bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological Effects and Use of PrP
Sc
- and PrP-Specific Antibodies Generated by Immunization with Purified Full-Length Native Mouse Prions
Authors: Petsch Benjamin , Müller-Schiffmann Andreas , Lehle Anna , Zirdum Elizabeta , Prikulis Ingrid , Kuhn Franziska , Raeber Alex J. , Ironside James W. , Korth Carsten , Stitz Lothar
Published: February 2011

The prion agent is the infectious particle causing spongiform encephalopathies in animals and humans and is thought to consist of an altered conformation (PrP
Sc
) of the normal and ubiquitous prion protein PrP
C
. The interaction of the prion agent with the immune system, particularly the humoral immune response, has remained unresolved. Here we investigated the immunogenicity of full-length native and infectious prions, as well as the specific biological effects of the resulting monoclonal antibodies (MAbs) on the binding and clearance of prions in cell culture and in
in vivo
therapy. Immunization of prion knockout (

Prnp
0/0

) mice with phosphotungstic acid-purified mouse prions resulted in PrP-specific monoclonal antibodies with binding specificities selective for PrP
Sc
or for both PrP
C
and PrP
Sc
. PrP
Sc
-specific MAb W261, of the IgG1 isotype, reacted with prions from mice, sheep with scrapie, deer with chronic wasting disease (CWD), and humans with sporadic and variant Creutzfeldt-Jakob disease (CJD) in assays including a capture enzyme-linked immunosorbent assay (ELISA) system. This PrP
Sc
-specific antibody was unable to clear prions from mouse neuroblastoma cells (ScN2a) permanently infected with scrapie, whereas the high-affinity MAb W226, recognizing both isoforms, PrP
Sc
and PrP
C
, did clear prions from ScN2a cells, as determined by a bioassay. However, an attempt to treat intraperitoneally prion infected mice with full-length W226 or with a recombinant variable-chain fragment (scFv) from W226 could only slightly delay the incubation time. We conclude that (i) native, full-length PrP
Sc
elicits a prion-specific antibody response in PrP knockout mice, (ii) a PrP
Sc
-specific antibody had no prion-clearing effect, and (iii) even a high-affinity MAb that clears prions
in vitro
(W226) may not necessarily protect against prion infection, contrary to previous reports using different antibodies.
Chimpanzee-Human Monoclonal Antibodies for Treatment of Chronic Poliovirus Excretors and Emergency Postexposure Prophylaxis
Authors: Chen Zhaochun , Chumakov Konstantin , Dragunsky Eugenia , Kouiavskaia Diana , Makiya Michelle , Neverov Alexander , Rezapkin Gennady , Sebrell Andrew , Purcell Robert
Published: February 2011

Six poliovirus-neutralizing Fabs were recovered from a combinatorial Fab phage display library constructed from bone marrow-derived lymphocytes of immunized chimpanzees. The chimeric chimpanzee-human full-length IgGs (hereinafter called monoclonal antibodies [MAbs]) were generated by combining a chimpanzee IgG light chain and a variable domain of heavy chain with a human constant Fc region. The six MAbs neutralized vaccine strains and virulent strains of poliovirus. Five MAbs were serotype specific, while one MAb cross-neutralized serotypes 1 and 2. Epitope mapping performed by selecting and sequencing antibody-resistant viral variants indicated that the cross-neutralizing MAb bound between antigenic sites 1 and 2, thereby covering the canyon region containing the receptor-binding site. Another serotype 1-specific MAb recognized a region located between antigenic sites 2 and 3 that included parts of capsid proteins VP1 and VP3. Both serotype 2-specific antibodies recognized antigenic site 1. No escape mutants to serotype 3-specific MAbs could be generated. The administration of a serotype 1-specific MAb to transgenic mice susceptible to poliovirus at a dose of 5 μg/mouse completely protected them from paralysis after challenge with a lethal dose of wild-type poliovirus. Moreover, MAb injection 6 or 12 h after virus infection provided significant protection. The MAbs described here could be tested in clinical trials to determine whether they might be useful for treatment of immunocompromised chronic virus excretors and for emergency protection of contacts of a paralytic poliomyelitis case.
Comparison of ADAMTS-1, -4 and -5 expression in culprit plaques between acute myocardial infarction and stable angina
Authors: Lee Cheol Whan , Hwang Ilseon , Park Chan-Sik , Lee Hyangsin , Park Duk-Woo , Kang Su-Jin , Lee Seung-Hwan , Kim Young-Hak , Park Seong-Wook , Park Seung-Jung
Published: February 2011

Background

ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) proteases might contribute to plaque destabilisation by weakening the fibrous cap. However, little is known about the expression of ADAMTS proteases in coronary atherosclerotic plaques.

Objective

To examine the expression of ADAMTS proteases in coronary atherectomy samples obtained from patients with acute myocardial infarction (AMI) or stable angina.

Methods

Atherectomy specimens were obtained from 34 patients with AMI (n=23) or stable angina (n=11) who underwent directional coronary atherectomy. The specimens were stained with H&E and analysed immunohistochemically using antibodies specific to ADAMTS-1, -4 and -5; versican cleavage products; and markers for endothelial cells, macrophages and smooth muscle cells.

Results

Baseline characteristics were similar between the two groups. The proportion of CD31 and CD68 immunopositive areas did not differ between the two groups, but the area immunopositive for smooth muscle α-actin was smaller in the AMI group. The relative area immunopositive for ADAMTS-1 in AMI (1.04% (IQR 0.59–2.09%)) was significantly greater than that in stable angina (0.24% (0.15–0.39%); p<0.001). In contrast, the proportion of areas immunopositive for ADAMTS-4 or -5 was similar in the two groups. Areas that stained for ADAMTS-1 largely overlapped with those positive for CD68 and versican cleavage products. The areas immunopositive for ADAMTS-1 were significantly correlated with CD68 immunostained areas (r=0.50, p=0.003).

Conclusions

ADAMTS-1, -4 and -5 were present in human coronary atherosclerotic plaques, and ADATS-1 was more strongly expressed in AMI plaques than in stable plaques. ADAMTS-1 may play a role in plaque instability.
Freezing Shrinkage in Compacted Clays
Authors: Hamilton A B
Published: February 2011

This paper presents the results of volume change measurements on laboratory-compacted samples of five Alberta clay soils which have been subjected to closed-system, unidirectional freezing. It was found that for Standard AASHO compaction effort, maximum shrinkage occurred at degrees of saturation between 60 and 70 per cent. The compacted degree of saturation required for 0 per cent total volume change ranged from 86 to 90 per cent. Maximum freezing shrinkage was found to increase with an increase in plasticity of the soil. Increasing the compactive effort from Standard to Modified AASHO caused a reduction in the maximum measured shrinkage in a highly plastic, lacustrine clay. A hypothesis, based on Powers' and Helmuth's theory of volume changes in cement pastes on freezing, is suggested as a simplified explanation of the observed behaviour. Field data are presented showing the effects of subgrade freezing on the changes in surface elevation of an asphalt-surfaced highway.
Factors Influencing the Results of Vane Tests
Authors: Flaate Kaare
Published: February 2011

The influence of disturbance in evaluating the results of in situ vane shear tests in clays is examined in the paper. The influence of other factors, such as non-homogeneity of the soil mass and the mode of failure induced by the vane apparatus, are also examined and recommendations are made concerning testing methods and interpretation in order to take such factors into account.
PREDICTING THE RESULT OF NERVE CONDUCTION TESTS IN CARPAL TUNNEL SYNDROME USING A QUESTIONNAIRE
Authors: Bridges M. J. , Robertson D. C. , Chuck A. J.
Published: February 2011

We performed a study to determine whether the results of a questionnaire could be used to predict the results of nerve conduction tests in patients with suspected carpal tunnel syndrome. Two hundred and eleven consecutive patients underwent electrophysiological testing, and completed the questionnaire designed by Kamath and Stothard. Two questionnaire threshold scores were identified, which classified with high sensitivity and high specificity those patients who had normal, and abnormal nerve conduction tests respectively. Patients who scored greater than 6 on the questionnaire could be classified with 87% specificity as having abnormal tests, and patients scoring below 3 on the questionnaire could be classified with 87% sensitivity as having normal studies. We suggest therefore that patients who score above 6, or below 3 on this questionnaire may not need to be referred for nerve conduction tests, as the result can be predicted with adequate accuracy.
MORPHOMETRIC AND BIOMECHANICAL COMPARISON OF TENDONS USED FOR INTERPOSITION ARTHROPLASTY IN CARPOMETACARPAL ARTHRITIS OF THE THUMB
Authors: Dargel Jens , Pennig Dietmar , Springorum Hans Philipp , Koebke Jürgen , Eysel Peer , Michael Joern. W.-P.
Published: February 2011

Purpose: To identify the wrist tendon most effectively maintaining the trapezial space in interpositional arthroplasty in osteoarthritis of the carpometacarpal joint of the thumb.

Methods: The morphometrics of the os trapezium and the tendons of the flexor carpi radialis, extensor carpi radialis longus, and abductor pollicis longus were determined. The stiffness and compressive loading characteristics of the rolled-up tendons were compared to the os trapezium.

Results: No significant morphometric differences between the three tendons were found. The mass and volume of the trapezium was significantly larger when compared to the tendon balls. No significant differences in the compressive loading resistance were found between the tendons, but the mean stiffness was 85% lower when compared to the os trapezium.

Conclusions: Neither tendon material approached the volume nor the stiffness provided by the os trapezium. Any tendon is considered to insufficiently maintain the trapezial space following trapeziectomy.
Palynological evidence for Pennsylvanian extra-basinal vegetation in Atlantic Canada
Authors: Dimitrova Tatyana K. , Cleal Christopher J. , Thomas Barry A.
Published: February 2011

Pollen preserved in latest Westphalian and early Stephanian clastic deposits of the Sydney Coalfield, Cape Breton Island, suggest that there were zones of different vegetational habitats surrounding the wetlands where the coal-forming peat was formed. On the margins of the wetlands was a narrow band with large cordaitanthacean trees. This was surrounded by ‘occasionally dry' habitats supporting
Schuetzia
-plants, ruflorioid-plants and
Aethophyllum
-like herbaceous conifers. Around this were mesic or seasonally dry habitats, dominated by walchian conifers and disaccate-producing peltasperms. These in turn were surrounded by xeric or seasonally wet habitats, dominated by ullmanniacean-like conifers, cycads and monosaccate-producing peltasperms. During latest Westphalian and early Stephanian times, the mesic and xeric habitats encroached nearer the wetlands, although the vegetation of the wetlands themselves remained essentially unaffected. This vegetation change was not a response to climate change, but probably to changing drainage patterns and topography in the surrounding hinterland. The
Florinites
-producing cordaitanthaceans appear not to have been upland trees, as previously suggested, but occupied mainly coastal habitats, or riparian habitats on the margins of the wetlands.
A conifer-dominated palynological assemblage from Pennsylvanian (late Moscovian) alluvial drylands in Atlantic Canada: implications for the vegetation of tropical lowlands during glacial phases
Authors: Dolby Graham , Falcon-Lang Howard J. , Gibling Martin R.
Published: February 2011

New research suggests that Pennsylvanian Coal Forests were commonly replaced by conifer-dominated vegetation during seasonally dry glacial phases. Here we describe palynological assemblages from stacked sequences of the Middle Pennsylvanian (late Moscovian) Sydney Mines Formation of Nova Scotia, Canada, which lends some support to this hypothesis. One critical sample from a widespread redbed succession below the Harbour Coal is dominated by conifer pollen (55%), together with abundant representatives of cordaitaleans, other coniferopsids, and rare pteridosperms, ferns and lepidodendrids. It differs markedly from 13 other samples obtained from coals, their roof shale–limestone and associated channel bodies, which are dominated by lepidodendrids, marattialean tree-ferns, cordaitaleans and/or calamiteans. The latter beds represent coastal wetlands, and are attributed to late transgressive and highstand systems tracts, whereas the conifer-bearing sample represents a dryland alluvial plain and may be attributed to lowstand or earliest transgressive systems tracts. Three additional samples from grey shale below a sequence boundary (late highstand) and between a redbed succession and major coal seam (early to mid-transgressive deposits) contain transitional palynofloras with a high proportion of herbaceous gleicheniaceous and sphenopteroid ferns, herbaceous lycopsids, and sphenophylls interspersed with cordaitaleans and/or lepidodendrids. The dominance of conifer pollen within the dryland components of well-defined sequences, which have been linked to relative sea-level change promoted by Gondwanan glaciation, supports the view that Pennsylvanian tropical biomes responded to the beat of glacial–interglacial cycles.
Probabilistic longevity estimate for the LUSI mud volcano, East Java
Authors: Davies Richard J. , Mathias Simon A. , Swarbrick Richard E. , Tingay Mark J.
Published: February 2011

A new method for estimating the duration of a mud volcano eruption is applied to the LUSI mud volcano in East Java. The estimate is based upon carbonates at depths in the range 2500–3500 m being the water source, with an estimated area of 100–600 km
2
, thickness of 0.2–1.0 km, porosity of 0.15–0.25, an initial pressure between 13.9 and 17.6 MPa, and a separate, shallower source of mud (
c
. 1200–1800 m depth). The resulting 50 percentile for the time it takes for flow to decline to <0.1 Ml day
−1
is 26 years. By analogy with natural mud volcanoes it can be expected to continue to flow at lower rates for thousands of years. Assuming subsidence rates of between 1 and 5 cm day
−1
, land surface subsidence of between
c
. 95 and
c
. 475 m can be expected to develop within the 26 year time period.
Network Service Description and Discovery for High-Performance Ubiquitous and Pervasive Grids
Authors: Duan Qiang
Published: February 2011

Ubiquitous and pervasive Grid computing is an emerging computing paradigm that will have a significant impact on the next-generation information infrastructure. Communication networks form a significant integrant of ubiquitous and pervasive Grids and must be utilized effectively by the Grids. The notion of Grid network service may greatly facilitate integrating networking systems into the Grid architecture, and network service description and discovery play a crucial role in the network-Grid integration. Current service description and discovery technologies must be enhanced to meet the special requirements of network service description and discovery for high-performance ubiquitous and pervasive Grids. Network service description needs a model for service provisioning capability and network service discovery must be able to select those networks that meet certain performance requirements. The wide variety of networking systems in ubiquitous and pervasive Grids require general and flexible network service description and discovery approaches that are applicable to heterogeneous networks. The research presented in this article aims at developing network service description and discovery technologies for high-performance ubiquitous and pervasive Grid computing. The main contributions of this article include a general model for describing service capabilities of various networking systems, a service discovery technology for selecting network services that meet the performance requirements specified by Grid applications, and a resource allocation scheme for Grid network services to provide networking performance guarantees. The developed model and technologies are general and flexible; thus are applicable to the wide variety of heterogeneous networks in ubiquitous and pervasive Grid computing environments.
Etched Surface Morphology of Heteroepitaxial Nonpolar  ( 112̄0 )  and Semipolar  ( 112 ¯ 2 )  GaN Films by Photoenhanced Chemical Wet Etching
Authors: Baik Kwang Hyeon , Song Hoo-Young , Hwang Sung-Min , Jung Younghun , Ahn Jaehui , Kim Jihyun
Published: February 2011

We investigated how selective wet etching changes the surface morphologies of nonpolar a-plane

(
11

2

¯

0
)

and semipolar

(
11

2

¯

2
)

GaN films grown on sapphire substrates. Trigonal prisms with various widths are seen on the top surface and the tapered sidewall facet of the a-plane GaN films along the c-axis direction. Inclined trigonal unit cells are observed on the semipolar

(
11

2

¯

2
)

GaN films after wet etching. The specific crystallographic planes of

(
10

1

¯

0
)

,

(
01

1

¯

0
)

, and (0001) were exposed in common for both the GaN films, indicating that these planes are chemically stable due to atomic bond configurations and smaller density of atoms. Photoenhanced chemical wet etching proceeds on the a-plane and semipolar GaN films until chemically stable m-plane GaN surfaces as well as c-plane GaN surfaces are exposed.
Device Performance and Photoelectron Resonance in Double-Barrier Superlattice Infrared Photodetectors
Authors: Lin Shih-Hung , Feng David Jui-Yang , Lu Jen-Hsiang , Wu Kun-Jheng , Lay Tsong-Sheng , Kuan Chieh-Hsiung
Published: February 2011

A double-barrier superlattice infrared photodetector (SLIP) that contains a superlattice sandwiched by the thin and thick barriers has been developed. Photoelectrons can bounce back and forth between the two barriers and inject through the thin barrier to enhance the photocurrent. In comparison with the single-barrier SLIP, this structure shows at least one-order higher magnitude of photocurrent at low bias and the associated 80 K detectivity is also increased for more than one order. This detector also shows high-temperature operation above 100 K with an appropriate detectivity at low bias (1.1 × 109 cm Hz1/2/W at 0.17 V). A simple photoelectron resonance model is given to analyze the resonance phenomenon. It is found that photoelectrons excited by 9.2 µm wavelength can resonate in the bottom of the second miniband by 42 to 49 times from 0.05 to 0.15 V to enhance the photocurrent dramatically.
Durability of Carbon-Supported La-Mn-Based Perovskite-Type Oxides as Oxygen Reduction Catalysts in Strong Alkaline Solution
Authors: Yuasa Masayoshi , Yamazoe Noboru , Shimanoe Kengo
Published: February 2011

The durability of carbon-supported La-Mn-based perovskites for the oxygen reduction reaction in strong alkaline solutions was investigated. Carbon-supported perovskite-type oxide nanoparticles were prepared by using a reverse micelle method. The durability of the carbon-supported LaMnO3 nanoparticles was compared with that of carbon-supported LaMnO3 prepared by the mechanical mixing of LaMnO3 with the carbon support. As a result, the durability of the carbon-supported LaMnO3 nanoparticles was less than that of the carbon-supported LaMnO3 prepared by the mixing method due to a difference in the surface area of LaMnO3, which has an effect on the oxygen reduction reaction. In order to improve the durability of the carbon-supported LaMnO3 nanoparticles, Ca and Fe were substituted at the A-sites and B-sites of the perovskite lattice, respectively. As a result, it was found that the partial substitution of Ca and Fe is effective in improving the durability of LaMnO3 under cathodic polarization in strong alkaline solutions. In particular, the substitution of Ca at the A-site not only improved the durability of the oxide but also enhanced the oxygen reduction activity owing to an increase in the average valence state of the B-sites of the perovskite lattice.
The time course of the tonic oculomotor proprioceptive signal in area 3a of somatosensory cortex
Authors: Xu Yixing , Wang Xiaolan , Peck Christopher , Goldberg Michael E.
Published: February 2011

A proprioceptive representation of eye position exists in area 3a of primate somatosensory cortex (Wang X, Zhang M, Cohen IS, Goldberg ME. Nat Neurosci 10: 640–646, 2007). This eye position signal is consistent with a fusimotor response (Taylor A, Durbaba R, Ellaway PH, Rawlinson S. J Physiol 571: 711–723, 2006) and has two components during a visually guided saccade task: a short-latency phasic response followed by a tonic response. While the early phasic response can be excitatory or inhibitory, it does not accurately reflect the eye's orbital position. The late tonic response appears to carry the proprioceptive eye position signal, but it is not clear when this component emerges and whether the onset of this signal is reliable. To test the temporal dynamics of the tonic proprioceptive signal, we used an oculomotor smooth pursuit task in which saccadic eye movements and phasic proprioceptive responses are suppressed. Our results show that the tonic proprioceptive eye position signal consistently lags the actual eye position in the orbit by ∼60 ms under a variety of eye movement conditions. To confirm the proprioceptive nature of this signal, we also studied the responses of neurons in a vestibuloocular reflex (VOR) task in which the direction of gaze was held constant; response profiles and delay times were similar in this task, suggesting that this signal does not represent angle of gaze and does not receive visual or vestibular inputs. The length of the delay suggests that the proprioceptive eye position signal is unlikely to be used for online visual processing for action, although it could be used to calibrate an efference copy signal.
Bulk electroporation and population calcium imaging in the adult mammalian retina
Authors: Briggman Kevin L. , Euler Thomas
Published: February 2011

The optical recording of light-evoked activity in populations of neurons in the mammalian retina offers several benefits over the use of multielectrode arrays. However, population imaging has been hindered by the effective loading of synthetic fluorescent indicators, especially in the mature tissue. We have therefore developed an electroporation method to label the complete ganglion cell layer of the adult mammalian retina. We optimized the protocol such that the retina recovers from electroporation and generates responses to visual stimuli. The method can be used with a diverse set of indicators with a range of affinities and emission wavelengths. It therefore can be combined with transgenic animals expressing fluorescent markers to target specific neuronal types. Importantly, the ganglion cell layer remains accessible for subsequent intracellular recording and morphological identification.
Evaluating EML Modeling Tools for Insurance Purposes: A Case Study
Authors: Gustavsson Mikael , Shahriari Mohammad , Lindgren Mats
Published: February 2011

As with any situation that involves economical risk refineries may share their risk with insurers. The decision process generally includes modelling to determine to which extent the process area can be damaged. On the extreme end of modelling the so-called Estimated Maximum Loss (EML) scenarios are found. These scenarios predict the maximum loss a particular installation can sustain. Unfortunately no standard model for this exists. Thus the insurers reach different results due to applying different models and different assumptions. Therefore, a study has been conducted on a case in a Swedish refinery where several scenarios previously had been modelled by two different insurance brokers using two different softwares, ExTool and SLAM. This study reviews the concept of EML and analyses the used models to see which parameters are most uncertain. Also a third model, EFFECTS, was employed in an attempt to reach a conclusion with higher reliability.
The Effect of Airway Pressure Release Ventilation on Pulmonary Catheter Readings: Specifically Pulmonary Capillary Wedge Pressure in a Swine Model
Authors: Slim Ahmad M. , Martinho Shaun , Slim Jennifer , Davenport Eddie , Castillo-Rojas Luadino M. , Shry Eric A.
Published: February 2011

Background. Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that theoretically believed to improve cardiac output by lowering right atrial pressure. However, hemodynamic parameters have never been formally assessed.Methods. Seven healthy swine were intubated and sedated. A baseline assessment of conventional ventilation (assist control) and positive end-expiratory pressure (PEEP) of 5 cm H2O was initiated. Ventilator mode was changed to APRV with incremental elevations of CPAP-high from 10 to 35 cm H2O. After a 3-to-5-minute stabilization period, measurements of hemodynamic parameters (PCWP, LAP, and CVP) were recorded at each level of APRV pressure settings.Results. Increasing CPAP caused increased PCWP and LAP measurements above their baseline values. Mean PCWP and LAP were linearly related (LAP = 0.66∗PCWP + 4.5 cm H2O, , and ) over a wide range of high and low CPAP values during APRV. With return to conventional ventilation, PCWP and LAP returned to their baseline values.Conclusion. PCWP is an accurate measurement of LAP during APRV over variable levels of CPAP. However, PCWP and LAP may not be accurate measurements of volume when CPAP is utilized.
Breakdown of Counterflow Superfluidity in a Disordered Quantum Hall Bilayer
Authors: Lee D. K. K. , Eastham P. R. , Cooper N. R.
Published: February 2011

We present a theory for the regime of coherent interlayer tunneling in a disordered quantum Hall bilayer at total filling factor one, allowing for the effect of static vortices. We find that the system consists of domains of polarized superfluid phase. Injected currents introduce phase slips between the polarized domains which are pinned by disorder. We present a model of saturated tunneling domains that predicts a critical current for the breakdown of coherent tunneling that is extensive in the system size. This theory is supported by numerical results from a disordered phase model in two dimensions. We also discuss how our picture might be used to interpret experiments in the counterflow geometry and in two-terminal measurements.
Factors Related to the Absence of Anemia in Hemodialysis Patients
Authors: Verdalles Ursula , Abad Soraya , Vega Almudena , Ruiz Caro Caridad , Ampuero Jara , Jofre Rosa , Lopez-Gomez Juan Manuel
Published: February 2011

Background: A small number of hemodialysis (HD) patients have normal hemoglobin (Hb) levels without the need for erythropoiesis-stimulating agents (ESAs). The factors associated with this condition have been little studied. The objective of this prospective study was to determine these factors in a prevalent population of HD patients. Materials and Methods: All patients who had normal Hb levels and who had not received ESAs in the last 6 months (non-ESA group) were included. Epidemiological and laboratory data were collected and we performed an abdominal ultrasound to assess hepatic and renal cysts. This group was compared to a control group of 205 prevalent HD patients on ESA therapy (control group). Results: We included 45 patients (16% from the whole group) in the non-ESA group. In this group, there was a higher proportion of men (76.5 vs. 61%), patients were younger (61.1 ± 14.7 vs. 67.5 ± 15.2 years), had a longer duration of renal replacement therapy (RRT) (9.4 ± 8.3 vs. 5.3 ± 5.8 years) and had a higher prevalence of adult polycystic kidney disease (APKD) and hepatitis C virus (HCV) liver disease (42.2 vs. 10.2%), p < 0.01. In the non-ESA group, HCV+ patients had a lower prevalence of APKD (2.2 vs. 38.4%) and hepatic cysts (2.2 vs. 19.2%), but significantly higher endogenous erythropoietin levels (55.8 ± 37.1 vs. 30.9 ± 38.4 mU/ml). No significant differences in anemia, iron metabolism, insulin, IGF-1 and renin were found between non-ESA and control groups. Non-ESA patients had a significantly higher number of renal (90.6 vs. 36.5%) and hepatic cysts (12.5 vs. 3.4%), and these were also larger in size (3.3 ± 2.4 vs. 1.5 ± 0.8 cm). In the multivariate Cox analysis, independent predictor factors for absence of anemia in HD patients were number of renal cysts >10 cysts (95% CI 1.058–1.405; p = 0.00), HCV+ liver disease (95% CI 1.147–1.511; p = 0.05) and time on RRT (95% CI 1.002–1.121; p = 0.05). Conclusions: The absence of anemia in HD patients is not infrequent. Its frequency is higher in men and younger patients with long-term RRT, in patients with HCV+ liver disease and in APKD. It is associated with increased endogenous erythropoietin production and the presence of renal and hepatic cysts.
Nouvelles approches thérapeutiques de la phénylcétonurie
Authors: Eavri Ronen , Lorberboum-Galski Haya
Published: February 2011

Depuis sa découverte en 1934 par Følling, la phénylcétonurie (PCU) a fait l’objet de nombreuses recherches pluridisciplinaires: génétique humaine, biochimie, développement, neurobiologie... Pendant les 75 dernières années, différentes mutations sur les gènes responsables de la maladie ont été cartographiées, les mécanismes biochimiques et les causes des symptômes cliniques ont été élucidés. De plus, les programmes de dépistage néonatal basés sur le test de Guthrie, les analyses biochimiques supplémentaires réalisées chez les nouveau-nés suspects, et le régime hypoprotéique contrôlé en phénylalanine (Phe) ont eu un impact considérable sur la façon dont sont considérés ces troubles innés du métabolisme de nos jours. En fait, le régime hypoprotéique contrôlé en Phe, un traitement simple et efficace de la PCU, est considéré comme un progrès majeur dans le traitement de cette maladie, permettant le maintien de concentrations basses en Phe dans le sang, évitant ainsi que des niveaux élevés et persistants de Phe altèrent le développement normal du cerveau. Cependant, malgré la simplicité et l’efficacité de ce régime, la non compliance de certains patients et les conséquences qui en découlent ont conduit les scientifiques à chercher en permanence de nouvelles alternatives au régime hypoprotéique contrôlé en Phe. Dans cet article, nous présentons les avancées thérapeutiques majeures de la PCU, et notamment les nouveaux traitements proposés. Nous restons optimistes quant à l’éventualité qu’une ou plusieurs de ces propositions évoluent par la suite en futurs médicaments pour les patients phénylcétonuriques.
Nicorandil Inhibits Angiotensin-II-Induced Proliferation of Cultured Rat Cardiac Fibroblasts
Authors: Liou Jer-Young , Hong Hong-Jye , Sung Li-Chin , Chao Hung-Hsing , Chen Po-Yuan , Cheng Tzu-Hurng , Chan Paul , Liu Ju-Chi
Published: February 2011

Background/Aims: Nicorandil, an ATP-sensitive potassium (KATP) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. Results: Nicorandil (0.1–10 µmol/l) caused a concentration-dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the KATP channel blocker glibenclamide (1 µmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. Conclusion: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening KATP channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.
Mycobacterial Strains That Stimulate the Immune System Most Efficiently as Candidates for the Treatment of Bladder Cancer
Authors: Yuksel Zehra Stara , Buber Esra , Kocagoz Tanil , Alp Alpaslan , Saribas Zeynep , Acan N. Leyla
Published: February 2011

Background: Intravesical bacillus Calmette-Guérin (BCG) application is widely used in the treatment of superficial bladder carcinoma. Despite being an effective therapy, the pathogenicity and lethal side effects of BCG limits its usage. Intensive research has been carried out to find less toxic and more potent therapeutic agents for the treatment of bladder cancer. Researchers have focused on Mycobacterium phlei as an alternative. The cell wall extract of M. phlei is sufficient for antitumoral activity. Our preliminary experiments indicate that the fractions rich in cell wall proteins cause activation of tumor necrosis factor (TNF)-α and interleukin (IL)-12. This study aims to identify powerful and less harmful mycobacteria among 88 strains in terms of how they stimulate the immune system. Methods: Eighty-eight mycobacterial strains were grown in Middlebrook 7H9 medium. The bacterial cells were sonicated after heat treatment. The supernatants were incubated with the monocytic cell line THP-1, followed by measurement of TNF-α and IL-12 response. Results and Conclusion: In addition to M. phlei, the following 12 mycobacterial strains were selected as candidates for superficial bladder tumor treatment: M. agri, M. aichiense, M. aurum, M. brumae, M. chitae, M. chubuense, M. diernhoferi, M. gadium, M. murale, M. obuense, M. tokaiense and M. vaccae.
A Double-Blind Placebo-Controlled Randomized Trial of Melissa officinalis Oil and Donepezil for the Treatment of Agitation in Alzheimer’s Disease
Authors: Burns Alistair , Perry Elaine , Holmes Clive , Francis Paul , Morris Julie , Howes Melanie-Jayne R. , Chazot Paul , Lees George , Ballard Clive
Published: February 2011

Background/Aims: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer’s disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer’s disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD. Methods and Findings: The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer’s disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both. Main Outcome: The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks. Conclusion: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer’s disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer’s disease.
Why Is the Thyroid So Prone to Autoimmune Disease?
Authors: Saranac L. , Zivanovic S. , Bjelakovic B. , Stamenkovic H. , Novak M. , Kamenov B.
Published: February 2011

The thyroid gland plays a major role in the human body; it produces the hormones necessary for appropriate energy levels and an active life. These hormones have a critical impact on early brain development and somatic growth. At the same time, the thyroid is highly vulnerable to autoimmune thyroid diseases (AITDs). They arise due to the complex interplay of genetic, environmental, and endogenous factors, and the specific combination is required to initiate thyroid autoimmunity. When the thyroid cell becomes the target of autoimmunity, it interacts with the immune system and appears to affect disease progression. It can produce different growth factors, adhesion molecules, and a large array of cytokines. Preventable environmental factors, including high iodine intake, selenium deficiency, and pollutants such as tobacco smoke, as well as infectious diseases and certain drugs, have been implicated in the development of AITDs in genetically predisposed individuals. The susceptibility of the thyroid to AITDs may come from the complexity of hormonal synthesis, peculiar oligoelement requirements, and specific capabilities of the thyroid cell’s defense system. An improved understanding of this interplay could yield novel treatment pathways, some of which might be as simple as identifying the need to avoid smoking or to control the intake of some nutrients.
Disrupted Junctional Membrane Complexes and Hyperactive Ryanodine Receptors After Acute Junctophilin Knockdown in Mice
Authors: van Oort Ralph J. , Garbino Alejandro , Wang Wei , Dixit Sayali S. , Landstrom Andrew P. , Gaur Namit , De Almeida Angela C. , Skapura Darlene G. , Rudy Yoram , Burns Alan R. , Ackerman Michael J. , Wehrens Xander H.T.
Published: February 2011

Background—

Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca
2+
channels and Ca
2+
release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca
2+
-induced Ca
2+
release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy.

Methods and Results—

To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma–sarcoplasmic reticulum distance.

Conclusions—

Loss of JPH2 had profound effects on Ca
2+
release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca
2+
release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA–mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca
2+
release in the heart.
Reversal of Hyperlipidemia With a Genetic Switch Favorably Affects the Content and Inflammatory State of Macrophages in Atherosclerotic Plaques
Authors: Feig Jonathan E. , Parathath Sajesh , Rong James X. , Mick Stephanie L. , Vengrenyuk Yuliya , Grauer Lisa , Young Stephen G. , Fisher Edward A.
Published: February 2011

Background—

We previously showed that the progression of atherosclerosis in the Reversa mouse (
Ldlr

−/−
Apob
100/100
Mttp
fl/fl

Mx1
Cre
+/+
) was arrested when the hyperlipidemia was normalized by inactivating the gene for microsomal triglyceride transfer protein. Here, we tested whether atherosclerosis would regress if the lipid levels were reduced after advanced plaques formed.

Methods and Results—

Reversa mice were fed an atherogenic diet for 16 weeks. Plasma lipid levels were then reduced. Within 2 weeks, this reduction led to decreased monocyte-derived (CD68
+
) cells in atherosclerotic plaques and was associated with emigration of these cells out of plaques. In addition, the fall in lipid levels was accompanied by lower plaque lipid content and by reduced expression in plaque CD68
+
cells of inflammatory genes and higher expression of genes for markers of antiinflammatory M2 macrophages. Plaque composition was affected more than plaque size, with the decreased content of lipid and CD68
+
cells balanced by a higher content of collagen. When the reduced lipid level was combined with the administration of pioglitazone to simulate the clinical aggressive lipid management and proliferator-activated receptor-γ agonist treatment, the rate of depletion of plaque CD68
+
cells was unaffected, but there was a further increase in their expression of antiinflammatory macrophage markers.

Conclusion—

The Reversa mouse is a new model of atherosclerosis regression. After lipid lowering, favorable changes in plaque composition were independent of changes in size. In addition, plaque CD68
+
cells became less inflammatory, an effect enhanced by treatment with pioglitazone.
Stochastic Averaging of Idealized Climate Models
Authors: Monahan Adam H. , Culina Joel
Published: February 2011

Variability in the climate system involves interactions across a broad range of scales in space and time. While models of slow “climate” variability may not explicitly account for fast “weather” processes, the dynamical influence of these unresolved scales cannot generally be ignored. Perspectives from statistical physics indicate that if the scale separation between slow and fast scales is sufficiently large, deterministic parameterizations are appropriate, while for smaller scale separations the parameterizations should be nondeterministic. The method of “stochastic averaging” provides a framework for the reduction of coupled fast–slow systems into an effective dynamics of the slow variables. This study describes the hierarchy of approximations associated with stochastic averaging and applies this reduction methodology to two idealized models: a Stommel-type model of the meridional overturning circulation and a model of coupled atmosphere–ocean boundary layers. Finally, stochastic averaging is compared to other stochastic reduction strategies that have been applied to climate models.
Evaluation of the HOMME Dynamical Core in the Aquaplanet Configuration of NCAR CAM4: Rainfall
Authors: Mishra Saroj K. , Taylor Mark A. , Nair Ramachandran D. , Lauritzen Peter H. , Tufo Henry M. , Tribbia Joseph J.
Published: February 2011

The NCAR Community Climate System Model, version 4 (CCSM4), includes a new dynamical core option based on NCAR’s High-Order Method Modeling Environment (HOMME). HOMME is a petascale-capable high-order element-based conservative dynamical core developed on the cubed-sphere grid. Initial simulations have been completed in an aquaplanet configuration of the Community Atmosphere Model, version 4 (CAM4), the atmospheric component of CCSM4. The authors examined the results of this simulation and assessed its fidelity in simulating rainfall, which is one of the most important components of the earth’s climate system. For this they compared the results from two other dynamical cores of CAM4: the finite volume (FV) and Eulerian (EUL).

Instantaneous features of rainfall in HOMME are similar to FV and EUL. Similar to EUL and FV, HOMME simulates a single-peak intertropical convergence zone (ITCZ) over the equator. The strength of the ITCZ is found to be almost the same in HOMME and EUL but more in FV. It is observed that in HOMME and EUL, there is higher surface evaporation, which supplies more moisture to the deep tropics and gives more rainfall over the ITCZ. The altitude of maximum precipitation is found to be at almost the same level in all three dynamical cores. The eastward propagation of rainfall bands is organized and more prominent in FV and HOMME than in EUL. The phase speed of the eastward propagation in HOMME is found to be higher than in FV. The results show that, in general, the rainfall simulated by HOMME falls in a regime between that of FV and EUL. Hence, they conclude that the key aspects of rainfall simulation with HOMME falls into an acceptable range, as compared to the existing dynamical cores used in the model.
Evaluation of MERRA Land Surface Estimates in Preparation for the Soil Moisture Active Passive Mission
Authors: Yi Yonghong , Kimball John S. , Jones Lucas A. , Reichle Rolf H. , McDonald Kyle C.
Published: February 2011

The authors evaluated several land surface variables from the Modern-Era Retrospective Analysis for Research and Applications (MERRA) product that are important for global ecological and hydrological studies, including daily maximum (Tmax) and minimum (Tmin) surface air temperatures, atmosphere vapor pressure deficit (VPD), incident solar radiation (SWrad), and surface soil moisture. The MERRA results were evaluated against in situ measurements, similar global products derived from satellite microwave [the Advanced Microwave Scanning Radiometer for Earth Observing System (EOS) (AMSR-E)] remote sensing and earlier generation atmospheric analysis [Goddard Earth Observing System version 4 (GEOS-4)] products. Relative to GEOS-4, MERRA is generally warmer (~0.5°C for Tmin and Tmax) and drier (~50 Pa for VPD) for low- and middle-latitude regions (<50°N) associated with reduced cloudiness and increased SWrad. MERRA and AMSR-E temperatures show relatively large differences (>3°C) in mountainous areas, tropical forest, and desert regions. Surface soil moisture estimates from MERRA (0–2-cm depth) and two AMSR-E products (~0–1-cm depth) are moderately correlated (R ~ 0.4) for middle-latitude regions with low to moderate vegetation biomass. The MERRA derived surface soil moisture also corresponds favorably with in situ observations (R = 0.53 ± 0.01, p < 0.001) in the midlatitudes, where its accuracy is directly proportional to the quality of MERRA precipitation. In the high latitudes, MERRA shows inconsistent soil moisture seasonal dynamics relative to in situ observations. The study’s results suggest that satellite microwave remote sensing may contribute to improved reanalysis accuracy where surface meteorological observations are sparse and in cold land regions subject to seasonal freeze–thaw transitions. The upcoming NASA Soil Moisture Active Passive (SMAP) mission is expected to improve MERRA-type reanalysis accuracy by providing accurate global mapping of freeze–thaw state and surface soil moisture with 2–3-day temporal fidelity and enhanced (≤9 km) spatial resolution.