Fecal excretion of Maillard reaction products and the gut microbiota composition of rats fed with bread crust or bread crumb.
A comparison between the impacts of advanced (Nε-carboxymethyllysine - CML) and terminal (melanoidins) Maillard reaction products from bread on gut microbiota was carried out in this study. Gut microbiota composition as well as fecal excretion of CML from both bread crust and bread crumb, and of melanoidins from bread crust were assessed on a rodent model. Rats were fed with pellets supplemented or not with 13% of bread crust, bread crumb, a fiber-free bread crust model (glucose, starch and gluten heated together) or a fiber-free-melanoidin-free bread model (glucose-starch and gluten heated separately) for four weeks. These model systems were developed to limit the presence of wheat-native dietary fibers such as cellulose, hemicelluloses and lignin. CML and melanoidins in pellets and feces were evaluated by LC/MS-MS and HPLC/fluorescence respectively, and gut microbiota composition was determined by cultivation and molecular approaches. Diets supplemented with crumb or the fiber-free-melanoidin-free model contained respectively 17% and 64% less melanoidins than their respective controls. A higher excretion of melanoidins was observed for rats fed with crust or bread crust model compared to their controls, confirming that melanoidins are in contact with gut microbiota. No impact of diets was observed on Firmicutes, Bacteroidetes and lactic flora. A decrease of enterobacteria was only observed for rats fed with the diet supplemented with the fiber-free bread crust model. Moreover, a significant increase of bifidobacteria numbers in the presence of crust, crumb and both bread models was observed, showing that this bifidogenic effect of bread is not due to the presence of melanoidins or wheat-native dietary fibers.


Staphylococcus aureus corneal infections: effect of the Panton-Valentine leukocidin (PVL) and antibody to PVL on virulence and pathology.
Community-associated methicillin-resistant Staphylococcus aureus strains expressing Panton-Valentine leukocidin (PVL) are associated with severe skin and soft tissue infections, necrotizing pneumonia, and eye infections. We determined PVL's toxicity on infected mouse and cultured human corneal epithelial cells and the role of PVL and antibody to PVL in pathogenesis of murine keratitis. Cytotoxicity on corneas and corneal epithelial cells was evaluated by LDH assays. Scratched corneas of female A/J mice were inoculated with approximately 10⁷ CFU/eye of either WT S. aureus, isogenic ΔPVL, or strains overproducing PVL. Antibodies to PVL or control sera were topically applied to infected corneas 0, 24, and 32 hours postinfection, corneas scored for pathology and tissue levels of S. aureus were determined. PVL expression augmented the cytotoxicity of S. aureus on infected mouse corneas and human cultured corneal epithelial cells. Variable effects on leukocyte recruitment, pathogenesis, and immunity were obtained in the in vivo studies. Inactivation of PVL in USA300 strains caused reduced pathology and bacterial counts. Results were variable when comparing WT and ΔPVL USA400 strains, while USA400 strains overproducing PVL caused increased bacterial burdens. Topical treatment with polyclonal antibody to PVL yielded significant reductions in corneal pathology and bacterial CFU in corneas infected with USA300 strains, whereas effects were inconsistent in eyes infected with USA400 strains. PVL enhanced the virulence of a subset of MRSA strains in a keratitis model. Coupled with a variable effect of antibody treatment, it appears that PVL plays an inconsistent role in pathogenesis and immunity to S. aureus corneal infection.


Cell lineage analysis in human brain using endogenous retroelements.
Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain. Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sublineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain.


Artificial forisomes are ideal models of forisome assembly and activity that allow the development of technical devices.
Forisomes are protein polymers found in leguminous plants that have the remarkable ability to undergo reversible "muscle-like" contractions in the presence of divalent cations and in extreme pH environments. To gain insight into the molecular basis of forisome structure and assembly, we used confocal laser scanning microscopy to monitor the assembly of fluorescence-labeled artificial forisomes in real time, revealing two distinct assembly processes involving either fiber elongation or fiber alignment. We also used scanning and transmission electron microscopy and X-ray diffraction to investigate the ultrastructure of forisomes, finding that individual fibers are arranged into compact fibril bundles that disentangle with minimal residual order in the presence of calcium ions. To demonstrate the potential applications of artificial forisomes, we created hybrid protein bodies from forisome subunits fused to the B-domain of staphylococcal protein A. This allowed the functionalization of the artificial forisomes with antibodies that were then used to target forisomes to specific regions on a substrate, providing a straightforward approach to develop forisome-based technical devices with precise configurations. The functional contractile properties of forisomes are also better preserved when they are immobilized via affinity reagents rather than by direct contact to the substrate. Artificial forisomes produced in plants and yeast therefore provide an ideal model for the investigation of forisome structure and assembly and for the design and testing of tailored artificial forisomes for technical applications.


Thermal denaturation of influenza virus and its relationship to membrane fusion.
The X-31 strain of influenza virus was studied by differential scanning calorimetry (DSC), CD and SDS/PAGE analysis as a function of both temperature and pH. A bromelain-treated virus was also studied by these methods. The major transition observed in the intact virus was a result of the denaturation of the haemagglutinin (HA) protein. At pH 7.4, this transition was similar in the intact virus and the isolated HA, but was absent in the bromelain-treated virus. However, at pH 5 the denaturation temperature and enthalpy were both higher for HA in the virus than in the isolated protein, indicating that HA interacts with other molecular components in the intact virus. The transition observed by DSC occurs at a higher temperature than does the thermal transition observed by CD. The temperature of the CD transition coincides with the temperature at which the fusogenicity of the virus increases, and probably corresponds to the formation of an extended coiled-coil conformation. Analysis by SDS/PAGE at neutral pH under non-reducing conditions demonstrates a selective loss of the HA protein trimer, resulting in the formation of aggregates in the range of temperatures of 55 to 70 degrees C. In contrast, at acidic pH, the HA protein is largely in the monomeric form at 25 degrees C, and there is little change with temperature. There is thus a weakening of the quaternary structure of HA at acidic pH prior to heating. At the temperature at which the virus exhibits an increased fusogenicity at neutral pH, there is a loss of secondary structure and a beginning of a destabilization of the trimeric form of HA. This temperature is lower than that required for the major endothermic peak observed in DSC experiments. The results demonstrate that there is no kinetically trapped high-energy form of HA at neutral pH.


The development of hindlimb motor activity studied in the isolated spinal cord of the chick embryo.
The development of hindlimb motor activity was studied in an isolated preparation of the chick spinal cord. The motor output from lumbosacral segments was characterized by recording the pattern of ventral root and muscle nerve discharge in 6-14-d-old embryos. In addition, the synaptic drive underlying motoneuron activity was monitored electrotonically from the ventral roots. Spontaneous motor activity consisted of recurring episodes of cyclical motoneuron discharge. During development, both the number of cycles in each episode and the intensity of discharge in each cycle progressively increased. Monophasic, positive ventral root potentials accompanied each cycle of motoneuron discharge. Prior to the innervation of hindlimb muscles at stage 26, ventral root discharge was barely detectable despite the presence of large ventral root potentials. Following hindlimb muscle innervation, each cycle of activity was initiated by a brief, intense discharge that coincided with the rising phase of the ventral root potential. In embryos older than stage 30, the initial discharge was followed, after a delay, by a more prolonged discharge. The duration of ventral root potentials was shortest in the stage 26 embryos, but was similar in embryos at stage 29 and older. The developmental changes in the coordination of antagonist activity were documented by recording the pattern of discharge in sartorius (flexor) and caudilioflexorius (extensor) muscle nerves between stage 30 and stage 36. At stage 30 both sets of motoneurons were coactivated during the brief discharge that initiated each cycle. By stage 31 a second discharge occurred in each cycle. The second discharge was delayed in flexor, but not in extensor, motoneurons, which led to an alternating pattern of activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in Mono Mac 6 cells and human polymorphonuclear leukocytes.
The leukotrienes are inflammatory mediators derived from arachidonic acid. It was demonstrated that the priming of leukocytes with phorbol-12-myristate-13-acetate (PMA) leads to the increased formation of 5-lipoxygenase (5-LO) products in parallel with the increased association of 5-LO with the nucleus and the activation of kinases that can phosphorylate 5-LO in vitro. Stimulation of the monocytic cell line Mono Mac 6 with calcium ionophore gave low 5-LO product formation and no detectable redistribution of 5-LO. However, after priming of Mono Mac 6 cells with phorbol esters, ionophore led to the association of 45% to 75% of cellular 5-LO with the nuclear membrane, to 5-LO kinase activation, to enhanced release of arachidonate, and to substantial leukotriene synthesis. Similar results were obtained for human polymorphonuclear leukocytes stimulated with low-dose ionophore. In addition, for each cell type, PMA priming up-regulated leukotriene biosynthesis in the presence of exogenous arachidonic acid. A protein kinase inhibitor, calphostin C, reduced the association of 5-LO with the nucleus and 5-LO kinase activity, and the formation of 5-LO products was inhibited. These results suggest that PMA up-regulates leukotriene biosynthesis not only by increasing the release of endogenous arachidonate, but also by increasing the capacity for 5-LO phosphorylation and for the translocation of 5-LO to the nucleus in leukocytes.


Protection from experimental asthma by an endogenous bronchodilator.
Mechanisms that protect against asthma remain poorly understood. S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted from asthmatic airways, suggesting a protective role. We report that, following allergen challenge, wild-type mice exhibiting airway hyperresponsivity have increased airway levels of the enzyme GSNO reductase (GSNOR) and are depleted of lung S-nitrosothiols (SNOs). In contrast, mice with genetic deletion of GSNOR exhibit increases in lung SNOs and are protected from airway hyperresponsivity. Our results indicate that endogenous SNOs, governed by GSNOR, are critical regulators of airway responsivity and may provide new therapeutic approaches to asthma.


Metal based synthetic routes to heavy alkaline earth aryloxo complexes involving ligands of moderate steric bulk.
Treatment of an alkaline earth metal (Ca, Sr, Ba) with 2,4,6-trimethylphenol (HOmes) at elevated temperatures in the presence of mercury under solvent-free conditions, followed by extraction of the reaction mixture with 1,2-dimethoxyethane (dme), afforded dinuclear alkaline earth aryloxo complexes [Ae2(Omes)4(dme)4] (Ae = Ca 1, Sr 3, Ba 6). Extraction of the Ca metal and HOmes reaction mixture with thf afforded [Ca3(Omes)6(thf)] 2. In contrast, redox transmetallation ligand exchange reactions between an alkaline earth metal, diphenylmercury and HOmes in dme yielded solely 1 for Ca metal, a mixture of 3 and the methoxide bridged cage [Sr5(Omes)5(OMe)5(dme)4] x 2dme 4 for Sr metal, and solely [Ba5(Omes)5(OMe)5(dme)4] x dme 7 for Ba metal. The methoxide ligands originate from the C-O activation of the dme solvent. Treatment of liquid ammonia activated Sr or Ba metal with HOmes in thf afforded the linear species [Ae3(Omes)6(thf)6] (Ae = Sr 5, Ba 8), and 8 was also obtained from barium metal and HOmes in refluxing thf. The structures of 1 and 3, determined by X-ray crystallography, consist of two six coordinate Ae metal atoms, to each of which is bound a terminal aryloxide ligand, two bridging aryloxide ligands, and chelating and unidentate dme ligands. The structures of 4 and 7 contain five Ae metal atoms arranged on the vertices of a distorted square based pyramid. The Ae atoms are linked by four mu3-OMe ligands and a mu4-OMe ligand. Four bridging aryloxide ligands and four chelating dme ligands complete the coordination spheres of the four seven coordinate Ae atoms at the base of the pyramid, and a terminal aryloxide ligand is bound to the five coordinate apical Ae atom. The structures of 5 and 8 consist of a trinuclear linear array of Ae metal atoms, and contain solely bridging aryloxide ligands. Three thf ligands are bound to each terminal Ae atom, giving all Ae atoms a coordination number of six.


[Involvement of the amygdala on place aversion induced by naloxone in single-dose morphine-treated rats].
Signs characteristic of opiate withdrawal symptoms can be precipitated by an opiate antagonist after short-term infusion or even a single dose of an opiate both in humans and in animals. This phenomenon has been referred to as acute dependence. In contrast to extensive studies on chronic dependence, less is known about the neural mechanisms mediating acute dependence. It will benefit the development of appropriate therapies to facilitate opiate abstinence and reduced craving to better understand the mechanisms underlying acute opiate dependence and to determine whether there are dissociation and similarity between the early and fully developed stages of dependence. In the present study, we examined the influence of c-Fos expression in the amygdala in acquisition of conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h earlier. The effect of microinjection into the central amygdaloid nucleus (CeA) of various kinds of glutamatergic neurotransmission inhibitors was also investigated. Findings showed that CeA displayed significant increase in c-Fos expression in the acquisition of CPA. Furthermore, CPA was attenuated significantly and dose-dependently by microinjection into CeA of all glutamatergic neurotransmission inhibitors (NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801), AMPA receptor antagonist 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI52466), metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), and glutamate release inhibitor riluzole). These findings suggest that CeA involves the acquisition of CPA induced by naloxone-precipitated withdrawal from a single morphine exposure, and the function of the glutamatergic system projected from the amygdala to nucleus accumbens plays a facilitative role in formation of morphine dependence.


HSC20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis.
Friedreich's ataxia is a neurodegenerative disorder caused by mutations in the frataxin gene that produces a predominantly mitochondrial protein whose primary function appears to be mitochondrial iron-sulfur cluster (ISC) biosynthesis. Previously we demonstrated that frataxin interacts with multiple components of the mammalian ISC assembly machinery. Here we demonstrate that frataxin interacts with the mammalian mitochondrial chaperone HSC20. We show that this interaction is iron-dependent. We also show that like frataxin, HSC20 interacts with multiple proteins involved in ISC biogenesis including the ISCU/Nfs1 ISC biogenesis complex and the GRP75 ISC chaperone. Furthermore, knockdown of HSC20 caused functional defects in activity of mitochondrial ISC-containing enzymes and also defects in ISC protein expression. Alterations up or down of frataxin expression caused compensatory changes in HSC20 expression inversely, as expected of two cooperating proteins operating in the same pathway and suggesting a potential therapeutic strategy for the disease. Knockdown of HSC20 altered cytosolic and mitochondrial iron pools and increased the expression of transferrin receptor 1 and iron regulatory protein 2 consistent with decreased iron bioavailability. These results indicate that HSC20 interacts with frataxin structurally and functionally and is important for ISC biogenesis and iron homeostasis in mammals. Furthermore, they suggest that HSC20 may act late in the ISC pathway as a chaperone in ISC delivery to apoproteins and that HSC20 should be included in multi-protein complex studies of mammalian ISC biogenesis.


Agents for facilitation of laryngeal mask airway insertion: a comparative study between thiopentone sodium and propofol.
Development of endotracheal intubation to avoid deleterious effect on hemodynamic responses occurring during laryngoscopy and intubation compelled researchers to venture into alternative measures of airway management with subtle hemodynamic responses. This study was carried out to compare the conditions for laryngeal mask airways LMA insertion with widely used intravenous induction agents, thiopentone sodium and propofol, and also to compare the undesired responses occurring during LMA insertion with them. The study was prospective, randomized, and double blind. All patients selected were randomly allocated into two groups: Group 1 (propofol) and group II (thiopentone). Preinduction heart rate and blood pressure were recorded. Sixty healthy adult patients of either sex belonging to age group of 20-60 years and ASA grade I or II, to undergo surgery less than 1 h, were selected for the study-Patients were randomly allocated in two groups, 30 in each group. Premedication with midazolam 0.04 mg/kg and fentanyl 2 mg/kg done in both groups. Thereafter, group 1 was induced with 2 mg/kg of propofol and group 2 with 5 mg/kg of thiopentone sodium. The study revealed that, ease of insertion of LMA, was statistically significantly greater in group 1 when compared with group 2 (P 0.05). The time required for successful insertion of LMA was lesser in group 1 patients (53.8 ± 7.77 s) than in group 2 patients (84.7 ± 16.54 s) (P 0.001). Severity of undesired responses were more in group 2, as incremental boluses of respective induction agents were required in 20% patients in thiopentone group compared to only 6% patients in propofol group and 13% of patients in thiopentone group required rescue succinylcholine.


Undertreatment of disease activity in systemic lupus erythematosus patients with endstage renal failure is associated with increased all-cause mortality.
In a cohort of systemic lupus erythematosus (SLE) patients with endstage renal failure, to evaluate whether continuing rheumatology followup visits and immunosuppressive therapy after starting renal replacement were associated with increased survival. We identified all SLE patients over 21 years old who started renal replacement therapy between 2005 and 2011 at an urban tertiary care center. Mortality data were obtained using in-hospital records and the US Social Security Death Index database. We identified 80 SLE patients undergoing renal replacement therapy. Twenty-two patients (28%) were followed in rheumatology clinics frequently (2 or more visits per year) after starting renal replacement therapy, and 58 patients (72%) were followed infrequently (fewer than 2 visits per year). Survival rates were significantly higher in transplant patients compared with dialysis patients. Patients with SLE followed frequently after starting dialysis had significantly higher 4-year survival rates compared with patients followed infrequently after starting dialysis (log-rank p = 0.03). In the Cox proportional hazards model, treatment with prednisone alone or with no medication was associated with a hazard ratio (HR) of death = 6.1 (95% CI 1.1, 34; p = 0.04) and HR = 13 (95% CI 1.5, 106; p = 0.02), respectively, compared with patients treated with a combination of immunosuppressive therapy with or without prednisone, adjusted for age at SLE diagnosis, sex, transplant status, and the frequency of rheumatology visits after the development of endstage renal failure. Active disease in patients with SLE undergoing renal replacement therapy may be underrecognized and undertreated, leading to increased mortality.


Partial-thickness tears of the gluteus medius: rationale and technique for trans-tendinous endoscopic repair.
Tears in the gluteus medius and minimus tendons, often misdiagnosed as trochanteric bursitis, have recently emerged as an important cause of recalcitrant greater trochanter pain syndrome. Advances in endoscopic surgery of the hip have created opportunities to better evaluate and treat pathology in the peritrochanteric compartment. We reviewed the literature on trochanteric pain syndrome and gluteus medius tendon injuries. Existing techniques for endoscopic and open gluteus tendon repair and potential challenges in restoration of abductor function were analyzed. Partial-thickness undersurface tears of the gluteus medius were identified as a common pathologic entity. Although these tears are otherwise analogous to partial-thickness tears of the rotator cuff, the lack of arthroscopic access to the deep side of the gluteus medius tendon represents a unique technical challenge. To address the difficulty in visualizing and thus repairing undersurface tears of the gluteus medius, a novel endoscopic trans-tendinous repair technique was developed. The purposes of this article are to review the anatomy, pathology, and existing repair techniques of gluteus medius tendon tears and to describe the rationale and surgical steps for endoscopic trans-tendinous repair.


The utility of acute physiology and chronic health evaluation II scores for prediction of mortality among intensive care unit (ICU) and non-ICU patients with methicillin-resistant Staphylococcus aureus bacteremia.
Bloodstream infections due to methicillin-resistant Staphylococcus aureus (MRSA) have been associated with significant risk of in-hospital mortality. The acute physiology and chronic health evaluation (APACHE) II score was developed and validated for use among intensive care unit (ICU) patients, but its utility among non-ICU patients is unknown. The aim of this study was to determine the ability of APACHE II to predict death at multiple time points among ICU and non-ICU patients with MRSA bacteremia. Retrospective cohort study. Secondary analysis of data from 200 patients with MRSA bacteremia at 2 hospitals. Logistic regression models were constructed to predict overall in-hospital mortality and mortality at 48 hours, 7 days, 14 days, and 30 days using APACHE II scores separately in ICU and non-ICU patients. The performance of APACHE II scores was compared with age adjustment alone among all patients. Discriminatory ability was assessed using the c-statistic and was compared at each time point using χ(2) tests. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. APACHE II was a significant predictor of death at all time points in both ICU and non-ICU patients. Discrimination was high in all models, with c-statistics ranging from 0.72 to 0.84, and was similar between ICU and non-ICU patients at all time points. APACHE II scores significantly improved the prediction of overall and 48-hour mortality compared with age adjustment alone. The APACHE II score may be a valid tool to control for confounding or for the prediction of death among ICU and non-ICU patients with MRSA bacteremia.


High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies.
Previous studies on consumption of caffeine and risk of multiple sclerosis (MS) have yielded inconclusive results. We aimed to investigate whether consumption of coffee is associated with risk of MS. Using two population-representative case-control studies (a Swedish study comprising 1620 cases and 2788 controls, and a US study comprising 1159 cases and 1172 controls), participants with different habits of coffee consumption based on retrospective data collection were compared regarding risk of MS, by calculating ORs with 95% CIs. Logistic regression models were adjusted for a broad range of potential confounding factors. Compared with those who reported no coffee consumption, the risk of MS was substantially reduced among those who reported a high consumption of coffee exceeding 900 mL daily (OR 0.70 (95% CI 0.49 to 0.99) in the Swedish study, and OR 0.69 (95% CI 0.50 to 0.96) in the US study). Lower odds of MS with increasing consumption of coffee were observed, regardless of whether coffee consumption at disease onset or 5 or 10 years prior to disease onset was considered. In accordance with studies in animal models of MS, high consumption of coffee may decrease the risk of developing MS. Caffeine, one component of coffee, has neuroprotective properties, and has been shown to suppress the production of proinflammatory cytokines, which may be mechanisms underlying the observed association. However, further investigations are needed to determine whether exposure to caffeine underlies the observed association and, if so, to evaluate its mechanisms of action.


The gender dimensions of social networks and help-seeking behaviors of young adults in Soweto, South Africa.
Young people constitute a major proportion of the general population and are influenced by a variety of factors, especially in regards to seeking help. An understanding of help-seeking behaviors among young people is important for designing and implementing effective targeted health services. We conducted in-depth interviews with 23 young adults aged 21-22 years in Soweto, South Africa, to explore the gender dimensions of social networks and help-seeking behaviors. We found that young men had larger peer social networks than young women and that young women's social networks centered on their households. For general health, both young men and young women often sought help from an older, maternal figure. However, for sexual health, young men consulted their group of peers, whereas young women were more likely to seek information from one individual, such as an older female friend or family member. These differences in help-seeking behaviors have important implications for the delivery of health information in South Africa and how health promotion is packaged to young men and women, especially for sexual and reproductive health issues. Peer educators might be very effective at conveying health messages for young men, whereas women might respond better to health information presented in a more confidential setting either through community health workers or mHealth technologies. Provision of or linkage to health services that is consistent with young people's health-seeking behavior, such as using peer educators and community health care workers, may increase the reach and utilization of these services among young people.


Vital pulp therapy in dogs: 190 cases (2001-2011).
To evaluate factors associated with the outcome of vital pulp therapy (VPT) in dogs. Retrospective study. 190 teeth in 138 dogs. Medical records were reviewed; radiographs obtained before, immediately after, and during the last available follow-up examination for VPT were evaluated. Treatment was categorized as successful (with radiographic evidence of continued secondary dentin production, continued root formation in immature teeth, and absence of clinical and radiographic signs of apical periodontitis and internal or external inflammatory root resorption), having no evidence of failure (with signs for success fulfilled except the width of the apical periodontal ligament space, which could be wider than but no more than double the width of the periodontal ligament space in other areas), or failed (with radiographic evidence of pulp necrosis, apical periodontitis, or inflammatory root resorption). Associations between diagnostic or treatment-related variables and outcome were assessed with multinomial logistic regression. Overall, treatment was classified as successful for 162 of 190 (85%) teeth, including 23 (12%) teeth with no evidence of failure, and as having failed for 28 (15%) teeth. The overall success rate was 137 of 149 (92%) for teeth treated with mineral trioxide aggregate alone and 21 of 36 (58%) for teeth treated with Ca(OH)2 alone. Use of Ca(OH)2 and deep penetration of dressing material into the vital pulp were each significantly associated with increased odds of treatment failure. Results indicated that VPT with mineral trioxide aggregate was an effective option for use in crown reduction to treat malocclusion and for treatment of recent crown fractures in immature or mature permanent teeth.


PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets.
Familial hypophosphatemic rickets is a rare disease, which is mostly transmitted as an X-linked dominant trait, and mutations on the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) gene are responsible for the disease in most familial cases. In this study we analyzed PHEX in a large cohort of 118 pedigrees representing 56 familial cases and 62 sporadic cases. The high-resolution melting curves technique was tested as a screening method, along with classical sequencing. PHEX mutations have been found in 87% of familial cases but also in 72% of sporadic cases. Missense mutations were found in 16 probands, two of which being associated with other PHEX mutations resulting into truncated proteins. By plotting missense mutations described so far on a 3D model of PHEX we observed that these mutations focus on two regions located in the inner part of the PHEX protein. Family members of 13 sporadic cases were analyzed and a PHEX mutation was detected in one of the apparently healthy mother. These results highlight the major role of PHEX in X-linked dominant hypophosphatemic rickets, and give new clues regarding the genetic analysis of the disease. A screening of the different family members should be mandatory when a PHEX mutation is assessed in a sporadic case and the search for another PHEX mutation should be systematically proceed when facing a missense mutation.


Complete genome sequence and comparative genomics of Shigella flexneri serotype 2a strain 2457T.
We determined the complete genome sequence of Shigella flexneri serotype 2a strain 2457T (4,599,354 bp). Shigella species cause >1 million deaths per year from dysentery and diarrhea and have a lifestyle that is markedly different from those of closely related bacteria, including Escherichia coli. The genome exhibits the backbone and island mosaic structure of E. coli pathogens, albeit with much less horizontally transferred DNA and lacking 357 genes present in E. coli. The strain is distinctive in its large complement of insertion sequences, with several genomic rearrangements mediated by insertion sequences, 12 cryptic prophages, 372 pseudogenes, and 195 S. flexneri-specific genes. The 2457T genome was also compared with that of a recently sequenced S. flexneri 2a strain, 301. Our data are consistent with Shigella being phylogenetically indistinguishable from E. coli. The S. flexneri-specific regions contain many genes that could encode proteins with roles in virulence. Analysis of these will reveal the genetic basis for aspects of this pathogenic organism's distinctive lifestyle that have yet to be explained.


Effects of boron supplementation on the severity and duration of pain in primary dysmenorrhea.
Primary dysmenorrhea refers to painful menstrual cramps without pelvic pathology. The condition is highly prevalent among women and exerts negative effects on their quality of life. Considering the evidence for anti-inflammatory properties of Boron, the present study aimed to determine the effects of Boron supplementation on the severity and duration of menstrual pain in female university students. This triple-blind randomized clinical trial study recruited 113 university students. The participants were matched for the severity and duration of dysmenorrhea and randomly allocated into the case and control groups (n = 58 and 55, respectively). The case group consumed 10 mg/day Boron from two days before the menstrual flow until its third day. The control group received placebo capsules (similar to those distributed among the cases). All subjects were asked to take the capsules for two consecutive menstrual cycles. Pain severity (measured on a visual analog scale) and duration (in hours) were measured at baseline and during the two cycles. The two groups had no significant differences in the severity and duration of pain at baseline. After the intervention, however, the severity and duration of pain were significantly lower in the case group than in the control group (P < 0.05). Based on our findings, Boron supplementation can reduce the severity and duration of menstrual pain through exerting anti-inflammatory effects. In order to clarify the effects of Boron on dysmenorrhea, future studies are required to measure the levels of hormones and inflammatory biomarkers.


Outbreak response immunisation: The experience of Chad during recurrent measles epidemics in 2005 and 2010.
Despite impressive gains in measles control globally, measles epidemics continue to occur in countries with insufficient vaccination coverage. WHO guidelines now recommend outbreak response immunisation (ORI) for controlling measles outbreaks in certain contexts. The objective of this study was to describe late and early response vaccination activities during two consecutive measles outbreaks that occurred in 2005 and 2010 in N'Djamena, Chad. Using Lot Quality Assurance Sampling, vaccination coverage was estimated to be low before the interventions. Following mass vaccination campaigns, measles cases declined. The timeliness and quality of ORI activities are crucial determinants of success. However, effective outbreak response should be accompanied by strong routine vaccination programmes to ensure sustainable high vaccination coverage.


The mutation masculinizer (man) defines a sex-determining gene with maternal and zygotic functions in Musca domestica L.
In Musca domestica, the primary signal for sex determination is the dominant factor M, which is assumed to regulate a postulated female-determining gene F. Presence of M prevents expression of F so that male development ensues. In the absence of M, F can become active, which dictates the female pathway. The existence of F is inferred from FD. a dominant factor that is epistatic to M. We describe a new mutation masculinizer, which has all the properties expected for a null or strongly hypomorphic allele of F: (1) it maps to the same chromosomal location as FD, (2) homozygous man/man animals develop as males, (3) homozygous man/man clones generated in man/+ female larvae differentiate male structures, (4) man has a sex-determining maternal effect. About a third of the morphological males synthesize yolk proteins, which indicates that they are intersexual in internal structures. The maternal effect of man is complete in offspring that derive from homozygous man/man pole cells transplanted into female hosts. In this case, all man/+ progeny become fertile males that do not produce yolk proteins A sex-determining maternal effect has previously been demonstrated for FD. Like F, maternal man' is needed for zygotic man' to become active, providing further evidence that man is a loss-of-function allele of F.


Position clamping in a holographic counterpropagating optical trap.
Optical traps consisting of two counterpropagating, divergent beams of light allow relatively high forces to be exerted along the optical axis by turning off one beam, however the axial stiffness of the trap is generally low due to the lower numerical apertures typically used. Using a high speed spatial light modulator and CMOS camera, we demonstrate 3D servocontrol of a trapped particle, increasing the stiffness from 0.004 to 1.5 μN m(-1). This is achieved in the "macro-tweezers" geometry [Thalhammer, J. Opt. 13, 044024 (2011); Pitzek, Opt. Express 17, 19414 (2009)], which has a much larger field of view and working distance than single-beam tweezers due to its lower numerical aperture requirements. Using a 10×, 0.2 NA objective, active feedback produces a trap with similar effective stiffness to a conventional single-beam gradient trap, of order 1 μN m(-1) in 3D. Our control loop has a round-trip latency of 10 ms, leading to a resonance at 20 Hz. This is sufficient bandwidth to reduce the position fluctuations of a 10 μm bead due to Brownian motion by two orders of magnitude. This approach can be trivially extended to multiple particles, and we show three simultaneously position-clamped beads.


Physiological Responses of a Model Marine Diatom to Fast pH Changes: Special Implications of Coastal Water Acidification.
Diatoms and other phytoplankton in coastal waters experience rapid pH changes in milieu due to high biological activities and/or upwelled CO2-rich waters. While CO2 concentrating mechanisms (CCMs) are employed by all diatoms tested to counter low CO2 availability in seawater, little is known how this mechanism responds to fast pH changes. In the present study, the model diatom Thalassiosira pseudonana was acclimated for 20 generations to low pH (7.81) at an elevated CO2 of 1000 μatm (HC) or to high pH (8.18) at ambient CO2 levels of 390 μatm (LC), then its physiological characteristics were investigated as cells were shifted from HC to LC or vice versa. The maximal electron transport rate (ETRmax) in the HC-acclimated cells was immediately reduced by decreased CO2 availability, showing much lower values compared to that of the LC-acclimated cells. However, the cells showed a high capacity to regain their photochemical performance regardless of the growth CO2 levels, with their ETRmax values recovering to initial levels in about 100 min. This result indicates that this diatom might modulate its CCMs quickly to maintain a steady state supply of CO2, which is required for sustaining photosynthesis. In addition, active uptake of CO2 could play a fundamental role during the induction of CCMs under CO2 limitation, since the cells maintained high ETR even when both intracellular and periplasmic carbonic anhydrases were inhibited. It is concluded that efficient regulation of the CCM is one of the key strategies for diatoms to survive in fast changing pH environment, e.g. for the tested species, which is a dominant species in coastal waters where highly fluctuating pH is observed.


Automatic detection of EEG artefacts arising from head movements using EEG and gyroscope signals.
Contamination of EEG signals by artefacts arising from head movements has been a serious obstacle in the deployment of automatic neurological event detection systems in ambulatory EEG. In this paper, we present work on categorizing these head-movement artefacts as one distinct class and on using support vector machines to automatically detect their presence. The use of additional physical signals in detecting head-movement artefacts is also investigated by means of support vector machines classifiers implemented with gyroscope waveforms. Finally, the combination of features extracted from EEG and gyroscope signals is explored in order to design an algorithm which incorporates both physical and physiological signals in accurately detecting artefacts arising from head-movements.


Thirdhand smoke uptake to aerosol particles in the indoor environment.
Aerosol composition measurements made in an indoor classroom indicate the uptake of thirdhand smoke (THS) species to indoor particles, a novel exposure route for THS to humans indoors. Chemical speciation of the organic aerosol fraction using mass spectrometric data and factor analysis identified a reduced nitrogen component, predominantly found in the indoor environment, contributing 29% of the indoor submicron aerosol mass. We identify this factor as THS compounds partitioning from interior surfaces to gas phase and then aerosol phase. Partitioning of THS vapors to aerosols requires an aqueous phase for reactive uptake of the reduced nitrogen species (RdNS), leading to seasonal differences in THS concentration indoors. RdNS protonate under the acidic conditions expected for indoor aerosols of outdoor origin. Controlled laboratory measurements performed using cigarette smoke deposited into a Pyrex vessel showed a similar partitioning behavior to aerosol of outdoor origin and mass spectral features comparable to the measured indoor THS factor after 1 week of residence time in the closed vessel. This study reports a new, potentially large THS exposure route from partitioning of surface volatile organic compounds into the aerosol phase and subsequent dispersion in a mechanically ventilated building.


Natural capsaicinoids improve swallow response in older patients with oropharyngeal dysphagia.
There is no pharmacological treatment for oropharyngeal dysphagia (OD). The aim of this study was to compare the therapeutic effect of stimulation of oropharyngeal transient receptor potential vanilloid type 1 (TRPV1) with that of thickeners in older patients with OD. A clinical videofluoroscopic non-randomised study was performed to assess the signs of safety and efficacy of swallow and the swallow response in (1) 33 patients with OD (75.94 ± 1.88 years) while swallowing 5, 10 and 20 ml of liquid (20.4 mPa.s), nectar (274.4 mPa.s), and pudding (3930 mPa.s) boluses; (2) 33 patients with OD (73.94 ± 2.23 years) while swallowing 5, 10 and 20 ml nectar boluses, and two series of nectar boluses with 150 μM capsaicinoids and (3) 8 older controls (76.88 ± 1.51 years) while swallowing 5, 10 and 20 ml nectar boluses. Increasing bolus viscosity reduced the prevalence of laryngeal penetrations by 72.03% (p < 0.05), increased pharyngeal residue by 41.37% (p < 0.05), delayed the upper esophageal sphincter opening time and the larynx movement and did not affect the laryngeal vestibule closure time and maximal hyoid displacement. Treatment with capsaicinoids reduced both, penetrations by 50.% (p < 0.05) and pharyngeal residue by 50.% (p < 0.05), and shortened the time of laryngeal vestibule closure (p < 0.001), upper esophageal sphincter opening (p < 0.05) and maximal hyoid and laryngeal displacement. Stimulation of TRPV1 by capsaicinoids strongly improved safety and efficacy of swallow and shortened the swallow response in older patients with OD. Stimulation of TRPV1 might become a pharmacologic strategy to treat OD.


Image structure at the center of gaze during free viewing.
It is generally believed that the visual system is adapted to the statistics of the visual world. Measuring and understanding these statistics require precise knowledge of the structure of the signals reaching fovea during image scanning. However, despite the fact that eye movements cause retinal stimulation to change several times in a second, it is implicitly assumed that images are sampled uniformly during natural viewing. By analyzing the eye movements of three rhesus monkeys freely viewing natural scenes, we report here significant anisotropy in stimulus statistics at the center of gaze. We find that fixation on an image patch is more likely to be followed by a saccade to a nearby patch of similar orientation structure or by a saccade to a more distant patch of largely dissimilar orientation structure. Furthermore, we show that orientation-selective neurons in the primary visual cortex (V1) can take advantage of eye movement statistics to selectively improve their discrimination performance.


How do abnormalities in the brain's spontaneous activity translate into symptoms in schizophrenia? From an overview of resting state activity findings to a proposed spatiotemporal psychopathology.
Schizophrenia is a complex neuropsychiatric disorder with a variety of symptoms that include sensorimotor, affective, cognitive, and social changes. The exact neuronal mechanisms underlying these symptoms remain unclear though. Neuroimaging has focused mainly on the brain's extrinsic activity, specifically task-evoked or stimulus-induced activity, as related to the sensorimotor, affective, cognitive, and social functions. Recently, the focus has shifted to the brain's spontaneous activity, otherwise known as its resting state activity. While various spatial and temporal abnormalities have been observed in spontaneous activity in schizophrenia, their meaning and significance for the different psychopathological symptoms in schizophrenia, are yet to be defined. The first aim in this paper is to provide an overview of recent findings concerning changes in the spatial (e.g., functional connectivity) and temporal (e.g., couplings between different frequency fluctuations) properties of spontaneous activity in schizophrenia. The second aim is to link these spatiotemporal changes to the various psychopathological symptoms of schizophrenia, with a specific focus on basic symptoms, formal thought disorder, and ego-disturbances. Based on the various findings described, we postulate that the spatiotemporal changes on the neuronal level of the brain's spontaneous activity transform into corresponding spatiotemporal changes on the psychological level which, in turn, leads to the different kinds of psychopathological symptoms. We consequently suggest a spatiotemporal rather than cognitive or sensory approach to the condition, amounting to what we describe as "Spatiotemporal Psychopathology".


A sulfurtransferase is required in the transfer of cysteine sulfur in the in vitro synthesis of molybdopterin from precursor Z in Escherichia coli.
It has been shown that conversion of precursor Z to molybdopterin (MPT) by Escherichia coli MPT synthase entails the transfer of the sulfur atom of the C-terminal thiocarboxylate from the small subunit of the synthase to generate the dithiolene group of MPT and that the moeB mutant of E. coli contains inactive MPT synthase devoid of the thiocarboxylate. The data presented here demonstrate that l-cysteine can serve as the source of the sulfur for the biosynthesis of MPT in vitro but only in the presence of a persulfide-containing sulfurtransferase such as IscS, cysteine sulfinate desulfinase (CSD), or CsdB. A fully defined in vitro system has been developed in which an inactive form of MPT synthase can be activated by incubation with MoeB, Mg-ATP, l-cysteine, and one of the NifS-like sulfurtransferases, and the addition of precursor Z to the in vitro system gives rise to MPT formation. The use of radiolabeled l-[(35)S]cysteine has demonstrated that both sulfurs of the dithiolene group of MPT originate from l-cysteine. It was found that MPT can be produced from precursor Z in an E. coli iscS mutant strain, indicating that IscS is not required for the in vivo sulfuration of MPT synthase. A comparison of the ability of the three sulfurtransferases to provide the sulfur for MPT formation showed the highest activity for CSD in the in vitro system.


Where the lay and the technical meet: Using an anthropology of interfaces to explain persistent reproductive health disparities in West Africa.
Despite impressive global investment in reproductive health programs in West Africa, maternal mortality remains unacceptably high and obstetric care is often inadequate. Fertility is among the highest in the world, while contraceptive prevalence remains among the lowest. This paper explores the social and technical dimensions of this situation. We argue that effective reproductive health programs require analyzing the interfaces between technical programs and the social logics and behaviors of health professionals and client populations. Significant gaps between health programs' goals and the behaviors of patients and health care professionals have been observed. While public health projects aim to manage reproduction, sexuality, fertility, and professional practices are regulated socially. Such projects may target technical practices, but access to care is greatly influenced by social norms and ethics. This paper shows how an empirical anthropology that investigates the social and technical interfaces of reproduction can contribute to improved global health.


Mom knows best: the universality of maternal microbial transmission.
The sterile womb paradigm is an enduring premise in biology that human infants are born sterile. Recent studies suggest that infants incorporate an initial microbiome before birth and receive copious supplementation of maternal microbes through birth and breastfeeding. Moreover, evidence for microbial maternal transmission is increasingly widespread across animals. This collective knowledge compels a paradigm shift—one in which maternal transmission of microbes advances from a taxonomically specialized phenomenon to a universal one in animals. It also engenders fresh views on the assembly of the microbiome, its role in animal evolution, and applications to human health and disease.


A High-Carbohydrate, High-Fiber, Low-Fat Diet Results in Weight Loss among Adults at High Risk of Type 2 Diabetes.
Background: Weight loss is a key factor in reducing diabetes risk. The Diabetes Prevention Program (DPP) is a completed clinical trial that randomly assigned individuals at high risk of diabetes to a placebo (PLBO), metformin (MET), or intensive lifestyle intervention (ILS) group, which included physical activity (PA) and reduced dietary fat intake.Objective: We aimed to evaluate the associations between diet and weight at baseline and to identify specific dietary factors that predicted weight loss among DPP participants.Methods: Diet was assessed by a food frequency questionnaire. The associations between intakes of macronutrients and various food groups and body weight among DPP participants at baseline were assessed by linear regression, adjusted for race/ethnicity, age, sex, calorie intake, and PA. Models that predicted weight loss at year 1 were adjusted for baseline weight, change in calorie intake, and change in PA and stratified by treatment allocation (MET, ILS, and PLBO). All results are presented as estimates ± SEs.Results: A total of 3234 participants were enrolled in the DPP; 2924 had completed dietary data (67.5% women; mean age: 50.6 ± 10.7 y). Adjusted for calorie intake, baseline weight was negatively associated with carbohydrate intake (-1.14 ± 0.18 kg body weight/100 kcal carbohydrate, P < 0.0001) and, specifically, dietary fiber (-1.26 ± 0.28 kg/5 g fiber, P < 0.0001). Baseline weight was positively associated with total fat (1.25 ± 0.21 kg/100 kcal, P < 0.0001), saturated fat (1.96 ± 0.46 kg/100 kcal, P < 0.0001), and protein (0.21 ± 0.05 kg/100 kcal, P < 0.0001). For all groups, weight loss after 1 y was associated with increases in carbohydrate intake, specifically dietary fiber, and decreases in total fat and saturated fat intake.Conclusions: Higher carbohydrate consumption among DPP participants, specifically high-fiber carbohydrates, and lower total and saturated fat intake best predicted weight loss when adjusted for changes in calorie intake. Our results support the benefits of a high-carbohydrate, high-fiber, low-fat diet in the context of overall calorie reduction leading to weight loss, which may prevent diabetes in high-risk individuals. This trial was registered at clinicaltrials.gov as NCT00004992.


[Effect and mechanism of L-arginine therapy for fetal growth retardation due to pregnancy-induced hypertension].
To investigate the therapeutic effect of L-arginine (L-Arg) administration on fetus growth retardation (FGR) due to pregnancy-induced hypertension and explore its mechanism. Sixty-eight pregnant women with pregnancy-induced hypertension and FGR were enrolled in this study, and 25 of them were given L-Arg in addition to routine therapy. Umbilical artery flow parameters and serum NO concentrations in maternal and umbilical blood were measured, and the therapeutic effects were evaluated according to neonatal birth weight. L-Arg therapy markedly decreased the systolic/diastolic value, pulse index and resistant index (P=0.000,0), while increased the fast blood velocity rate(P=0.000,0). NO contents in maternal and umbilical blood were 60.45-/+22.68 and 28.45-/+11.35 micromol/L in L-Arg group, respectively, significantly higher than those in routine treatment group (P=0.000,0 and 0.001,7, respectively) but lower than those in the control group (P=0.000,8 and 0.000,0, respectively). The neonatal birth weights were 2.9-/+0.3 kg in L-Arg group, significantly higher than that in routine treatment group (2.7-/+0.3 kg, P=0.006,8) and similar with that of the control group (3012.9-/+295.9 g, P=0.176,2). L-Arg promote intrauterine growth of the fetus by increasing NO production and improving the umbilical artery flow in pregnant women with pregnancy-induced hypertension and FGR.


Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma.
The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma. We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing ≥ 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected. In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue. Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted.


Effects of electronic billboards on driver distraction.
There is an increase in electronic advertising billboards along major roads, which may cause driver distraction due to the highly conspicuous design of the electronic billboards. Yet limited research on the impact of electronic billboards on driving performance and driver behavior is available. The Swedish Transport Administration recently approved the installation of 12 electronic billboards for a trial period along a 3-lane motorway with heavy traffic running through central Stockholm, Sweden. The aim of this study was to evaluate the effect of these electronic billboards on visual behavior and driving performance. A total of 41 drivers were recruited to drive an instrumented vehicle passing 4 of the electronic billboards during day and night conditions. A driver was considered visually distracted when looking at a billboard continuously for more than 2 s or if the driver looked away from the road for a high percentage of time. Dependent variables were eye-tracking measures and driving performance measures. The visual behavior data showed that drivers had a significantly longer dwell time, a greater number of fixations, and longer maximum fixation duration when driving past an electronic billboard compared to other signs on the same road stretches. No differences were found for the factors day/night, and no effect was found for the driving behavior data. Electronic billboards have an effect on gaze behavior by attracting more and longer glances than regular traffic signs. Whether the electronic billboards attract too much attention and constitute a traffic safety hazard cannot be answered conclusively based on the present data.


A network of enzymes involved in repair of oxidative DNA damage in Neisseria meningitidis.
Although oxidative stress is a key aspect of innate immunity, little is known about how host-restricted pathogens successfully repair DNA damage. Base excision repair is responsible for correcting nucleobases damaged by oxidative stress, and is essential for bloodstream infection caused by the human pathogen, Neisseria meningitidis. We have characterized meningococcal base excision repair enzymes involved in the recognition and removal of damaged nucleobases, and incision of the DNA backbone. We demonstrate that the bi-functional glycosylase/lyases Nth and MutM share several overlapping activities and functional redundancy. However, MutM and other members of the GO system, which deal with 8-oxoG, a common lesion of oxidative damage, are not required for survival of N. meningitidis under oxidative stress. Instead, the mismatch repair pathway provides back-up for the GO system, while the lyase activity of Nth can substitute for the meningococcal AP endonuclease, NApe. Our genetic and biochemical evidence shows that DNA repair is achieved through a robust network of enzymes that provides a flexible system of DNA repair. This network is likely to reflect successful adaptation to the human nasopharynx, and might provide a paradigm for DNA repair in other prokaryotes.


Powerful bactericidal activity of sparfloxacin (AT-4140) against Mycobacterium tuberculosis in mice.
The bactericidal activities of various monotherapies and combined regimens were compared in mice at different stages after infection with Mycobacterium tuberculosis. These therapies mimicked the initial and continuation phases of chemotherapy for human tuberculosis. As monotherapy, the bactericidal activity of sparfloxacin (SPFX) was dose related; the activity of SPFX at 100 mg/kg of body weight was comparable to that of rifampin (RMP) and was significantly greater than those of isoniazid (INH), pyrazinamide (PZA), or ofloxacin (OFLO) during both the initial and continuation phases of chemotherapy. During the initial phase, the addition of SPFX did not enhance or diminish the activities of the combinations INH-RMP-PZA or RMP-PZA; the combinations SPFX-PZA-streptomycin (SM) and SPFX-PZA-kanamycin (KANA) displayed powerful bactericidal activity. Because the area under the plasma concentration-time curve of SPFX (100 mg/kg) in mice is similar to that of SPFX (400 mg) in humans, the promising bactericidal activity displayed by SPFX in mice might be achieved in humans by administration of the drug in a clinically tolerated dosage. In addition, the combinations SPFX-PZA-SM and SPFX-PZA-KANA may be useful for the treatment of multidrug-resistant tuberculosis.


Detection of nerve agent stimulants based on photoluminescent porous silicon interferometer.
Porous silicon (PSi) exhibiting dual optical properties, both Fabry-Pérot fringe and photolumincence, was developed and used as chemical sensors. PSi samples were prepared by an electrochemical etch of p-type silicon under the illumination of 300-W tungsten lamp during the etch process. The surface of PSi was characterized by cold field-emission scanning electron microscope. PSi samples exhibited a strong visible orange photoluminescence at 610 nm with an excitation wavelength of 460 nm as well as Fabry-Pérot fringe with a tungsten light source. Both reflectivity and photoluminescence were simultaneously measured under the exposure of organophosphate vapors. An increase of optical thickness and quenching photoluminescences under the exposure of various organophosphate vapors were observed.


Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown. We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).


Computational Planning in Facial Surgery.
This article reflects the research of the last two decades in computational planning for cranio-maxillofacial surgery. Model-guided and computer-assisted surgery planning has tremendously developed due to ever increasing computational capabilities. Simulators for education, planning, and training of surgery are often compared with flight simulators, where maneuvers are also trained to reduce a possible risk of failure. Meanwhile, digital patient models can be derived from medical image data with astonishing accuracy and thus can serve for model surgery to derive a surgical template model that represents the envisaged result. Computerized surgical planning approaches, however, are often still explorative, meaning that a surgeon tries to find a therapeutic concept based on his or her expertise using computational tools that are mimicking real procedures. Future perspectives of an improved computerized planning may be that surgical objectives will be generated algorithmically by employing mathematical modeling, simulation, and optimization techniques. Planning systems thus act as intelligent decision support systems. However, surgeons can still use the existing tools to vary the proposed approach, but they mainly focus on how to transfer objectives into reality. Such a development may result in a paradigm shift for future surgery planning.


The use of onlay bone grafting for implant restoration in the extremely atrophic anterior maxilla. A case series
Functional and aesthetic treatments are challenging when ensuring maintain long-term successful prosthetic rehabilitation after alveolar ridge resorption of the anterior maxilla. The goal of this case series was to evaluate implant success rate, prosthetic stability and patient satisfaction in patients treated by onlay bone grafting in atrophic premaxilla. Nineteen patients treated for severe atrophic anterior maxilla by reconstruction using onlay bone grafting and implant restoration between 2002 and 2012 were examined. The surgical procedure was designed to allow the insertion of 49 endosseous implants in the grafted anterior maxillae. Bone resorption and implant success rate were retrospectively evaluated after a follow-up period of 5 years (from 5 to 15 years) subsequent to reconstruction. A questionnaire was the medium used to evaluate patient satisfaction and highlight functional and aesthetic outcomes. The bone grafting success rate was 74%. None of the grafted bones were reported to be infected. Four implants were removed. Implant survival rate was 91.8% after 8.9 years. The permanent reconstruction was fixed in 74% of the cases and removable in 26%. The level of patient satisfaction reported was 6.5/7. In conclusion, his study suggests that onlay bone grafting can be considered a predictable technique for rehabilitation in atrophic premaxilla. The procedure has a high implant survival rate, acceptable bone resorption over time, and promotes graft stability for longterm prosthetic fixation, thereby increasing patient satisfaction.


Effect of the C-terminal amino acid of the peptide on the structure and mechanical properties of alginate-peptide hydrogels across length-scales.
Alginate is a natural anionic polysaccharide that exhibits excellent biocompatibility and biodegradability. Alginate hydrogels have many different applications in the field of regenerative medicine especially when peptides are conjugated to the alginate backbone. Here, we systematically investigate the effect of six arginine-glycine-aspartic acid (RGD)-containing peptides, G6KRGDY/S, A6KRGDY/S and V6KRGDY/S, on the macroscopic and microscopic physical properties and spatial organization of alginate-peptides hydrogels. Using rheology, small angle X-ray scattering and nanoindentation measurements we show a strong correlation between the macroscopic-bulk properties and the microscopic-local properties of the alginate-peptide hydrogels. Furthermore, our results indicate that the identity of the amino acid at the C-terminal of the peptide plays a major role in determining the structure and mechanical properties of the hydrogel across length-scales, where the presence of tyrosine (Y) terminated peptides introduce more junction-zones and consequently larger stiffness than those terminated with serine (S).


Plant natriuretic peptides: systemic regulators of plant homeostasis and defense that can affect cardiomyoblasts.
Immunologic evidence has suggested the presence of biologically active natriuretic peptide (NPs) hormones in plants because antiatrial NP antibodies affinity purify biologically active plant NPs (PNP). In the model plant, an Arabidopsis thaliana PNP (AtPNP-A) has been identified and characterized. AtPNP-A belongs to a novel class of molecules that share some similarity with the cell wall loosening expansins but do not contain the carbohydrate-binding wall anchor thus suggesting that PNPs and atrial natriuretic peptides are heterologs. AtPNP-A acts systemically, and this is consistent with its localization in the apoplastic extracellular space and the conductive tissue. Furthermore, AtPNP-A signals via the second messenger cyclic guanosine 3',5'-monophosphate and modulates ion and water transport and homeostasis. It also plays a critical role in host defense against pathogens. AtPNP-A can be classified as novel paracrine plant hormone because it is secreted into the apoplastic space in response to stress and can enhance its own expression. Interestingly, purified recombinant PNP induces apoptosis in a dose-dependent manner and was most effective on cardiac myoblast cell lines. Because PNP is mimicking the effect of ANP in some instances, PNP may prove to provide useful leads for development of novel therapeutic NPs.


The morphological and functional characteristics of the pineal gland.
The pineal gland is a photo-neuro-endocrine organ situated inside the brain, that secretes serotonin, melatonin and N,N-dymethyltriptamine. This narrative review will address the latest information gathered on this function of the gland as well as the unknown roles it may have. The different histological and pathological findings of the pineal gland have demonstrated a role in clinical manifestations of numerous endocrine, neurological and psychiatric pathologies. For this narrative review we used the NCBI website database PubMed. The search terms were "Pineal Gland" AND/OR "histology, melatonin, DMT, pathology". Total number of articles included were 86. We have reviewed physiological information of melatonin and DMT, anatomical, histological and histopathological information on the pineal gland and its role in endocrine, neurological and psychiatric pathology. The role of melatonin in immunity and its potential therapeutic effects show promising potential for further research. DMT seems to have a role in psychiatric pathology and potential therapeutic effects. Proper tumoral screening and diagnostic protocol are required.


Health insurance knowledge among Medicare beneficiaries.
To assess the effect of new consumer information materials about the Medicare program on beneficiary knowledge of their health care coverage under the Medicare system. A telephone survey of 2,107 Medicare beneficiaries in the 10-county Kansas City metropolitan statistical area. Beneficiaries were randomly assigned to a control group and three treatment groups each receiving a different set of Medicare informational materials. The "handbook-only" group received the Health Care Financing Administration's new Medicare & You 1999 handbook. The "bulletin" group received an abbreviated version of the handbook, and the "handbook + CAHPS" group received the Medicare & You handbook plus the Consumer Assessment of Health Plans (CAHPS) survey report comparing the quality of health care provided by Medicare HMOs. Beneficiaries interested in receiving information were oversampled. Data were collected during two separate telephone surveys of Medicare beneficiaries: one survey of new beneficiaries and another survey of experienced beneficiaries. The intervention materials were mailed to sample members in advance of the interviews. Knowledge for the treatment groups was measured shortly after beneficiaries received the intervention materials. Respondents' knowledge was measured using a psychometrically valid and reliable 15-item measure. Beneficiaries who received the intervention materials answered significantly more questions correctly than control group members. The effect on beneficiary knowledge of providing the information was modest for all intervention groups but varied for experienced beneficiaries only, depending on the intervention they received. The findings suggest that all of the new materials had a positive effect on beneficiary knowledge about Medicare and the Medicare + Choice program. While the absolute gain in knowledge was modest, it was greater than increases in knowledge associated with traditional Medicare information sources.


Impact of repeated community-based selective chemotherapy on morbidity due to schistosomiasis mansoni.
The impact of repeated chemotherapy on morbidity due to schistosomiasis mansoni was evaluated in Gihungwe (initial prevalence 58%) and Buhandagaza/Kizina (33%), two village clusters in Burundi. Surveys were carried out with reference to the first treatment (month 0) at months -6, -3, 0, 3, 6, 9, 12, 24, and 36. Praziquantel (40 mg/kg) was given at months 0, 12, 24, and 36 to those showing eggs in the feces with a single 28-mg Kato slide. At each survey, duplicate Kato smears were examined, and all participants responded to a standardized medical history interview and underwent a clinical examination. In the three preintervention surveys, spleen and liver rates remained stable at the community and the individual level. The frequencies of diarrhea and abdominal pain varied to some extent, but they were consistently higher in the most heavily infected villages and age groups and remained relatively stable at the individual level. At the final survey, the prevalence of infection had decreased to 25%, and the frequency of diarrhea from 19-26% to 10% in both village clusters. This impact was strongest in the younger age groups. The frequency of abdominal pain was reduced only at the short term and in selected age groups. Organomegaly decreased only to a limited extent in those treated, and increased in those not treated, possibly due to the impact of malaria. The net result was that no measurable impact of the treatments on organomegaly at the community level could be demonstrated. In the light of these results, the relevance of community-based chemotherapy in moderate foci is questioned.


Age-related decline in circadian output.
Disruptions in sleep/wake cycles, including decreased amplitude of rhythmic behaviors and fragmentation of the sleep episodes, are commonly associated with aging in humans and other mammals. While there are undoubtedly many factors contributing to these changes, a body of literature is emerging, suggesting that an age-related decline in the central circadian clock in the suprachiasmatic nucleus (SCN) may be a key element responsible. To explore age-related changes in the SCN, we have performed in vivo multiunit neural activity (MUA) recordings from the SCN of freely moving young (3-5 months) and middle-aged (13-18 months) mice. Importantly, the amplitude of day-night difference in MUA was significantly reduced in the older mice. We also found that the neural activity rhythms are clearly degraded in the subparaventricular zone, one of the main neural outputs of the SCN. Surprisingly, parallel studies indicate that the molecular clockwork in the SCN as measured by PER2 exhibited only minor deficits at this same age. Thus, the circadian output measured at the level of neural activity rhythms in the SCN is degraded by aging, and this decline occurs before the disruption of key components of the molecular clockwork.


Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma.
The aim of the present study was to compare the effectiveness, safety and health economics of budesonide/formoterol maintenance and a novel reliever therapy with conventional best practice in patients with persistent asthma in Canada. After 2 weeks of usual therapy, 1,538 patients were randomised for 6 months to open-label budesonide/formoterol maintenance and reliever therapy 160/4.5 microg twice daily and as needed, or to guideline-based conventional best practice. Severe asthma exacerbations, reliever medication use and total inhaled corticosteroid dose were analysed in all patients and airway inflammation was assessed in a sub-study of 115 patients. No differences were seen in time to first severe exacerbation and severe asthma exacerbation rate. There were numerically fewer emergency room visits or hospitalisations with budesonide/formoterol maintenance and reliever therapy (4.4 versus 7.5 events per 100 patients x yr(-1), 41% reduction); however, this did not reach statistical significance. Mean total inhaled corticosteroid dose, reliever use, asthma medication costs and total annual costs per patient were all significantly lower with budesonide/formoterol maintenance and reliever therapy. Mean sputum eosinophil cell counts remained in the range for controlled inflammation in both groups. In conclusion, budesonide/formoterol maintenance and reliever therapy achieved similar or improved clinical control compared with conventional best practice, with significantly lower total inhaled corticosteroid dose and lower cost, while maintaining similar control of eosinophilic inflammation.


Palliative options of last resort: a comparison of voluntarily stopping eating and drinking, terminal sedation, physician-assisted suicide, and voluntary active euthanasia.
Palliative care is generally agreed to be the standard of care for the dying, but there remain some patients for whom intolerable suffering persists. In the face of ethical and legal controversy about the acceptability of physician-assisted suicide and voluntary active euthanasia, voluntarily stopping eating and drinking and terminal sedation have been proposed as ethically superior responses of last resort that do not require changes in professional standards or the law. The clinical and ethical differences and similarities between these 4 practices are critically compared in light of the doctrine of double effect, the active/passive distinction, patient voluntariness, proportionality between risks and benefits, and the physician's potential conflict of duties. Terminal sedation and voluntarily stopping eating and drinking would allow clinicians to remain responsive to a wide range of patient suffering, but they are ethically and clinically more complex and closer to physician-assisted suicide and voluntary active euthanasia than is ordinarily acknowledged. Safeguards are presented for any medical action that may hasten death, including determining that palliative care is ineffective, obtaining informed consent, ensuring diagnostic and prognostic clarity, obtaining an independent second opinion, and implementing reporting and monitoring processes. Explicit public policy about which of these practices are permissible would reassure the many patients who fear a bad death in their future and allow for a predictable response for the few whose suffering becomes intolerable in spite of optimal palliative care.


Comparison of Risk of Preterm Labor between Vaginal Progesterone and17-Alpha-Hydroxy-Progesterone Caproate in Women with Threatened Abortion: A Randomized Clinical Trial.
Threatened miscarriage is a common complication in pregnancy that leads to adverse pregnancy outcomes such as preterm labor. This study aimed to compare the vaginal progesterone (Cyclogest) versus 17-alpha-hydroxyprogesterone caproate (Proluton) on preventing preterm labor in pregnant women with threatened abortion at less than 34 weeks' gestational age. This balanced randomized, double-blind, single-center controlled clinical trial included 190 women with threatened abortion. They were then randomly allocated into Cyclogest (n=95) and 17-alpha-hydroxyprogesterone caproate (Proluton, n=95) groups. Interested outcome was preterm labor less than 34 weeks. The Pearson chi-square and Student's t test were used to compare two groups. The data were analyzed by Stata software version 13. The risks of preterm labor less than 34 weeks in Proluton and Cyclogest groups were 8.6 and 6.52%, respectively. There was no significant difference for risk of preterm labor less than 34 weeks [relative ratio (RR): 1.31, 95% confidence interval (CI): 0.47- 3.66, P=0.59] between two groups. Risk of preterm labor in the vaginal progesterone group and 17-alpha-hydroxyprogesterone caproate group in pregnant women with threatened abortion is the same ( IRCT2014123120504N1).


In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions.
Epilepsy is a chronic neurological disorder, characterized by recurrent, spontaneous, and transient seizures, and affects more than 70 million people worldwide. Although two dozen antiepileptic drugs (AEDs) are approved and available in the market, seizures remain poorly controlled in one-third of epileptic patients who are suffering from drug resistance or various adverse effects. Recently, the xanthone skeleton has been regarded as an attractive scaffold for the discovery and development of emerging anticonvulsants. We had isolated several dihydroxanthone derivatives previously, including oliganthin H, oliganthin I, and oliganthin N, whose structures were similar and delicately elucidated by spectrum analysis or X-ray crystallographic data, from extracts of leaves of Garcinia oligantha. These xanthone analogues were evaluated for anticonvulsant activity, and a novel xanthone, oliganthin H, has been identified as a sound and effective natural inhibitor of convulsions in zebrafish in vivo. A preliminary structure-activity relationship analysis on the relationship between structures of the xanthone analogues and their activities was also conducted. Oliganthin H significantly suppressed convulsant behavior and reduced to about 25% and 50% of PTZ-induced activity, in 12.5 and 25 μM treatment groups (P < 0.01 and 0.001), respectively. Meanwhile, it reduced seizure activity, velocity, seizure duration, and number of bursts in zebrafish larvae (P < 0.05). Pretreatment of oliganthin H significantly restored aberrant induction of gene expressions including npas4a, c-fos, pyya, and bdnf, as well as gabra1, gad1, glsa, and glula, upon PTZ treatment. In addition, in silico analysis revealed the stability of the oliganthin H-GABAA receptor complex and their detailed binding pattern. Therefore, direct interactions with the GABAA receptor and involvement of downstream GABA-glutamate pathways were possible mechanisms of the anticonvulsant action of oliganthin H. Our findings present the anticonvulsant activity of oliganthin H, provide a novel scaffold for further modifications, and highlight the xanthone skeleton as an attractive and reliable resource for the development of emerging AEDs.


Association between the use of surveillance PET/CT and the detection of potentially salvageable occult recurrences among patients with resected high-risk melanoma.
The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III-IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I-II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68-6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94-93.31%), specificity (90%, 95% CI=88.56-91.56%), and negative predictive value (99%, 95% CI=98.46-99.52%). However, the positive predictive value was only 37% (95% CI=31.32-43.68%). In patients with resected stage III-IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities.


High Level of Tobacco Carcinogen-Derived DNA Damage in Oral Cells Is an Independent Predictor of Oral/Head and Neck Cancer Risk in Smokers.
Exposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is recognized to play an important role in the development of oral/head and neck squamous cell cancer (HNSCC). We recently reported higher levels of TSNA-associated DNA adducts in the oral cells of smokers with HNSCC as compared with cancer-free smokers. In this study, we further investigated the tobacco constituent exposures in the same smokers to better understand the potential causes for the elevated oral DNA damage in smokers with HNSCC. Subjects included cigarette smokers with HNSCC (cases, n = 30) and cancer-free smokers (controls, n = 35). At recruitment, tobacco/alcohol use questionnaires were completed, and urine and oral cell samples were obtained. Analysis of urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and N'-Nitrosonornicotine (NNN; TSNA biomarkers), 1-hydroxypyrene (1-HOP, a PAH), cotinine, 3'-hydroxycotinine, and the nicotine metabolite ratio (NMR) were performed. Cases and controls differed in mean age, male preponderance, and frequency of alcohol consumption (but not total alcoholic drinks). Univariate analysis revealed similar levels of NNN, 1-HOP, and cotinine between groups but, as reported previously, significantly higher DNA adduct formation in the cases. Multiple regression adjusting for potential confounders showed persistent significant difference in DNA adduct levels between cases and controls [ratio of geometric means, 20.0; 95% CI, 2.7-148.6). Our cohort of smokers with HNSCC demonstrates higher levels of TSNA-derived oral DNA damage in the setting of similar exposure to nicotine and tobacco carcinogens. Among smokers, DNA adduct formation may act as a predictor of eventual development of HNSCC that is independent of carcinogen exposure indicators. Cancer Prev Res; 10(9); 507-13. ©2017 AACRSee related editorial by Johnson and Bauman, p. 489.


Associated motivational salience impacts early sensory processing of human faces.
Facial expressions of emotion have an undeniable processing advantage over neutral faces, discernible both at behavioral level and in emotion-related modulations of several event-related potentials (ERPs). Recently it was proposed that also inherently neutral stimuli might gain salience through associative learning mechanisms. The present study investigated whether acquired motivational salience leads to processing advantages similar to biologically determined origins of inherent emotional salience by applying an associative learning paradigm to human face processing. Participants (N=24) were trained to categorize neutral faces to salience categories by receiving different monetary outcomes. ERPs were recorded in a subsequent test phase consisting of gender decisions on previously associated faces, as well as on familiarized and novel faces expressing happy, angry or no emotion. Previously reward-associated faces boosted the P1 component, indicating that acquired reward-associations modulate early sensory processing in extrastriate visual cortex. However, ERP modulations to emotional - primarily angry - expressions expanded to subsequent processing stages, as reflected in well-established emotion-related ERPs. The present study offers new evidence that motivational salience associated to inherently neutral stimuli can sharpen sensory encoding but does not obligatorily lead to preferential processing at later stages.


Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy.
Many patients with temporal lobe epilepsy display neuron loss in the dentate gyrus. One potential epileptogenic mechanism is loss of GABAergic interneurons and inhibitory synapses with granule cells. Stereological techniques were used to estimate numbers of gephyrin-positive punctae in the dentate gyrus, which were reduced short-term (5 days after pilocarpine-induced status epilepticus) but later rebounded beyond controls in epileptic rats. Stereological techniques were used to estimate numbers of synapses in electron micrographs of serial sections processed for postembedding GABA-immunoreactivity. Adjacent sections were used to estimate numbers of granule cells and glutamic acid decarboxylase-positive neurons per dentate gyrus. GABAergic neurons were reduced to 70% of control levels short-term, where they remained in epileptic rats. Integrating synapse and cell counts yielded average numbers of GABAergic synapses per granule cell, which decreased short-term and rebounded in epileptic animals beyond control levels. Axo-shaft and axo-spinous GABAergic synapse numbers in the outer molecular layer changed most. These findings suggest interneuron loss initially reduces numbers of GABAergic synapses with granule cells, but later, synaptogenesis by surviving interneurons overshoots control levels. In contrast, the average number of excitatory synapses per granule cell decreased short-term but recovered only toward control levels, although in epileptic rats excitatory synapses in the inner molecular layer were larger than in controls. These findings reveal a relative excess of GABAergic synapses and suggest that reports of reduced functional inhibitory synaptic input to granule cells in epilepsy might be attributable not to fewer but instead to abundant but dysfunctional GABAergic synapses.


Genetics of dispersal.
Dispersal is a process of central importance for the ecological and evolutionary dynamics of populations and communities, because of its diverse consequences for gene flow and demography. It is subject to evolutionary change, which begs the question, what is the genetic basis of this potentially complex trait? To address this question, we (i) review the empirical literature on the genetic basis of dispersal, (ii) explore how theoretical investigations of the evolution of dispersal have represented the genetics of dispersal, and (iii) discuss how the genetic basis of dispersal influences theoretical predictions of the evolution of dispersal and potential consequences. Dispersal has a detectable genetic basis in many organisms, from bacteria to plants and animals. Generally, there is evidence for significant genetic variation for dispersal or dispersal-related phenotypes or evidence for the micro-evolution of dispersal in natural populations. Dispersal is typically the outcome of several interacting traits, and this complexity is reflected in its genetic architecture: while some genes of moderate to large effect can influence certain aspects of dispersal, dispersal traits are typically polygenic. Correlations among dispersal traits as well as between dispersal traits and other traits under selection are common, and the genetic basis of dispersal can be highly environment-dependent. By contrast, models have historically considered a highly simplified genetic architecture of dispersal. It is only recently that models have started to consider multiple loci influencing dispersal, as well as non-additive effects such as dominance and epistasis, showing that the genetic basis of dispersal can influence evolutionary rates and outcomes, especially under non-equilibrium conditions. For example, the number of loci controlling dispersal can influence projected rates of dispersal evolution during range shifts and corresponding demographic impacts. Incorporating more realism in the genetic architecture of dispersal is thus necessary to enable models to move beyond the purely theoretical towards making more useful predictions of evolutionary and ecological dynamics under current and future environmental conditions. To inform these advances, empirical studies need to answer outstanding questions concerning whether specific genes underlie dispersal variation, the genetic architecture of context-dependent dispersal phenotypes and behaviours, and correlations among dispersal and other traits.


Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons.
Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population. We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4 and CD8 T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8 cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue. Adipose tissue had a higher percentage of CD3CD8 T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8HLA-DR T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8CD57 T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8 T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05). Adipose tissue is enriched for activated and late-differentiated CD8 T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.


Temporal clinical exacerbation of summer pasture-associated recurrent airway obstruction and relationship with climate and aeroallergens in horses.
To describe the seasonal pattern of clinical exacerbation of summer pasture-associated recurrent airway obstruction (SPA-RAO) in relation to climate and aeroallergens in horses. 19 horses with SPA-RAO and 10 nonaffected horses. Daily examinations were performed on all horses while they were kept on pasture for 3 years. Onset and progression of clinical exacerbation based on a clinical score of respiratory effort were evaluated in relation to changes in maximum temperature, minimum temperature, mean temperature, maximum dew-point temperature, minimum dew-point temperature, and delta dew-point temperature. Seasonal pattern of clinical exacerbation was evaluated in relation to aeroallergen counts (20 types of fungal spores and 28 types of pollen). Seasonal pattern of clinical exacerbation of SPA-RAO was associated with increases in temperature (heat) and dew-point temperature (humidity), counts of fungal spores, and counts of grass pollen grains. Seasonal pattern of clinical exacerbation paralleled and was associated with increases in counts of specific types of fungal spores, particularly Basidiospore, Nigrospora, and Curvularia spp. Although a causal relationship could not be determined, the seasonal pattern of clinical exacerbation of SPA-RAO was associated with hot and humid conditions and high environmental counts for fungal spores and grass pollen grains. It is not known yet whether these are aeroallergens that cause clinical exacerbation of the disease.