bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum BAFF and APRIL might be associated with disease activity and kidney damage in patients with anti‐glomerular basement membrane disease
Authors: Xin Gang , Cui Zhao , Su Yun , Xu Li‐Xia , Zhao Ming‐Hui , Li Kang‐Sheng
Published: January 2013

Aim

B cell activating factor belonging to the tumour necrosis factor family (BAFF) and a proliferation inducing ligand (APRIL) are two tumour necrosis factor (TNF)‐like cytokines that were found to be elevated in many autoimmune diseases. Anti‐glomerular basement membrane (GBM) disease is a typical severe autoimmune disease characterized by raised serum anti‐GBM antibodies. In this study we aimed to detect the serum levels of BAFF and APRIL in patients with anti‐GBM disease, and their clinical significance was further analyzed.

Methods

Forty‐seven patients with anti‐GBM disease were enrolled in this study. Forty‐eight healthy individuals were used as normal controls. The levels of serum BAFF and APRIL were assessed using commercially available enzyme linked immunosorbent assay kits. The association between the levels of serum BAFF and APRIL, and the clinical and pathological parameters were further evaluated.

Results

The serum levels of BAFF and APRIL in patients with anti‐GBM disease were significantly higher than that in normal controls (12.3 ± 14.1 ng/mL vs. 0.9 ± 0.3 ng/mL, P < 0.001; 19.1 ± 22.9 ng/mL vs. 1.6 ± 4.6 ng/mL, P < 0.001), respectively. The levels of serum APRIL were correlated with the titres of anti‐GBM antibodies (r = 0.347, P = 0.041), and the levels of serum BAFF were associated with the percentage of glomeruli with crescents (r = 0.482, P = 0.015) in patients with anti‐GBM disease.

Conclusion

The levels of serum BAFF and APRIL were raised in patients with anti‐GBM disease and might be associated with disease activity and kidney damage.
Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains
Authors: Wu R. Y. , Pasyk M. , Wang B. , Forsythe P. , Bienenstock J. , Mao Y.–K. , Sharma P. , Stanisz A. M. , Kunze W. A.
Published: January 2013

Background  Commensal bacteria such as probiotics that are neuroactive acutely affect the amplitudes of intestinal migrating motor complexes (MMCs). What is lacking for an improved understanding of these motility effects are region specific measurements of velocity and frequency. We have combined intraluminal pressure recordings with spatiotemporal diameter maps to analyze more completely effects of different strains of beneficial bacteria on motility.

Methods  Intraluminal peak pressure (PPr) was measured and video recordings made of mouse ex vivo jejunum and colon segments before and after intraluminal applications of Lactobacillus rhamnosus (JB‐1) or Lactobacillus reuteri (DSM 17938). Migrating motor complex frequency and velocity were calculated.

Key Results  JB‐1 decreased jejunal frequencies by 56% and 34% in colon. Jejunal velocities increased 171%, but decreased 31% in colon. Jejunal PPr decreased by 55% and in colon by 21%. DSM 17938 increased jejunal frequencies 63% and in colon 75%; jejunal velocity decreased 57%, but increased in colon 146%; jejunal PPr was reduced 26% and 12% in colon. TRAM‐34 decreased frequency by 71% and increased velocity 200% for jejunum, but increased frequency 46% and velocity 50% for colon; PPr was decreased 59% for jejunum and 39% for colon.

Conclusions & Inferences  The results show that probiotics and other beneficial bacteria have strain and region‐specific actions on gut motility that can be successfully discriminated using spatiotemporal mapping of diameter changes. Effects are not necessarily the same in colon and jejunum. Further research is needed on the detailed effects of the strains on enteric neuron currents for each gut region.
The diagnostic potential of salivary protease activities in periodontal health and disease
Authors: Thomadaki K , Bosch JA , Oppenheim FG , Helmerhorst EJ
Published: January 2013

Periodontal disease is characterised by proteolytic processes involving enzymes that are released by host immune cells and periodontal bacteria. These enzymes, when detectable in whole saliva, may serve as valuable diagnostic markers for disease states and progression. Because the substrate specificities of salivary proteases in periodontal health and disease are poorly characterised, we probed these activities using several relevant substrates: (i) gelatin and collagen type IV; (ii) the Arg/Lys–rich human salivary substrate histatin‐5; and (iii) a histatin‐derived synthetic analog benzyloxycarbonyl‐Arg‐Gly‐Tyr‐Arg‐methyl cumaryl amide (Z‐RGYR‐MCA). Substrate degradation was assessed in gel (zymography) and in solution. Whole saliva supernatant enzyme activities directed at gelatin, quantified from the 42 kDa, 92 kDa and 130 kDa bands in the zymograms, were 1.3, 1.4 and 2.0‐fold higher, respectively, in the periodontal patient group (P < 0.01), consistent with enhanced activities observed towards collagen type IV. On the other hand, histatin 5 degraded equally fast in healthy and periodontal patients' whole saliva supernatant samples (P > 0.10). Likewise, the hydrolysis rates of the Z‐RGYR‐MCA substrate were the same in the healthy and periodontal patient groups (P > 0.10). In conclusion, gelatinolytic/collagenolytic activities but not trypsin‐like activities in human saliva differentiate health from periodontal disease and may thus provide an adjuvant to diagnosis for monitoring disease activity.
Comparison of optic area measurement using fundus photography and Optical Coherence Tomography between optic nerve head drusen and control subjects
Authors: Flores‐Rodríguez Patricia , Gili Pablo , Martín‐Ríos María Dolores , Grifol‐Clar Eulalia
Published: January 2013

Purpose

To compare optic disc area measurement between optic nerve head drusen (ONHD) and control subjects using fundus photography, time‐domain optical coherence tomography (TD‐OCT) and spectral‐domain optical coherence tomography (SD‐OCT). We also made a comparison between each of the three techniques.

Methods

We performed our study on 66 eyes (66 patients) with ONHD and 70 healthy control subjects (70 controls) with colour ocular fundus photography at 20º (Zeiss FF 450 IR plus), TD‐OCT (Stratus OCT) with the Fast Optic Disc protocol and SD‐OCT (Cirrus OCT) with the Optic Disc Cube 200 × 200 protocol for measurement of the optic disc area. The measurements were made by two observers and in each measurement a correction of the image magnification factor was performed. Measurement comparison using the Student's t‐test/Mann–Whitney U test, the intraclass correlation coefficient, Pearson/Spearman rank correlation coefficient and the Bland‐Altman plot was performed in the statistical analysis.

Results

Mean and standard deviation (SD) of the optic disc area in ONHD and in controls was 2.38 (0.54) mm2 and 2.54 (0.42) mm2, respectively with fundus photography; 2.01 (0.56) mm2 and 1.66 (0.37) mm2, respectively with TD‐OCT, and 2.03 (0.49) mm2 and 1.75 (0.38) mm2, respectively with SD‐OCT. In ONHD and controls, repeatability of optic disc area measurement was excellent with fundus photography and optical coherence tomography (TD‐OCT and SD‐OCT), but with a low degree of agreement between both techniques.

Conclusions

Optic disc area measurement is smaller in ONHD compared to healthy subjects with fundus photography, unlike time‐domain and spectral‐domain optical coherence tomography in which the reverse is true. Both techniques offer good repeatability, but a low degree of correlation and agreement, which means that optic disc area measurement is not interchangeable or comparable between techniques.
Assessment of neuroretinal function in a group of functional amblyopes with documented LGN deficits
Authors: Brown Brian , Feigl Beatrix , Gole Glen A , Mullen Kathy , Hess Robert F
Published: January 2013

Purpose

In this study we examine neuroretinal function in five amblyopes, who had been shown in previous functional MRI (fMRI) studies to have compromised function of the lateral geniculate nucleus (LGN), to determine if the fMRI deficit in amblyopia may have its origin at the retinal level.

Methods

We used slow flash multifocal ERG (mfERG) and compared averaged five ring responses of the amblyopic and fellow eyes across a 35 deg field. Central responses were also assessed over a field which was about 6.3 deg in diameter. We measured central retinal thickness using optical coherence tomography. Central fields were measured using the MP1‐Microperimeter which also assesses ocular fixation during perimetry. MfERG data were compared with fMRI results from a previous study.

Results

Amblyopic eyes had reduced response density amplitudes (first major negative to first positive (N1‐P1) responses) for the central and paracentral retina (up to 18 deg diameter) but not for the mid‐periphery (from 18 to 35 deg). Retinal thickness was within normal limits for all eyes, and not different between amblyopic and fellow eyes. Fixation was maintained within the central 4° more than 80% of the time by four of the five participants; fixation assessed using bivariate contour ellipse areas (BCEA) gave rankings similar to those of the MP‐1 system. There was no significant relationship between BCEA and mfERG response for either amblyopic or fellow eye. There was no significant relationship between the central mfERG eye response difference and the selective blood oxygen level dependent (BOLD) LGN eye response difference previously seen in these participants.

Conclusions

Retinal responses in amblyopes can be reduced within the central field without an obvious anatomical basis. Additionally, this retinal deficit may not be the reason why the LGN BOLD (blood oxygen level dependent) responses are reduced for amblyopic eye stimulation.
Living as a family in the midst of chronic illness
Authors: Årestedt Liselott , Persson Carina , Benzein Eva
Published: January 2013

Aims and objectives

The aim of the study was to illuminate the meaning of lived experience of living as a family in the midst of chronic illness.

Background

Chronic illness implies a change for both the individual and the family. In this changed situation, all family members seem to benefit from sharing experiences and receiving support. Current research highlights the individual patient's or family member's perspectives on chronic illness, but family systems nursing (FSN) studies are warranted.

Design

A qualitative design with a FSN approach was chosen.

Method

Repeated qualitative narrative interviews with seven families living with chronic illness were performed. A phenomenological hermeneutic analysis, inspired by Ricoeur, was used to interpret the data.

Results

The phenomenon can be described as an ongoing movement towards well‐being. The results included two themes and five sub‐themes. The first theme was ‘Co‐creating a context for living with illness’ with the subthemes; ‘learning to live with the expressions of illness’ and ‘communicating the illness within and outside the family’. The second theme was ‘Co‐creating alternative ways for everyday life’ with the subthemes; ‘adapting to a new life rhythm’, ‘altering relationships’ and ‘changing roles and tasks in the family’.

Conclusions

Living as a family in the midst of chronic illness can be described as an ongoing process where the family members co‐create a context for living with illness. They also co‐create a context for alternative ways of everyday life.

Relevance to clinical practice

Knowledge about lived experience of living as a family in the midst of chronic illness can help nurses to adopt a FSN care perspective. This can increase the chances of taking advantage of the ways family members manage situations together, as well as highlight resources within the family.
Rostro‐caudal and dorso‐ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference
Authors: RAHM CHRISTOFFER , LIBERG BENNY , WIBERG‐KRISTOFFERSEN MARIA , ASPELIN PETER , MSGHINA MUSSIE
Published: January 2013

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks.
Identification of a cis‐element that mediates multiple pathways of the endoplasmic reticulum stress response in rice
Authors: Hayashi Shimpei , Takahashi Hideyuki , Wakasa Yuhya , Kawakatsu Taiji , Takaiwa Fumio
Published: January 2013

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress. Intracellular signalling pathways are activated to alleviate the stress. The ER stress sensor IRE1 induces the active form of key transcription factors, such as XBP1 in mammals and bZIP50 in Oryza sativa (rice), by mediating the unconventional splicing of their mRNAs. Although the characterization of cis‐elements that are recognized by these transcription factors is essential for understanding ER stress responses, such cis‐elements remain unidentified in plants. Here, a cis‐element named pUPRE–II was identified from promoters of bZIP50‐dependent genes using chromatin immunoprecipitation assays and electrophoretic mobility shift assays. The sequence of pUPRE–II (e.g. 5′–GATGACGCGTAC–3′ in the OsSAR1 promoter) was found to be flexible and not identical with that of mUPRE, a cis‐element that preferentially interacts with mammalian XBP1. Unexpectedly, the transcription factor bZIP60, another ER stress sensor in rice, and a counterpart of mammalian ATF6, also showed strong binding affinity for pUPRE–II without assistance from co‐factors. Reporter assays indicated that pUPRE–II significantly contributes to gene expression mediated by bZIP50 or bZIP60 in rice. Although both bZIP50 and bZIP60 bound to pUPRE–II, these transcription factors showed distinct requirements for transcriptional activation. This study provides a missing link between ER stress sensors and stress‐responsive genes in rice. Furthermore, the characteristics of pUPRE–II highlight the uniqueness of ER stress‐responsive transcription in plants.
Serotonergic control of Purkinje cell maturation and climbing fibre elimination by 5‐HT3 receptors in the juvenile mouse cerebellum
Authors: Oostland Marlies , Buijink M. Renate , van Hooft Johannes A.
Published: January 2013

Key points

Serotonin 3 (5‐HT3) receptors are expressed by excitatory granule cells in the cerebellum during early postnatal development.

Here we show a novel role for serotonin in the regulation of cerebellar postnatal development via 5‐HT3 receptors.

Using 5‐HT3A receptor knockout mice we show that 5‐HT3 receptors expressed by granule cells, via the glycoprotein reelin, regulate the morphological maturation of Purkinje cells.

The 5‐HT3A receptor knockout mice show abnormal physiological maturation of Purkinje cells and impaired short‐term plasticity at the parallel fibre–Purkinje cell synapse, resulting in delayed climbing fibre elimination.

With these results, we provide a better understanding of the role of serotonin in the developing brain, the control it has on the postnatal maturation of the cerebellum, and the cerebellum as a highly adaptive system during early postnatal development.

Abstract  Functional serotonin 3 (5‐HT3) receptors are transiently expressed by cerebellar granule cells during early postnatal development, where they modulate short‐term synaptic plasticity at the parallel fibre–Purkinje cell synapse. Here, we show that serotonin controls maturation of Purkinje cells in the mouse cerebellum. The 5‐HT3 receptors regulate morphological maturation of Purkinje cells during early postnatal development, and this effect is mediated by the glycoprotein reelin. Using whole‐cell patch‐clamp recordings we also investigated physiological development of Purkinje cells in 5‐HT3A receptor knockout mice during early postnatal development, and found abnormal physiological maturation, characterized by a more depolarized resting membrane potential, an increased input resistance and the ability to fire action potentials upon injection of a depolarizing current at an earlier age. Furthermore, short‐term synaptic plasticity was impaired at both the parallel fibre–Purkinje cell and the climbing fibre–Purkinje cell synapses, and both the amplitude and the frequency of spontaneous miniature events recorded from Purkinje cells were increased. The expedited morphological and physiological maturation affects the whole cerebellar cortical network, as indicated by delayed climbing fibre elimination in 5‐HT3A receptor knockout mice. There was no difference between wild‐type and 5‐HT3A receptor knockout mice in any of the morphological or physiological properties described above at later ages, indicating a specific time window during which serotonin regulates postnatal development of the cerebellum via 5‐HT3 receptors expressed by granule cells.
Hyperpolarisation‐activated cyclic nucleotide‐gated channels regulate the spontaneous firing rate of olfactory receptor neurons and affect glomerular formation in mice
Authors: Nakashima Noriyuki , Ishii Takahiro M. , Bessho Yasumasa , Kageyama Ryoichiro , Ohmori Harunori
Published: January 2013

Key points

Olfactory receptor neurons (ORNs) utilise the spontaneous firing activity for axonal targeting.

Cyclic AMP‐gated HCN channels depolarised the membranes of ORNs and enhanced their spontaneous firing activity.

Standing activation of the β‐adrenergic receptors maintained the basal cAMP level and resulted in the opening of HCN channels.

The over‐expression of HCN4 resulted in a decrease in the number of glomeruli in the olfactory bulb, which was rescued by suppressing HCN4 over‐expression.

HCN channels, together with the standing activation of G‐protein‐coupled receptors, maintained the spontaneous firing activity of ORNs and were essential to glomerular formation in the olfactory bulb.

Abstract  Olfactory receptor neurons (ORNs), which undergo lifelong neurogenesis, have been studied extensively to understand how neurons form precise topographical networks. Neural projections from ORNs are principally guided by the genetic code, which directs projections from ORNs that express a specific odorant receptor to the corresponding glomerulus in the olfactory bulb. In addition, ORNs utilise spontaneous firing activity to establish and maintain the neural map. However, neither the process of generating this spontaneous activity nor its role as a guidance cue in the olfactory bulb is clearly understood. Utilising extracellular unit‐recordings in mouse olfactory epithelium slices, we demonstrated that the hyperpolarisation‐activated cyclic nucleotide‐gated (HCN) channels in the somas of ORNs depolarise their membranes and boost their spontaneous firing rates by sensing basal cAMP levels; the odorant‐sensitive cyclic nucleotide‐gated (CNG) channels in cilia do not. The basal cAMP levels were maintained via the standing activation of β‐adrenergic receptors. Using a Tet‐off system to over‐express HCN4 channels resulted in the enhancement of spontaneous ORN activity and dramatically reduced both the size and number of glomeruli in the olfactory bulb. This phenotype was rescued by the administration of doxycycline. These findings suggest that cAMP plays different roles in cilia and soma and that basal cAMP levels in the soma are directly converted via HCN channels into a spontaneous firing frequency that acts as an intrinsic guidance cue for the formation of olfactory networks.
A defined heteromeric KV1 channel stabilizes the intrinsic pacemaking and regulates the output of deep cerebellar nuclear neurons to thalamic targets
Authors: Ovsepian Saak V. , Steuber Volker , Le Berre Marie , O’Hara Liam , O’Leary Valerie B. , Dolly J. Oliver
Published: January 2013

Key points

The result of cerebellar integration is encoded in the output of deep cerebellar nuclear (DCN) neurons in the form of dynamic changes in spontaneous firing rate and pattern.

The soma of these neurons has been demonstrated to be enriched with potassium channels (KV1) produced by mandatory multi‐merization of KV1.1, 1.2 α and KVβ2 subunits.

The outward K+ current (IKV1) mediated by these channels is proven to be a critical stabilizer for both the rate and temporal precision of self‐sustained firing of DCN neurons.

Activated from low‐threshold, IKV1 provides an effective counter‐balance to depolarizing inputs, attenuates the back‐propagating action potentials, favouring dominance of clock‐like somatic pace‐making of these cells – an important condition for accurate encoding of time variant inputs.

The relevance of these observations to physiology and integrative brain mechanisms is shown through a multi‐compartmental neuronal model as well as retro‐axonal tracing of neurons projecting to thalamic relay nuclei.

Abstract  The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with KV1 channels produced by mandatory multi‐merization of KV1.1, 1.2 α and KVβ2 subunits. Being constitutively active, the K+ current (IKV1) mediated by these channels stabilizes the rate and regulates the temporal precision of self‐sustained firing of these neurons. Placed strategically, IKV1 provides a powerful counter‐balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi‐stability. Somatic location with low activation threshold render IKV1 instrumental in voltage‐dependent de‐coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back‐propagating action potentials into the somato‐dendritic compartment. The latter is also demonstrated to secure the dominance of clock‐like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi‐compartmental modelling and retro‐axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established.
Experimental Modeling of Transients in Large SOFC Systems
Authors: Leone P. , Lanzini A.
Published: January 2013

This work investigates the dynamic operation of a large solid oxide fuel cell (SOFC) system using the system identification modeling approach. Transient modeling can be of particular interest in order to describe and optimize start-up and shut-down procedures in SOFC systems; moreover, mathematical description of transients is helpful in the diagnostic of hazardous conditions during dynamic operation (i.e., load following). Physical based models—described by differential equations—are usually complex and need significant computing time. To achieve real-time capability, the focus is on empirical models. In this study, the transient operation of a large SOFC generator is reproduced by using the system identification approach that is based on the definition of a black-box model and on the identification of main model coefficients based on real experimental data. In particular, the start-up of the system and its dynamics under fuel sensitivity experiments are investigated. First, the work valuably shows some experimental results of a large SOFC generator under dynamic operation. In particular, modeling results show that the system identification approach is an effective tool for the description of the transient behavior of SOFC large systems. The simulation of the start-up of a 100 kWe (electric) SOFC system shows the possibility to save ∼20% of start-up time using an electric air heater rated a 30% in power than the nominal one. The increase of natural gas flow during the start-up operation is instead not beneficial in term of yielding a faster procedure; rather, it leads to an excessive cooling of the stack due to internal reforming of natural gas (the higher amount of fuel burnt in the combustion zone does not lead to a more efficient way to preheat the cathode air). The results of this work are fully supported by experimental data available from a real generator running in Italy through years 2006–2009 and thus believed to be a valuable contribution for the scientific and engineering community.
Development of Production Technology for Membrane-Electrode Assemblies With Radical Capturing Layer
Authors: Kobayashi Toshiro , Hirai Etsuro , Itou Hideki , Moriga Takuya
Published: January 2013

This paper describes the development of mass-production technology for membrane-electrode assemblies (MEA) with a radical capturing layer and verifies its performance. Some of the authors of this paper previously developed an MEA with a radical capturing layer along the boundaries between the electrode catalyst layer and the polymer membrane to realize an endurance time of 20,000 h in accelerated daily start and daily stop (DSS) deterioration tests. Commercialization of these MEAs requires a production technology that suits mass production lines and provides reasonable cost performance. After developing a water-based slurry and selecting a gas diffusion layer (GDL), a catalyst layer forming technology uses a rotary screen method for electrode formation. Studies confirmed continuous formation of the catalyst layer, obtaining an anode/cathode thickness of 55 μm (+10/−20)/50 μm (+10/−20) by optimizing the opening ratio and thickness of the screen plate. A layer-forming technology developed for the radical capturing layer uses a two-fluid spraying method. Continuous formation of an 8 μm thick (±3 μm) radical capturing layer proved feasible by determining the appropriate slurry viscosity, spray head selection, and optimization of spraying conditions.
Torque Measurement With Compliant Mechanisms
Authors: Ma Raymond , Slocum Alexander H. , Sung Edward , Bean Jonathan F. , Culpepper Martin L.
Published: January 2013

This work focuses on the design, development, and testing of an inexpensive, low-profile, cartwheel flexure mechanism for torque measurement. It has been designed primarily for use in a rehabilitation and diagnostics instrument for the treatment of ankle injuries. The sensor is manufactured rapidly and at low-cost using an Omax™ abrasive waterjet machine. Strain gauges are bonded to the flexure beams to measure applied strain using a full wheatstone bridge circuit. Displacement, force, and torque are then calculated from the measured circuit voltage; power and velocity can also be determined if required by the application. Experimental results show that there exists a linear relationship between applied torque and output voltage of the wheatstone bridge for the nested cartwheel flexure design. Furthermore, results of preliminary tests of an ankle rehabilitation device show that it fulfills a need not currently satisfied by current rehabilitation and diagnostic technology in physical medicine and rehabilitation.
An Efficient Polymer Molecular Sieve for Membrane Gas Separations
Authors: Carta Mariolino , Malpass-Evans Richard , Croad Matthew , Rogan Yulia , Jansen Johannes C. , Bernardo Paola , Bazzarelli Fabio , McKeown Neil B.
Published: January 2013

Bicyclic Bridge to Improvement

Polymers of intrinsic microporosity are a recently developed class of contorted rigid glassy ladderlike polymers having very high free volume (open internal spaces). The intrinsic porosity of these materials has made them of interest for ultrahigh permeability gas separation membranes. However, while the polymers show good gas permeability, they have only moderate gas selectivity.

Carta
et al.

(p.
303
; see the Perspective by
Guiver and Lee
) hypothesized that if they could replace the dioxin-like rings in their polymers with stiffer bridged bicyclic rings, they could improve the membrane properties of the polymer. By exploiting reactions connected to the formation of Tröger's base to form the multiple covalent bonds needed to make the bicyclic rings, the resulting polymers showed significantly improved selectivity and permeability.
Structure of Histone mRNA Stem-Loop, Human Stem-Loop Binding Protein, and 3′hExo Ternary Complex
Authors: Tan Dazhi , Marzluff William F. , Dominski Zbigniew , Tong Liang
Published: January 2013

Recognizing a Stem-Loop Structure

Metazoan histone messenger RNAs (mRNAs) have a conserved stem-loop (SL) structure at their 3′-end. The stem-loop is bound by the stem-loop binding protein (SLBP), which is required for histone mRNA 3′-end processing, export, stability, and translation. The 3′-5′ exonuclease 3′hExo also binds the SL and trims off three nucleotides.

Tan
et al.

(p.
318
) determined the high-resolution structure of the SL bound by the RNA-binding domain (RBD) of human SLBP together with human 3′hExo. The conformation of the loop differed substantially from other RNA tetraloops and the SLBP RBD may function as a ruler that can measure the length of the stem. Although the SLBP directly recognizes the guanine base of the second nucleotide of the stem, it appears that SLBP and 3′hExo recognize the unique shape of the SL.
The FLIP Side of Life
Authors: Silke John , Strasser Andreas
Published: January 2013

The protein c-FLIP plays a role in preventing cell death by both apoptosis and necroptosis.
New Insight into Amphotericin B Resistance in Aspergillus terreus
Authors: Blum Gerhard , Hörtnagl Caroline , Jukic Emina , Erbeznik Thomas , Pümpel Thomas , Dietrich Hermann , Nagl Markus , Speth Cornelia , Rambach Günter , Lass-Flörl Cornelia
Published: January 2013

Amphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared the
in vivo
virulence of an AMB-resistant
Aspergillus terreus
(ATR) isolate with that of an AMB-susceptible
A. terreus
isolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistance
in vitro
by comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. The
in vitro
data demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.
The Novel CTX-M-116 β-Lactamase Gene Discovered in Proteus mirabilis Is Composed of Parts of the CTX-M-22 and CTX-M-23 Genes
Authors: Fursova N. , Pryamchuk S. , Kruglov A. , Abaev I. , Pecherskikh E. , Kartsev N. , Svetoch E. , Dyatlov I.
Published: January 2013

The novel β-lactamase geneblaCTX-M-116was identified in aProteus mirabilisnosocomial isolate recovered from the urine of a patient in Moscow in 2005. DNA sequence analysis showedblaCTX-M-116to be a hybrid gene consisting of 5′blaCTX-M-23(nucleotides 1 to 278) and 3′blaCTX-M-22(nucleotides 286 to 876) moieties separated by an intervening putative site of recombination (GTTAAAT). A retrospective analysis of availableblaCTX-Mgenes in the GenBank database revealed 19blaCTX-Mgenes that display the same hybrid structure.
Inhibitory and Fungicidal Effects of Antifungal Drugs against Aspergillus Species in the Presence of Serum
Authors: Elefanti Antigoni , Mouton Johan W. , Krompa Katerina , Al-Saigh Rafal , Verweij Paul E. , Zerva Loukia , Meletiadis Joseph
Published: January 2013

Given the high protein binding rates of antifungal drugs and the effect of serum proteins on
Aspergillus
growth, we investigated the
in vitro
pharmacodynamics of amphotericin B, voriconazole, and three echinocandins in the presence of human serum, assessing both inhibitory and fungicidal effects.
In vitro
inhibitory (IC) and fungicidal (FC) concentrations against 5 isolates of
Aspergillus fumigatus
,
Aspergillus flavus
, and
Aspergillus terreus
were determined with a CLSI M38-A2-based microdilution method using the XTT methodology after 48 h of incubation at 35°C with a medium supplemented with 50% human serum. In the presence of serum, the IC and FC of amphotericin B and the IC of echinocandins were increased (1.21- to 13.44-fold), whereas voriconazole IC and FC were decreased (0.22- to 0.90-fold). The amphotericin B and voriconazole FC/IC ratios did not change significantly (0.59- to 2.33-fold) in the presence of serum, indicating that the FC increase was due to the IC increase. At echinocandin concentrations above the minimum effective concentration (MEC), fungal growth was reduced by 10 to 50% in the presence of human serum, resulting in complete inhibition of growth for some isolates. Thus, the
in vitro
activities of amphotericin B and echinocandins were reduced, whereas that of voriconazole was enhanced, in the presence of serum. These changes could not be predicted by the percentage of protein binding, indicating that other factors and/or secondary mechanisms may account for the observed
in vitro
activities of antifungal drugs against
Aspergillus
species in the presence of serum.
Preclinical Investigations Reveal the Broad-Spectrum Neutralizing Activity of Peptide Pep19-2.5 on Bacterial Pathogenicity Factors
Authors: Heinbockel Lena , Sánchez-Gómez Susana , Martinez de Tejada Guillermo , Dömming Sabine , Brandenburg Julius , Kaconis Yani , Hornef Mathias , Dupont Aline , Marwitz Sebastian , Goldmann Torsten , Ernst Martin , Gutsmann Thomas , Schürholz Tobias , Brandenburg Klaus
Published: January 2013

Bacterial infections are known to cause severe health-threatening conditions, including sepsis. All attempts to get this disease under control failed in the past, and especially in times of increasing antibiotic resistance, this leads to one of the most urgent medical challenges of our times. We designed a peptide to bind with high affinity to endotoxins, one of the most potent pathogenicity factors involved in triggering sepsis. The peptide Pep19-2.5 reveals high endotoxin neutralization efficiency
in vitro
, and here, we demonstrate its antiseptic/anti-inflammatory effects
in vivo
in the mouse models of endotoxemia, bacteremia, and cecal ligation and puncture, as well as in an
ex vivo
model of human tissue. Furthermore, we show that Pep19-2.5 can bind and neutralize not only endotoxins but also other bacterial pathogenicity factors, such as those from the Gram-positive bacterium
Staphylococcus aureus
. This broad neutralization efficiency and the additive action of the peptide with common antibiotics makes it an exceptionally appropriate drug candidate against bacterial sepsis and also offers multiple other medication opportunities.
Regulation of Inhibition of Neutrophil Infiltration by the Two-Component Regulatory System CovRS in Subcutaneous Murine Infection with Group A Streptococcus
Authors: Li Jinquan , Zhu Hui , Feng Wenchao , Liu Mengyao , Song Yingli , Zhang Xiaolan , Zhou Yang , Bei Weicheng , Lei Benfang
Published: January 2013

Hypervirulent invasive group A streptococcus (GAS) isolates inhibit neutrophil infiltration more than pharyngitis isolates do, and the molecular basis of this difference is not well understood. This study was designed to first determine whether natural null mutation of the two-component regulatory system CovRS is responsible for the enhancement of the inhibition of neutrophil recruitment seen in hypervirulent GAS. Next, we examined the role of CovRS-regulated interleukin-8/CXC chemokine peptidase (SpyCEP), C5a peptidase (ScpA), and platelet-activating factor acetylhydrolase (SsE) in the enhanced innate immune evasion. Invasive isolate MGAS5005 induces less neutrophil infiltration and produced a greater lesion area than pharyngitis isolate MGAS2221 in subcutaneous infections of mice. It is known that MGAS5005, but not MGAS2221, has a natural 1-bp deletion in the
covS
gene. Replacement of
covS
Δ1bp
in MGAS5005 with wild-type
covS
resulted in the MGAS2221 phenotype. Deletion of
covS
from MGAS2221 resulted in the MGAS5005 phenotype. Tests of single, double, and triple deletion mutants of the MGAS5005
sse
,
spyCEP
, and
scpA
genes found that SsE plays a more important role than SpyCEP and ScpA in the inhibition of neutrophil recruitment and that SsE, SpyCEP, and ScpA do not have synergistic effects on innate immune evasion by MGAS5005. Deletion of
sse
, but not
spyCEP
or
scpA
, of MGAS2221 enhances neutrophil recruitment. Thus,
covS
null mutations can cause substantial inhibition of neutrophil recruitment by enhancing the expression of the chemoattractant-degrading virulence factors, and SsE, but not SpyCEP or ScpA, is required for CovRS-regulated GAS inhibition of neutrophil infiltration.
Antibodies to gp120 and PD-1 Expression on Virus-Specific CD8
+
T Cells in Protection from Simian AIDS
Authors: Vaccari Monica , Halwani Rabih , Patterson L. Jean , Boasso Adriano , Beal Jennifer , Tryniszewska Elzbieta , Hryniewicz Anna , Venzon David , Haddad Elias K. , El-Far Mohamed , Rosati Margherita , Pavlakis George N. , Felber Barbara K. , Al-Muhsen Saleh , Robert-Guroff Marjorie , Sekaly Rafick-Pierre , Franchini Genoveffa
Published: January 2013

We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4
+
and CD8
+
T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV
gag
,
pol
,
env
, and
Retanef
genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 × MVA) or twice (2 × MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV
gag
and
nef
genes but not
Retanef
or
env
(1 × MVA/Ad5). While two of the vaccine regimens (1 × MVA and 1 × MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 × MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8
+
CM9
+
effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8
+
T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8
+
T-cell responses.
Amateur boxing in the last 59 years. Impact of rules changes on the type of verdicts recorded and implications on boxers’ health
Authors: Bianco Massimiliano , Loosemore Mike , Daniele Gianlorenzo , Palmieri Vincenzo , Faina Marcello , Zeppilli Paolo
Published: January 2013

Background/aim

Several changes have occurred in Olympic boxing (OB) in the last few decades, influencing the results in official competitions. The aim of this study was to assess how the evolution of rules changed the rate of the results that can influence boxers’ health.

Methods

From a web-research, the results of OB tournaments from 1952 to 2011 were reviewed (29 357 bouts). For each event, rate of knockout (KO), referee-stop contest (RSC), RSC-Head (RSCH), RSC-Injury (RSCI), RSC-Outclassed (RSCO), abandon, disqualification and points decisions were recorded. In our analysis we investigated the changes that occurred after the introduction of the standing-count rule (1964), mandatory head guard (1984), computerised scoring system (1992), RSCO (2000–2009) and modification of bout formula 3×3 min rounds (3×3, until 1997, 5×2 min rounds (5×2) until 1999, 4×2 min rounds (4×2) until 2008, 3×3 from 2009).

Results

The most important results were: (1) an RSCI rate increase (0.72–2.42%, p<0.03) after the standing-count rule; (2) a lower RSCI (0.60%, p<0.001) and higher RSCH (1.31–4.92%, p<0.001) and RSC (9.71–13.05%, p<0.03) rate with mandatory head guard; (3) a KO rate reduction (6.44–2.09%, p<0.001) with the computerised scoring system; (4) an RSC (13.15–5.91%, p<0.05) and RSCH (4.23–1.41%, p<0.001) rate reduction comparing 5×2–4×2 bouts.

Conclusions

In the last six decades, along with rule changes in OB, a clear reduction of health challenging results was observed. In the near future, older rules will be adopted (no head guard and a manual scoring system). Continued medical surveillance is important to ensure that new rule changes do not result in poor medical outcomes for the boxers.
Early and intermediate survival after transcatheter aortic valve implantation: systematic review and meta-analysis of 14 studies
Authors: Messori Andrea , Trippoli Sabrina , Biancari Fausto
Published: January 2013

Background

Transcatheter aortic valve implants (TAVIs) is indicated as an alternative to surgical valve replacement for patients unfit for surgery. No systematic review has studied survival after 2 years and limited information is available on between-study heterogeneity.

Objectives

A systematic review and meta-analysis on intermediate survival after TAVI.

Data sources

PubMed, EMBASE, Scopus and references of selected articles.

Study eligibility criteria

Clinical studies evaluating TAVI, published between 2010 and 2012, reporting survival at 2 or more years.

Participants

About 3500 patients from 14 studies.

Study appraisal and synthesis methods

Proportion meta-analysis with 95% CI and heterogeneity assessment (I2and Cochran's Q). Meta-regression analysis was performed as well.

Results

Pooled immediate postoperative death rate was 7.8% (95% CI 6.2% to 9.8%, I2=40.8%; Cochran's Q=97.7 with 92.9 df, p<0.0001) and stroke rate was 3.8% (95% CI 2.8% to 5.0%, I2=34.3%; Cochran's Q=96.5 with 92.9 df, p<0.0001). Pooled death rates at 1, 2 and 3 years were 23.2%, 31.0% and 38.6%, respectively. Among studies reporting on concomitant percutaneous coronary intervention, pooled death rates at 30 days, 1 year and 2 years were 6.3%, 17.8% and 25.8%, respectively.

Limitations

Although our analysis examined a total of about 3500 patients, only a minority of these were actually followed up after 2 years.

Conclusions

Pooled survival rates after TAVI (at 2 years: 69.0%; at 3 years: 61.4%) can be considered excellent, particularly in the light of the high-risk profile of this patient population.

Implications of key findings

The favourable intermediate outcome in patients subjected to TAVI seems to justify its use in patients unfit for surgery. Such pooled results indicate that TAVI is a valid alternative to surgical valve replacement, but lack of data on late durability after TAVI prevents its use in low-risk patients with long expectancy of life.
How long has NICE taken to produce Technology Appraisal guidance? A retrospective study to estimate predictors of time to guidance
Authors: Casson Steven G , Ruiz Francis J , Miners Alec
Published: January 2013

Objectives

To assess how long the UK's National Institute for Health and Clinical Excellence's (NICE) Technology Appraisal Programme has taken to produce guidance and to determine independent predictors of time to guidance.

Design

Retrospective time to event (survival) analysis.

Setting

Technology Appraisal guidance produced by NICE.

Datasource

All appraisals referred to NICE by February 2010 were included, except those referred prior to 2001 and a number that were suspended.

Outcome measure

Duration from the start of an appraisal (when the scope document was released) until publication of guidance.

Results

Single Technology Appraisals (STAs) were published significantly faster than Multiple Technology Appraisals (MTAs) with median durations of 48.0 (IQR; 44.3–75.4) and 74.0 (IQR; 60.9–114.0) weeks, respectively (p <0.0001). Median time to publication exceeded published process timelines, even after adjusting for appeals. Results from the modelling suggest that STAs published guidance significantly faster than MTAs after adjusting for other covariates (by 36.2 weeks (95% CI −46.05 to −26.42 weeks)) and that appeals against provisional guidance significantly increased the time to publication (by 42.83 weeks (95% CI 35.50 to 50.17 weeks)). There was no evidence that STAs of cancer-related technologies took longer to complete compared with STAs of other technologies after adjusting for potentially confounding variables and only weak evidence suggesting that the time to produce guidance is increasing each year (by 1.40 weeks (95% CI −0.35 to 2.94 weeks)).

Conclusions

The results from this study suggest that the STA process has resulted in significantly faster guidance compared with the MTA process irrespective of the topic, but that these gains are lost if appeals are made against provisional guidance. While NICE processes continue to evolve over time, a trade-off might be that decisions take longer but at present there is no evidence of a significant increase in duration.
Chronic lower respiratory diseases among demolition and cement workers: a population-based register study
Authors: Mølgaard Ellen Fischer , Hannerz Harald , Tüchsen Finn , Brauer Charlotte , Kirkeskov Lilli
Published: January 2013

Objective

To estimate standardised hospitalisation ratios (SHR) for chronic lower respiratory diseases among demolition and cement workers in Denmark, 1995–2009.

Design

This is a population-based register study on data from ‘the Occupational Hospitalisation Register’. SHR of chronic obstructive pulmonary disease (COPD) was calculated for both demolition and cement workers.

Settings

Register study with data from all hospitals in Denmark.

Participants

895 demolition workers and 5633 cement and concrete workers were included in the study and all economical active men were used as reference group.

Results

We found a statistically significant high SHR for the cement workers, SHR=134 (95% CI 117 to 153). The SHR for demolition workers was 131 (95% CI 87 to 188).

Conclusions

We find a higher risk of being hospitalised due to COPD in cement and concrete workers (significant) and demolition workers (insignificant) compared to gainfully employed men.