effects of low levels of salts have not been well studied. In this study, we examined the growth of Arabidopsis thaliana plants under different NaCl concentrations. Interestingly, both shoot and root biomass increased in the presence of 5 mM NaCl, whereas more than 10 mM NaCl decreased plant biomass. To clarify the biological mechanism by which a low level of NaCl stimulated plant growth, we analyzed element accumulation in plants grown under different NaCl concentrations. In addition to the Na and Cl contents, C, S, Zn, and Cu contents were increased under 5 mM NaCl in shoots; this was not observed at higher NaCl concentrations. Adverse effects of high salinity, such as decreased levels of nitrate, phosphate, sulfate, and some cations, did not occur in the presence of 5 mM NaCl. An increase in C was possibly attributed to increased photosynthesis supported by Cl, Zn, and Cu, which also increased in shoots after NaCl application. Salt stress-responsive gene expression was enhanced under 20 mM NaCl but not at lower doses. Among the S metabolites analyzed, cysteine (Cys) was increased by 5 mM NaCl, suggesting that S assimilation was promoted by this dose of NaCl. These results indicate the usefulness of NaCl for plant growth stimulation.


Audio-Vestibular Findings in Increased Intracranial Hypertension Syndrome.
Idiopathic intracranial hypertension (IIH) can be manifested by audiological and vestibular complaints. The aim of the present study is to determine the audio-vestibular pathologies and their pathophysiologies in this syndrome by performing current audio-vestibular tests. The study was performed prospectively on 40 individuals (20 IIH patients, 20 healthy volunteers). Pure tone audiometry, tympanometry, vestibular evoked myogenic potentials, and electronystagmography tests were performed in both groups and the results were compared. The mean age of both groups was found to be 30.2±18.7. There were 11 females and 9 males in each group. The study group patients had significantly worse hearing levels. Pure tone averages were significantly higher in both ears of the study group (p<0.05). Ten patients (50%) in the study group and one healthy volunteer (5%) had pathologic ENG, possibly related to central pathologies (p=0.008). Eight patients (40%) and one (5%) control had variable abnormal VEMP records (p=0008). Many IIH patients initially visit otolaryngology clinics since cochlear and vestibular systems are frequently affected in this condition. Our test results suggest inner ear pathologies in these patients. Higher incidence of inferior vestibular nerve and/or saccule dysfunction is detected as a novelty. Increased intracranial pressure may affect the inner ear with similar mechanisms as in hydrops.


High Prevalence and Onward Transmission of Non-Pandemic HIV-1 Subtype B Clades in Northern and Northeastern Brazilian Regions.
The Human immunodeficiency virus type-1 (HIV-1) epidemic in Brazil is mainly driven by the subtype B pandemic lineage (BPANDEMIC), while Caribbean non-pandemic subtype B clades (BCAR) seem to account for a very low fraction of HIV-infections in this country. The molecular characteristics of the HIV-1 subtype B strains disseminated in the Northern and Northeastern Brazilian regions, however, have not been explored so far. In this study, we estimate the prevalence of the HIV-1 BPANDEMIC and BCAR clades across different Brazilian regions and we reconstruct the spatiotemporal dynamics of dissemination of the major Brazilian BCAR clades. A total of 2,682 HIV-1 subtype B pol sequences collected from 21 different Brazilian states from the five country regions between 1998 and 2013 were analyzed. Maximum Likelihood phylogenetic analyses revealed that the BCAR strains reached 16 out 21 Brazilian states here analyzed. The BCAR clades comprise a low fraction (<10%) of subtype B infections in most Brazilian states analyzed, with exception of Roraima (41%), Amazonas (14%) and Maranhão (14%). Bayesian phylogeographic analyses indicate that BCAR strains originally from the Hispaniola and Trinidad and Tobago were introduced at multiple times into different states from all Brazilian regions and a few of those strains, probably introduced into Roraima, Maranhão and São Paulo between the late 1970s and the early 1980s, established secondary outbreaks in the Brazilian population. These results support that the HIV-1 subtype B epidemics in some Brazilian states from the Northern and Northeastern regions display a unique molecular pattern characterized by the high prevalence of BCAR lineages, which probably reflects a strong epidemiological link with the HIV-1 epidemics in the Caribbean region.


Use and abuse of HOMA modeling.
Homeostatic model assessment (HOMA) is a method for assessing beta-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide concentrations. It has been reported in >500 publications, 20 times more frequently for the estimation of IR than beta-cell function. This article summarizes the physiological basis of HOMA, a structural model of steady-state insulin and glucose domains, constructed from physiological dose responses of glucose uptake and insulin production. Hepatic and peripheral glucose efflux and uptake were modeled to be dependent on plasma glucose and insulin concentrations. Decreases in beta-cell function were modeled by changing the beta-cell response to plasma glucose concentrations. The original HOMA model was described in 1985 with a formula for approximate estimation. The computer model is available but has not been as widely used as the approximation formulae. HOMA has been validated against a variety of physiological methods. We review the use and reporting of HOMA in the literature and give guidance on its appropriate use (e.g., cohort and epidemiological studies) and inappropriate use (e.g., measuring beta-cell function in isolation). The HOMA model compares favorably with other models and has the advantage of requiring only a single plasma sample assayed for insulin and glucose. In conclusion, the HOMA model has become a widely used clinical and epidemiological tool and, when used appropriately, it can yield valuable data. However, as with all models, the primary input data need to be robust, and the data need to be interpreted carefully.


A reproducibility evaluation of the effects of MRI defacing on brain segmentation.
Recent advances in magnetic resonance (MR) scanner quality and the rapidly improving nature of facial recognition software have necessitated the introduction of MR defacing algorithms to protect patient privacy. As a result, there are a number of MR defacing algorithms available to the neuroimaging community, with several appearing in just the last five years. While some qualities of these defacing algorithms, such as patient identifiability, have been explored in previous works, the potential impact of defacing on neuroimage processing has yet to be explored. We qualitatively evaluate eight MR defacing algorithms on 179 subjects from the OASIS-3 cohort and the 21 subjects from the Kirby-21 dataset. We also evaluate the effects of defacing on two neuroimaging pipelines-SLANT and FreeSurfer-by comparing the segmentation consistency between the original and defaced images. Defacing can alter brain segmentation and even lead to catastrophic failures, which are more frequent with some algorithms such as Quickshear, MRI_Deface, and FSL_deface. Compared to FreeSurfer, SLANT is less affected by defacing. On outputs that pass the quality check, the effects of defacing are less pronounced than those of rescanning, as measured by the Dice similarity coefficient. The effects of defacing are noticeable and should not be disregarded. Extra attention, in particular, should be paid to the possibility of catastrophic failures. It is crucial to adopt a robust defacing algorithm and perform a thorough quality check before releasing defaced datasets. To improve the reliability of analysis in scenarios involving defaced MRIs, it's encouraged to include multiple brain segmentation pipelines.


Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread.
The mechanism behind the lowered postprandial insulin demand observed after rye bread intake compared to wheat bread is unknown. The aim of this study was to use the metabolomics approach to identify potential metabolites related to amino acid metabolism involved in this mechanism. A sourdough fermented endosperm rye bread (RB) and a standard white wheat bread (WB) as a reference were served in random order to 16 healthy subjects. Test bread portions contained 50 g available carbohydrate. In vitro hydrolysis of starch and protein were performed for both test breads. Blood samples for measuring glucose and insulin concentrations were drawn over 4 h and gastric emptying rate (GER) was measured. Changes in the plasma metabolome were investigated by applying a comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics platform (GC × GC-TOF-MS). Plasma insulin response to RB was lower than to WB at 30 min (P = 0.004), 45 min (P = 0.002) and 60 min (P < 0.001) after bread intake, and plasma glucose response was significantly higher at time point 90 min after RB than WB intake (P = 0.045). The starch hydrolysis rate was higher for RB than WB, contrary to the in vitro protein digestibility. There were no differences in GER between breads. From 255 metabolites identified by the metabolomics platform, 26 showed significant postprandial relative changes after 30 minutes of bread intake (p and q values < 0.05). Among them, there were changes in essential amino acids (phenylalanine, methionine, tyrosine and glutamic acid), metabolites involved in the tricarboxylic acid cycle (alpha-ketoglutaric, pyruvic acid and citric acid) and several organic acids. Interestingly, the levels of two compounds involved in the tryptophan metabolism (picolinic acid, ribitol) significantly changed depending on the different bread intake. A single meal of a low fibre sourdough rye bread producing low postprandial insulin response brings in several changes in plasma amino acids and their metabolites and some of these might have properties beneficial for health.


Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E.
Apolipoprotein E (apo E) plays an important role in receptor mediated clearance of lipoprotein particles from plasma. Common genetic variation in apo E exists with three alleles coding for proteins called E2, E3, and E4. In in vitro receptor binding assays, E2 binds poorly, whereas E3 and E4 function normally. Recently, the apo E phenotype has been shown to have an effect on low density lipoprotein (LDL) cholesterol levels with levels in subjects with E2 lower and E4 higher than E3. We have examined the effect of the apo E polymorphism on dietary fat clearance using the vitamin A-fat loading test, which specifically labels intestinally derived lipoproteins with retinyl palmitate (RP). 27 normal subjects were studied, 10 with E3/3, 9 with E3/2, 7 with E4/3, and 1 with E4/4. After a vitamin A-containing fatty meal, postprandial RP concentrations were measured in chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions for 14 h. Compared with E3/3 subjects, E3/2 subjects had a significantly higher nonchylomicron RP concentration (P less than 0.05) (peak heights and areas below the curves) indicating slower clearance and the E4/3, E4/4 group had a significantly lower nonchylomicron RP concentration (P less than 0.05) indicating faster clearance. The clearance in the latter group was twice that of E3/2 subjects (P less than 0.01). Thus, heterozygosity for the defective form of apo E, E2, delays, and the surprising presence of a functionally normal allele, E4, increases clearance. This apo E effect on exogenous fat clearance may explain the recently described effect of the apo E phenotypes on LDL cholesterol levels.