bluuebunny/crossref_metadata_2025 huggingface dataset:
In silicoprediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype
Authors: Rekić Dinko , Röshammar Daniel , Mukonzo Jackson , Ashton Michael
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Rifampicin is known to reduce the exposure of efavirenz. Despite lack of adequate clinical support, most guidelines recommend an increased efavirenz dose in patients treated with both drugs, although some propose an increase only in patients weighing over 50 kg.

WHAT THIS STUDY ADDS

• An example of utilization ofin vitrodata to predictin vivoconsequences of metabolic drug–drug interactions, suggesting answers to specific questions difficult to study in patients. Here the efavirenz–rifampicin interaction was simulated with the specific question of whether or not to increase the efavirenz dose based on bodyweight.

• The results from this simulation suggest that increasing the efavirenz dose may be appropriate only in patients with bodyweights over 50 kg.

AIMSThis study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight‐based dosage recommendations used to counteract the rifampicin–efavirenz interaction.

METHODSEfavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population‐based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype.

RESULTSApart from the absorption phase, the simulation model predicted efavirenz concentration–time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co‐administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13–19) in efavirenz area under the concentration–time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status.

CONCLUSIONSOur findings, although based on a simulation approach using limitedin vitrodata, support the current recommendations for using a 50 kg bodyweight cut‐off for efavirenz dose increment when co‐treating with rifampicin.
Impact of allopurinol use on urate concentration and cardiovascular outcome
Authors: Wei Li , Mackenzie Isla S. , Chen Yang , Struthers Allan D. , MacDonald Thomas M.
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Guidelines recommend that the therapeutic goal of urate‐lowering therapy (ULT) is to achieve a urate concentration of ≤6 mg dl−1.

• High‐dose allopurinol is associated with reduced cardiovascular events and mortality in heart failure patients.

WHAT THIS STUDY ADDS

• Less than 50% of patients taking allopurinol reached target urate concentration.

• Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality in all patients on allopurinol treatment.

AIMS To characterize patients with urate measurements by urate‐lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes.

METHODS A cohort study using a record‐linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined.

RESULTS Six thousand and forty‐two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non‐ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non‐ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low‐dose (100 mg) users, high‐dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94).

CONCLUSIONS Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.
Interference ofBifidobacterium choerinumorEscherichia coliNissle 1917 withSalmonellaTyphimurium in gnotobiotic piglets correlates with cytokine patterns in blood and intestine
Authors: Splichalova A , Trebichavsky I , Rada V , Vlkova E , Sonnenborn U , Splichal I
Published: December 2010

The colonization, translocation and protective effect of two intestinal bacteria – PR4 (pig commensal strain of Bifidobacterium choerinum) or EcN (probiotic Escherichia coli strain Nissle 1917) – against subsequent infection with a virulent LT2 strain of Salmonella enterica serovar Typhimurium were studied in gnotobiotic pigs after oral association. The clinical state of experimental animals correlated with bacterial translocation and levels of inflammatory cytokines [a chemokine, interleukin (IL)-8, a proinflammatory cytokine, tumour necrosis factor (TNF)-α and an anti-inflammatory cytokine, IL-10] in plasma and intestinal lavages. Gnotobiotic pigs orally mono-associated with either PR4 or EcN thrived, and bacteria were not found in their blood. No significant inflammatory cytokine response was observed. Mono-association with Salmonella caused devastating septicaemia characterized by high levels of IL-10 and TNF-α in plasma and TNF-α in the intestine. Di-associated gnotobiotic pigs were given PR4 or EcN for 24 h. Subsequently, they were infected orally with Salmonella and euthanized 24 h later. Pigs associated with bifidobacteria before Salmonella infection suffered from severe systemic infection and mounted similar cytokine responses as pigs infected with Salmonella alone. In contrast, EcN interfered with translocation of Salmonella into mesenteric lymph nodes and systemic circulation. Pigs pre-associated with EcN thrived and their clinical condition correlated with the absence of IL-10 in their plasma and a decrease of TNF-α in plasma and ileum.
Therapeutic effects of TACI-Ig on rat with adjuvant arthritis
Authors: Wang D , Chang Y , Wu Y , Zhang L , Yan S , Xie G , Qin Q , Jin J , Wang W , Fang J , Wei W
Published: December 2010

Transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig) is a human fusion protein that binds and neutralizes both B lymphocyte stimulator (BLyS), a cytokine shown to be a key regulator of B cell maturation, proliferation and survival, and a proliferation-inducing ligand (APRIL). Rat adjuvant arthritis (AA) is an experimental animal model of rheumatoid arthritis (RA), which is mainly dependent on T cells and neutrophil-mediated cytokine production. The purpose of the present study was to investigate the effects of TACI-Ig on rat AA. Rat AA was induced by intradermal injection of 0·1 ml complete Freund's adjuvant (CFA). TACI-Ig (0·7, 2·1 and 6·3 mg/kg), recombinant human tumour necrosis factor-α receptor (rhTNFR) : Fc (2·8 mg/kg) and IgG-Fc (6·3 mg/kg) were administered subcutaneously every other day from days 16 to 34 after immunization. Arthritis was evaluated by arthritis global assessment and swollen joint count (SJC). The ankle joint and spleen were harvested for histopathological examination. Spleen index and thymus index were calculated. The levels of BLyS, interleukin (IL)-17, interferon (IFN)-γ, IgG1, IgG2a and IgM in AA rat spleen were measured by enzyme-linked immunosorbent assay. Administration of TACI-Ig significantly reduced the arthritis global assessment and SJC, decreased spleen index and ameliorated histopathological manifestations of rat AA. Suppressing the levels of BLyS, IL-17, IFN-γ and Ig in AA rat spleen were observed after administration of TACI-Ig. These results showed that TACI-Ig significantly inhibited the degree of rat AA, and the inhibitory effects might be associated with its ability to reduce BLyS, proinflammatory cytokines and Ig levels in spleen.
Effect of recall period on annual freshwater fishing effort estimates in New York
Authors: CONNELLY N. A. , BROWN T. L.
Published: December 2010

Abstract  Recall bias can influence estimates of fishing effort, with a general trend toward overestimation as the length of the recall period increases. Concern that recall bias may be affecting annual freshwater fishing effort estimates in New York led to the collection of effort data from three angler surveys during 2007 instead of one survey at the end of the year. However, to check for this potential bias and the impact that a change in recall period might have on comparisons with past surveys, a parallel survey with a 12‐month recall period was conducted. For the overall state‐wide estimate of fishing effort, the estimate from the three‐phase survey was slightly greater than from the 12‐month recall survey (the opposite of what was hypothesised). For the major water bodies, the differences were mostly significant but not always in the same direction between the two survey methods. Different results from one study compared with many others do not mean that past recommendations for shorter recall periods should be abandoned. However, the strength of this study – that the implementation methods (i.e. mail surveys) were identical – leads one to be more sceptical of past results.
Conserving pelagic habitats: seascape modelling of an oceanic top predator
Authors: Louzao Maite , Pinaud David , Péron Clara , Delord Karine , Wiegand Thorsten , Weimerskirch Henri
Published: December 2010

1. Currently pelagic ecosystems are changing significantly due to multiple threats. An important management policy is to establish marine protected areas, until now overlooked due to the difficulty of declaring ‘high seas’ protected areas, obtaining long‐term distribution data on indicator species and the dynamic nature of these ecosystems.

2. Within this framework, we developed predictive habitat suitability models of an oceanic predator, the vulnerable wandering albatross Diomedea exulans, in the highly dynamic Southern Ocean. Based on a long‐term tracking database (1998–2008), we estimated three quantitative ecological indices that complementarily describe the hierarchical habitat use of the species at multiple spatial scales: where the species (i) spent more time (the seascape, based on the time spent per area), (ii) searched for prey (the foraging habitat, based on zones of increased foraging intensity using first passage time), and (iii) fed (the feeding habitat, based on prey capture data).

3. Predictive habitat models reasonably matched the observed distribution patterns and described albatross multi‐scale habitat use as a hierarchical arrangement: albatrosses foraged over topographic features in subtropical waters, nested within the wider seascape due to the constraint imposed by the colony effect, whereas feeding occurred nested over the continental shelf and seamounts in areas of low oceanographic variability within the Polar Frontal Zone.

4. Within the current oceanographic conditions, the location of key pelagic habitats for albatrosses breeding in the southern Indian Ocean encompassed certain topographic features such as pelagic areas surrounding main breeding sites, seamounts and submarine mountain ranges. The placement of these pelagic hotspots depends on the current sea surface temperature conditions.

5. Synthesis and applications. The present study provides two key conservation and management tools. First, we provide the first map to support the development of a prospective network of priority conservation zones across the southern Indian Ocean based on habitat predictions of an oceanic indicator species. This could be used not only to support conservation of top predators but also the underlying biodiversity associated with pelagic key habitats. Secondly, the developed habitat modelling procedure is widely applicable and could be used to track changes in species distribution in both marine and terrestrial environments within the current global change scenario.
Response of raptors to a windfarm
Authors: Garvin Julia C. , Jennelle Christopher S. , Drake David , Grodsky Steven M.
Published: December 2010

1. The global growth of wind energy has outpaced our assessment of possible impacts on wildlife. There is a pressing need for studies with pre‐ and post‐construction data to determine whether wind facilities will have detrimental effects on susceptible avian groups such as raptors.

2. A pre‐ and post‐construction study was conducted to determine the impact of a windfarm on the abundance and behaviour of raptors in Wisconsin, USA. Variation in abundance and behaviour was examined both within and among years and relative to selected spatial, temporal and weather covariates. Raptor avoidance rates and indices of collision risk were calculated.

3. Raptor abundance post‐construction was reduced by 47% compared to pre‐construction levels. Flight behaviour varied by species, but most individuals remained at a distance of at least 100 m from turbines and above the height of the rotor zone.

4. Turkey vultures Cathartes aura and red‐tailed hawks Buteo jamaicensis displayed high‐risk flight behaviours more often than all other raptor species, but also showed signs of avoidance. Red‐tailed hawks were the only raptor species found dead beneath turbines during mortality searches. There were few observed mortalities and corrected mortality estimates were comparable to those from other windfarm studies.

5. Synthesis and applications. The decline in raptor abundance post‐construction together with other lines of evidence suggests some displacement from the windfarm project area. While certain species may be at risk, flight behaviour data and mortality estimates indicate that the majority of raptors may not be directly affected by the presence of turbines. The avoidance rates recorded in this study should be used to improve collision risk models, and both current and future windfarms should investigate avoidance behaviour post‐construction.
Negative impact of traffic noise on avian reproductive success
Authors: Halfwerk Wouter , Holleman Leonard J. M. , Lessells C(Kate). M. , Slabbekoorn Hans
Published: December 2010

1. Traffic affects large areas of natural habitat worldwide. As a result, the acoustic signals used by birds and other animals are increasingly masked by traffic noise. Masking of signals important to territory defence and mate attraction may have a negative impact on reproductive success. Depending on the overlap in space, time and frequency between noise and vocalizations, such impact may ultimately exclude species from suitable breeding habitat. However a direct impact of traffic noise on reproductive success has not previously been reported.

2. We monitored traffic noise and avian vocal activity during the breeding season alongside a busy Dutch motorway. We measured variation in space, time and spectrum of noise and tested for negative effects on avian reproductive success using long‐term breeding data on great tits Parus major.

3. Noise levels decreased with distance from the motorway, but we also found substantial spatial variation independent of distance. Noise also varied temporally with March being noisier than April, and the daytime being noisier than night‐time. Furthermore, weekdays were clearly noisier than weekends. Importantly, traffic noise overlapped in time as well as acoustic frequency with avian vocalization behaviour over a large area.

4. Traffic noise had a negative effect on reproductive success with females laying smaller clutches in noisier areas. Variation in traffic noise in the frequency band that overlaps most with the lower frequency part of great tit song best explained the observed variation.

5. Additionally, noise levels recorded in April had a negative effect on the number of fledglings, independent of clutch size, and explained the observed variation better than noise levels recorded in March.

6. Synthesis and applications. We found that breeding under noisy conditions can carry a cost, even for species common in urban areas. Such costs should be taken into account when protecting threatened species, and we argue that knowledge of the spatial, temporal and spectral overlap between noise and species‐specific acoustic behaviour will be important for effective noise management. We provide some cost‐effective mitigation measures such as traffic speed reduction or closing of roads during the breeding season.
Qualitative modelling of invasive species eradication on subantarctic Macquarie Island
Authors: Raymond Ben , McInnes Julie , Dambacher Jeffrey M. , Way Sarah , Bergstrom Dana M.
Published: December 2010

1. Invaded ecosystems present complex management issues. This problem is exacerbated in many situations by a lack of knowledge about the ecosystem. However, delaying conservation action to collect further data and so reduce such uncertainty is often either impractical or inadvisable.

2. The Macquarie Island Pest Eradication Project, currently underway, is attempting to eradicate rabbits, rats, and mice from the island. We undertook qualitative modelling of this project, examining a range of likely outcomes and their possible ecological consequences. The results were aggregated across a large number of possible models, in order to account for uncertainty concerning interactions within the ecosystem.

3. The results strongly support the current actions of simultaneous eradication of all three pest species, as simulated eradications of only one or two generally led to continued impacts on the island’s native biota. The results also provided support for the anticipated positive outcomes of the project, with predicted recoveries of tall tussock vegetation, and burrow‐ and surface‐nesting seabirds.

4. However, the model predictions also highlighted potential risks: the eradication of mice from the island may not succeed, due in part to the structural position of this species within the ecosystem. Successful eradication of all three target species could potentially release the self‐introduced, non‐native redpolls and starlings, allowing expansion of their populations, with possible impacts on macro‐invertebrates and vegetation.

5. Synthesis and applications. These results demonstrate that qualitative modelling approaches can in some cases deliver consistent results, despite high levels of uncertainty regarding interactions within the underlying ecosystem. Such outcomes can provide assistance in the development of strategic contingency plans and ongoing future management action.
The effects of changing land use and browsing on aspen abundance and regeneration: a 50‐year perspective from Sweden
Authors: Edenius Lars , Ericsson Göran , Kempe Göran , Bergström Roger , Danell Kjell
Published: December 2010

1. Management of trees with high conservation value under altered land use is challenging. This applies to European aspenPopulus tremula, a keystone tree species for species conservation in northern forests. Fire suppression in managed forest has reduced niches for sexual regeneration in aspen while levels of browsing have increased with increasing numbers of ungulate herbivores.

2. We combined observational and experimental data from 1953 to 2007 to unravel patterns and causes of changes in aspen abundance in Sweden, the country with the largest forests in the EU. The density of small‐sized aspen ramets showed a peak in the early 1970s, followed by a marked decrease. Numbers of mooseAlces alces,the most important browser on aspen, showed a similar temporal pattern, but moose numbers peaked 10 years later than aspen. During the same time period, the volume of aspen doubled.

3. The changes in aspen abundance correlate to large‐scale changes in forestry including the introduction of clear‐cutting practices and extensive clearing of aspen, and cessation of forest livestock grazing and abandonment of marginal farmland.

4. Using exclosures, and controlling for time since disturbance and regeneration status, we monitored aspen demographics for 5 years in an aspen rich landscape. There was an eightfold increase in recruitment rate of established ramets to a height safe from browsing (>3 m) in fenced plots. However, the finite rate of increase, λ, derived from a transition matrix model, was consistently below 1, i.e. the aspen growth rate was negative with or without browsing. This was associated with a decrease in sprouting rate over time.

5. Synthesis and applications.Our results suggest that changes in land use practices are the main cause of changes in aspen abundance at regional and national scales in Sweden during the last 50 years. Restoring regeneration niches, most importantly emulating natural disturbance processes, viz. fire at various spatial scales, and retaining aspen in cleaning and pre‐commercial thinnings are the most important management recommendations to secure regeneration of aspen. Protecting established aspen ramets at designated sites from browsing either by fencing or reducing ungulate numbers could be used as complementary management tools.
Elk distribution and spatial overlap with livestock during the brucellosis transmission risk period
Authors: Proffitt Kelly M. , Gude Justin A. , Hamlin Kenneth L. , Garrott Robert A. , Cunningham Julie A. , Grigg Jamin L.
Published: December 2010

1. The presence of Brucella abortus within free‐ranging wildlife populations is an important conservation and management issue because of the risk of brucellosis transmission between wildlife and livestock. Predicting wildlife distributions is necessary to forecast wildlife and livestock spatial overlap and the potential for brucellosis transmission.

2. We used Global Positioning System data collected from telemetry‐collared female elk Cervus elaphus to develop resource selection function (RSF) models during the brucellosis transmission risk period (the abortion and calving periods). We validated extrapolation of predictive models at two nearby elk ranges within the Greater Yellowstone Ecosystem. Additionally, we integrated extrapolated RSF maps and domestic livestock distributions to estimate the relative probability of elk and livestock commingling during the brucellosis transmission risk period.

3. The top‐ranked model predicted that areas selected by elk had a lower probability of wolf Canis lupus occupancy, were privately owned and south facing, and had steeper slopes, lower road densities and higher Normalized Difference Vegetation Index (NDVI). Elk selected forests and shrublands over grasslands; however, the strength of selection decreased as snowpack increased. Elk selection for privately owned lands may lead to spatial overlap with livestock and increase the risk of elk and livestock intermingling. Furthermore, if both elk and livestock concentrate in areas of higher NDVI, increased spatial overlap may occur in these areas.

4. Predictive accuracy was highest in the study area where the model was developed. When compared to the model development area, predictive accuracy of extrapolated RSF maps was similar or better in one of the elk ranges and lower in the other elk range.

5. Synthesis and applications. Extrapolated RSF and spatial overlap maps can provide a foundation for identifying the highest risk areas of elk and livestock spatial overlap during the brucellosis transmission risk period. However, the predictive accuracy of the models is limited when applied to different areas. Site‐specific models of spatial overlap would therefore be needed to provide the most accurate estimates of elk and livestock spatial overlap during the transmission risk period. The degree to which spatial overlap may lead to actual transmission risk needs to be investigated as this is not yet known and could have important implications for managing transmission risk.
BAC‐recombineering for studying plant gene regulation: developmental control and cellular localization of SnRK1 kinase subunits
Authors: Bitrián Marta , Roodbarkelari Farshad , Horváth Mihály , Koncz Csaba
Published: December 2010

Recombineering, permitting precise modification of genes within bacterial artificial chromosomes (BACs) through homologous recombination mediated by lambda phage‐encoded Red proteins, is a widely used powerful tool in mouse, Caenorhabditis and Drosophila genetics. As Agrobacterium‐mediated transfer of large DNA inserts from binary BACs and TACs into plants occurs at low frequency, recombineering is so far seldom exploited in the analysis of plant gene functions. We have constructed binary plant transformation vectors, which are suitable for gap‐repair cloning of genes from BACs using recombineering methods previously developed for other organisms. Here we show that recombineering facilitates PCR‐based generation of precise translational fusions between coding sequences of fluorescent reporter and plant proteins using galK‐based exchange recombination. The modified target genes alone or as part of a larger gene cluster can be transferred by high‐frequency gap‐repair into plant transformation vectors, stably maintained in Agrobacterium and transformed without alteration into plants. Versatile application of plant BAC‐recombineering is illustrated by the analysis of developmental regulation and cellular localization of interacting AKIN10 catalytic and SNF4 activating subunits of Arabidopsis Snf1‐related (SnRK1) protein kinase using in vivo imaging. To validate full functionality and in vivo interaction of tagged SnRK1 subunits, it is demonstrated that immunoprecipitated SNF4–YFP is bound to a kinase that phosphorylates SnRK1 candidate substrates, and that the GFP‐ and YFP‐tagged kinase subunits co‐immunoprecipitate with endogenous wild type AKIN10 and SNF4.
Evaluation of noninvasive methods for the estimation of haemoglobin content in red blood cell concentrates
Authors: Reikvam H. , van de Watering L. , Prowse C. , Devine D. , Heddle N. M. , Hervig T. ,   on behalf of the BEST collaborative
Published: December 2010

Objectives: Red blood cell concentrates (RCCs) are the major blood component transfused to patients. There is a great variability in patient response, depending on both the patient's blood volume and haemoglobin content in the RCC. Standardisation of transfusion practice is needed to improve the prediction of patient outcome.

Aim: We hypothesise that labelling of RCCs with haemoglobin content will add possibilities for the standardisation of transfusion practice.

Methods: Data from multiple international transfusion services regarding haemoglobin content and weight or volume of RCC were collected and analysed.

Results: We demonstrate a strong and highly significant correlation between haemoglobin content with both weight and volume of the RCCs. A linear regression model was used to assess these relationships, and it demonstrates how haemoglobin content can be estimated for different cell production processes.

Conclusions: We recommend the use of weight or volume of the RCCs as the basis of estimating haemoglobin in the RCC and postulate that this can be used in future studies to explore the effects of a haemoglobin dose‐based transfusion system. As the weight – and sometimes the volume – of the blood bag is easily accessible, in contrast to direct haemoglobin measurements from each individual unit, this method is feasible and simple.
In vitro activity of multiple antibiotic combinations against Nocardia: relationship with a short‐term treatment strategy in heart transplant recipients with pulmonary nocardiosis
Authors: Tripodi M.‐F. , Durante‐Mangoni E. , Fortunato R. , Cuccurullo S. , Mikami Y. , Farina C. , Utili R.
Published: December 2010

M.‐F. Tripodi, E. Durante‐Mangoni, R. Fortunato, S. Cuccurullo, Y. Mikami, C. Farina, R. Utili. In vitro activity of multiple antibiotic combinations against Nocardia: relationship with a short‐term treatment strategy in heart transplant recipients with pulmonary nocardiosis. Transpl Infect Dis 2011: 13: 335–343. All rights reserved

Background/objectives. Pulmonary nocardiosis (PN) chiefly affects immunocompromised patients, particularly transplant recipients. Cotrimoxazole is still the mainstay of treatment, but it is associated with nephro‐ and myelo‐toxicity, and can show unpredictable activity against Nocardia isolates.

Methods. Over a 20‐year period, Nocardia isolates were identified from 12 heart transplant (HTx) recipients with PN. The in vitro activity of various antibacterials, alone or in combination, was assessed using disk‐diffusion, minimal inhibitory concentration (MIC), and time‐kill methodology. The in vitro results were compared with the clinical outcome of the patients.

Results. Seven different Nocardia strains were identified. Disk diffusion and MIC determinations showed that all isolates were susceptible to amikacin, netilmicin, and linezolid, and that moxifloxacin was the most active of the fluoroquinolones. All but 1 of the isolates were susceptible to imipenem. Time‐kill studies showed that imipenem/amikacin and imipenem/moxifloxacin combinations were bactericidal for most isolates. Of 12 patients who received 3−4 weeks' intravenous (IV) treatment with amikacin or ciprofloxacin in combination with a beta‐lactam, followed by 1−3 months' oral cotrimoxazole, moxifloxacin, or linezolid, 11 were cured; 1 patient died, but not related to Nocardia.

Conclusion. Initial PN treatment in HTx recipients can be successfully carried out with bactericidal combinations such as imipenem plus amikacin or moxifloxacin, administered IV for 3–4 weeks. Within 1 month, a significant clinical and radiological improvement may be observed. In our experience, a <3 month oral regimen with cotrimoxazole, moxifloxacin, or doxycycline may then be used. This may allow a reduction of side effects and treatment‐related burden, without any recurrence.
World Health Organization collaborative study to calibrate the 3rd International Standard for Hepatitis C virus RNA nucleic acid amplification technology (NAT)‐based assays
Authors: Baylis S. A. , Heath A. B. ,   the Collaborative Study Group
Published: December 2010

Background and Objectives  A collaborative study was undertaken to evaluate a replacement World Health Organization International Standard for hepatitis C virus (HCV) RNA for nucleic acid amplification technology (NAT)‐based assays. The candidate preparations were calibrated in International Units (IUs).

Materials and Methods  Three new candidate preparations were produced from a single bulk containing anti‐HCV‐negative, genotype 1a HCV RNA–positive plasma. Two samples were lyophilized (coded Sample 2 and Sample 3), whilst a third (Sample 4) contained liquid/frozen material. The samples were distributed together with the 2nd International Standard (Sample 1, NIBSC code 96/798) for evaluation by thirty‐three laboratories, from fourteen countries. The panel of samples were assayed on four separate occasions. Stability studies were performed for the lyophilized samples by accelerated thermal degradation.

Results  Participants returned data from a wide range of commercial and in‐house quantitative and qualitative assays. Twenty‐five data sets were returned for quantitative assays and fourteen for qualitative assays. Excellent agreement was observed between laboratories and assay methods. The mean relative potencies of Samples 2–4 were 5·19, 5·41 and 5·70 log10 IU/ml, respectively, when compared against the 2nd International Standard. Samples 2 and 3 demonstrated stability of a similar order to the previous standards.

Conclusions  Based upon the results of the collaborative study, Sample 2 (code number 06/100) was established as the 3rd International Standard for HCV RNA with an assigned unitage of 5·19 log10 IU/ml. Each vial contains the equivalent of 0·5 ml of material; each vial contains 4·89 log10 IU of HCV RNA.
Core and surface temperatures in a red‐blood‐cell unit during storage and transport
Authors: Reiter U. , Wagner T. , Kozma N. , Reiter G. , Lanzer G.
Published: December 2010

Background and Objectives  Temperature tracing of stored red‐blood‐cell concentrates (RBCs) is inevitable with respect to RBC quality control. RBC temperature, which should not exceed 10°C, is usually assessed by devices attached to the surface of the RBC pouch, assuming that surface temperature adequately represents the thermal state of RBC. We investigated under which conditions this assumption is true.

Materials and Methods  Eighteen thermocouples (TC) equidistantly mounted on a two‐layer plastic grid were installed in a pouch to determine temperature distribution in the unit. Two TCs were attached to each side of the bag to evaluate surface temperatures. One was further installed in each investigation room to assess ambient room temperatures. Temperature distributions and time–temperature courses were measured under constant temperatures and various warming and cooling conditions.

Results  At homogeneous storage temperatures, only small gradients were measured between core and surface temperatures. Removed from cooling chamber to room temperature or back from room to storage temperature, core and surface time–temperature curves drifted apart. Surface and core temperature diverged the more, the faster ambient temperatures altered. The situation could be stabilized by thermal isolation: handled in a transport box, or even better in an air cushion envelope, surface and core courses approached and ultimately closely followed each other, respectively.

Conclusion  RBC temperature monitoring devices attached to the surface of the RBC pouch very well describe the core temperature under constant temperature conditions. During transport, thermal isolation of the RBC unit is necessary to control RBC temperature precisely by surface temperature measurements.
Individual income and falls among the elderly in Latin America
Authors: Trujillo Antonio J , Puvanachandra Prasanthi , Hyder Adnan A
Published: December 2010

Aim:  The burden of falls amongst the elderly raises important public health concerns. Empirical evidence suggests that macroeconomic growth may not be sufficient to reduce mortality and morbidity from injuries among the elderly. This paper consolidates macro‐ and microeconomic evidence of the effect of income on elderly falls in Latin America.

Method:  Using household databases, we estimate an empirical model to assess the relationship between income and falls.

Results:  The estimations indicate that an increase in personal income reduces the probability of falling; yet, the size of the effect is negligible. A 10% increase in income reduces the probability of falling between 0.001 and 0.002% while a 20% increase reduced the probability by up to 1%.

Conclusion:  These findings are consistent with macroeconomic data where morbidity and mortality among seniors are inelastic to economic growth. Policy implications of cash transfer programs targeting the elderly are discussed. Geriatr Gerontol Int 2011; 11: 180–190.
Contribution of glial–neuronal interactions to the neuroendocrine control of female puberty
Authors: Ojeda Sergio R. , Lomniczi Alejandro , Sandau Ursula
Published: December 2010

Mammalian puberty is initiated by an increased pulsatile release of the neuropeptide gonadotropin‐releasing hormone (GnRH) from hypothalamic neuroendocrine neurons. Although this increase is primarily set in motion by neuronal networks synaptically connected to GnRH neurons, glial cells contribute to the process via at least two mechanisms. One involves production of growth factors acting via receptors endowed with either serine–threonine kinase or tyrosine kinase activity. The other involves plastic rearrangements of glia–GnRH neuron adhesiveness. Growth factors of the epidermal growth factor family acting via erbB receptors play a major role in glia‐to‐GnRH neuron communication. In turn, neurons facilitate astrocytic erbB signaling via glutamate‐dependent cleavage of erbB ligand precursors. The genetic disruption of erbB receptors delays female sexual development due to impaired erbB ligand‐induced glial prostaglandin E2 release. The adhesiveness of glial cells to GnRH neurons involves at least two different cell–cell communication systems endowed with both adhesive and intracellular signaling capabilities. One is provided by synaptic cell adhesion molecule (SynCAM1), which establishes astrocyte–GnRH neuron adhesiveness via homophilic interactions and the other involves the heterophilic interaction of neuronal contactin with glial receptor‐like protein tyrosine phosphatase‐β. These findings indicate that the interaction of glial cells with GnRH neurons involves not only secreted bioactive molecules, but also cell‐surface adhesive proteins able to set in motion intracellular signaling cascades.
Role of astroglia in the neuroplastic and neuroprotective actions of estradiol
Authors: Azcoitia Iñigo , Santos‐Galindo María , Arevalo María A. , Garcia‐Segura Luis M.
Published: December 2010

Astrocyte–neuron cross‐talk is an essential component of the mechanisms involved in the neuroendocrine and neuroprotective actions of estradiol. Astrocytes express estrogen receptors, show morphological and functional modifications in response to estradiol and participate in the hormonal regulation of synaptic plasticity and neuroendocrine events. In addition, estradiol interferes with the activation of astrocytes under pathological conditions, modulating the release of neurotrophic factors and inflammatory molecules by these cells. Furthermore, under neurodegenerative conditions, astrocytes synthesize estradiol, which acts as a local neuroprotectant. The actions of estradiol on astrocytes can be imitated by selective estrogen receptor modulators. Some of these molecules, which are free of the peripheral risks associated with estrogen therapy, exert estradiol‐like anti‐inflammatory actions on astrocytes and are potential therapeutic candidates for the control of reactive astrogliosis.
The intimate relationship of gonadotropin‐releasing hormone neurons with the polysialylated neural cell adhesion molecule revisited across development and adult plasticity
Authors: Franceschini Isabelle , Desroziers Elodie , Caraty Alain , Duittoz Anne
Published: December 2010

The neurohormone gonadotropin‐releasing hormone (GnRH) is critical for all the aspects of reproductive life in vertebrates. GnRH is secreted by a small number of neurons dispersed within the preoptic‐hypothalamic region. These neurons are derived from the embryonic olfactory pit. They then migrate along olfactory, vomeronasal and terminal nerves to their final destination. Classical approaches to study the regulation of GnRH secretion during the reproductive cycle have focused on the various neuronal inputs on GnRH neurons and their regulation by ovarian steroids. However, it is well known that steroids will change the microenvironment of neuronal networks and can induce plasticity and functional changes. In this review, we will focus on the intimate relationship of developing and adult GnRH neurons with the polysialylated form of neural cell adhesion molecule (PSA‐NCAM), a major molecular actor in the morphogenesis and adult plasticity of the nervous system. We will first recapitulate the spatiotemporal relationship between PSA‐NCAM and migrating GnRH neurons during embryogenesis of various vertebrate species and discuss its importance for GnRH neuron development as shown by various loss of function studies. In the adult, we will review the relationships between PSA‐NCAM and GnRH neurons across various physiological states, and open the discussion to the use of new model systems that can help to unravel the function and mechanism of action of PSA‐NCAM on GnRH neuronal network activity and GnRH release.
Sex steroid‐induced neuroplasticity and behavioral activation in birds
Authors: Balthazart Jacques , Charlier Thierry D. , Barker Jennifer M. , Yamamura Takashi , Ball Gregory F.
Published: December 2010

The brain of adult homeothermic vertebrates exhibits a higher degree of morphological neuroplasticity than previously thought, and this plasticity is especially prominent in birds. In particular, incorporation of new neurons is widespread throughout the adult avian forebrain, and the volumes of specific nuclei vary seasonally in a prominent manner. We review here work on steroid‐dependent plasticity in birds, based on two cases: the medial preoptic nucleus (POM) of Japanese quail in relation to male sexual behavior, and nucleus HVC in canaries, which regulates song behavior. In male quail, POM volume changes seasonally, and in castrated subjects testosterone almost doubles POM volume within 2 weeks. Significant volume increases are, however, already observable after 1 day. Steroid receptor coactivator‐1 is part of the mechanism mediating these effects. Increases in POM volume reflect changes in cell size or spacing and dendritic branching, but are not associated with an increase in neuron number. In contrast, seasonal changes in HVC volume reflect incorporation of newborn neurons in addition to changes in cell size and spacing. These are induced by treatments with exogenous testosterone or its metabolites. Expression of doublecortin, a microtubule‐associated protein, is increased by testosterone in the HVC but not in the adjacent nidopallium, suggesting that neuron production in the subventricular zone, the birthplace of newborn neurons, is not affected. Together, these data illustrate the high degree of plasticity that extends into adulthood and is characteristic of avian brain structures. Many questions still remain concerning the regulation and specific function of this plasticity.
Aromatase, brain sexualization and plasticity: the fish paradigm
Authors: Le Page Yann , Diotel Nicolas , Vaillant Colette , Pellegrini Elisabeth , Anglade Isabelle , Mérot Yohann , Kah Olivier
Published: December 2010

In contrast to mammals, teleost fish have a very labile genetic sex determination. Sex differentiation is influenced by a combination of hormonal, social and environmental factors and teleost fishes exhibit many examples of hermaphroditism. This means that the brain of fish is not irreversibly sexualized early in life. This review aims at highlighting some unique features of fish that may explain their brain sexual plasticity. Unlike mammals, in which brain aromatase activity decreases after birth, adult teleosts exhibit an intense aromatase activity due to strong expression of one of two aromatase genes (aromatase A or cyp19a1a and aromatase B or cyp19a1b) that arose from a gene duplication event. Interestingly, aromatase B is only expressed in radial glial cells (RGC) of adult fish. These cells persist throughout life and act as progenitors in the brain of both developing and adult fish. In agreement with the fact that brain aromatase activity is correlated with sex steroid levels, the high expression of cyp19a1b is due to an autoregulatory loop through which estrogens and aromatizable androgens upregulate aromatase expression. Given the well‐established roles of estrogens and aromatase on brain sexualization, these features suggest that the brain of fish conserves properties of embryonic mammalian brain throughout life – high neurogenic activity and high aromatase expression in progenitor cells correlated with sex steroid levels. The permanent dialogue between the brain and the gonad would permit sex changes and thus the emergence of a variety of reproductive strategies. Other hypotheses are also discussed.
Emerging new sites for adult neurogenesis in the mammalian brain: a comparative study between the hypothalamus and the classical neurogenic zones
Authors: Migaud Martine , Batailler Martine , Segura Stéphanie , Duittoz Anne , Franceschini Isabelle , Pillon Delphine
Published: December 2010

In adult mammalian brain, two main germinative regions located in the subventricular zone of the lateral ventricle and in the subgranular cell layer of the hippocampal dentate gyrus have been considerably documented and are still under intense scrutiny. However, new neuron formation has recently been reported in various other brain areas including the hypothalamus. This central structure, responsible for the control of many major neuroendocrine functions such as reproduction, expresses high levels of PSA‐NCAM and nestin, both proteins being involved in structural and morphological plasticity mechanisms. Cell proliferation and new neuron production have been demonstrated in the adult hypothalamus of numerous species, although not hitherto described in non‐human primates and humans. Similarly to the subventricular zone and in the subgranular cell layer, the adult hypothalamic neurogenesis process is subject to dynamic regulation by various physiological and pharmacological signals. Several pieces of evidence support the hypothesis that a stem cell niche‐like architecture exist in the hypothalamus region lining the third ventricle thereby enabling adult neural stem cells to continuously generate neurons in vivo throughout life. Furthermore, recent data indicating that new hypothalamic neurons may become functionally implicated in sensory information processing endorse the assumption that the hypothalamus might be a neurogenic region.
Daily and seasonal adaptation of the circadian clock requires plasticity of the SCN neuronal network
Authors: Meijer Johanna H. , Michel Stephan , VanderLeest Henk T. , Rohling Jos H. T.
Published: December 2010

Circadian rhythms are an essential property of many living organisms, and arise from an internal pacemaker, or clock. In mammals, this clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and generates an intrinsic circadian rhythm that is transmitted to other parts of the CNS. We will review the evidence that basic adaptive functions of the circadian system rely on functional plasticity in the neuronal network organization, and involve a change in phase relation among oscillatory neurons. We will illustrate this for: (i) photic entrainment of the circadian clock to the light–dark cycle; and (ii) seasonal adaptation of the clock to changes in day length. Molecular studies have shown plasticity in the phase relation between the ventral and dorsal SCN during adjustment to a shifted environmental cycle. Seasonal adaptation relies predominantly on plasticity in the phase relation between the rostral and caudal SCN. Electrical activity is integrated in the SCN, and appears to reflect the sum of the differently phased molecular expression patterns. While both photic entrainment and seasonal adaptation arise from a redistribution of SCN oscillatory activity patterns, different neuronal coupling mechanisms are employed, which are reviewed in the present paper.