bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial transformations between superior colliculus visual and motor response fields during head‐unrestrained gaze shifts
Authors: Sadeh Morteza , Sajad Amirsaman , Wang Hongying , Yan Xiaogang , Crawford John Douglas
Published: October 2015

We previously reported that visuomotor activity in the superior colliculus (SC) – a key midbrain structure for the generation of rapid eye movements – preferentially encodes target position relative to the eye (Te) during low‐latency head‐unrestrained gaze shifts (DeSouza et al., 2011). Here, we trained two monkeys to perform head‐unrestrained gaze shifts after a variable post‐stimulus delay (400–700 ms), to test whether temporally separated SC visual and motor responses show different spatial codes. Target positions, final gaze positions and various frames of reference (eye, head, and space) were dissociated through natural (untrained) trial‐to‐trial variations in behaviour. 3D eye and head orientations were recorded, and 2D response field data were fitted against multiple models by use of a statistical method reported previously (Keith et al., 2009). Of 60 neurons, 17 showed a visual response, 12 showed a motor response, and 31 showed both visual and motor responses. The combined visual response field population (n = 48) showed a significant preference for Te, which was also preferred in each visual subpopulation. In contrast, the motor response field population (n = 43) showed a preference for final (relative to initial) gaze position models, and the Te model was statistically eliminated in the motor‐only population. There was also a significant shift of coding from the visual to motor response within visuomotor neurons. These data confirm that SC response fields are gaze‐centred, and show a target‐to‐gaze transformation between visual and motor responses. Thus, visuomotor transformations can occur between, and even within, neurons within a single frame of reference and brain structure.
Do projections from bioclimatic envelope models and climate change metrics match?
Authors: Garcia Raquel A. , Cabeza Mar , Altwegg Res , Araújo Miguel B.
Published: October 2015

Aim

Bioclimatic envelope models are widely used to describe changes in climatically suitable areas for species under future climate scenarios. Climate change metrics are applied independently of species data to characterize the spatio‐temporal dynamics of climate, and have also been used as indicators of the exposure of species to climate change. Here, we investigate whether these two approaches provide qualitatively similar indications about where biodiversity is potentially most exposed to climate change.

Location

Sub‐Saharan Africa.

Methods

We compared a range of climate change metrics for sub‐Saharan Africa with ensembles of bioclimatic envelope models for 2723 species of amphibians, snakes, mammals and birds. For each taxonomic group, we performed three comparisons between the two approaches: (1) is projected change in local climatic suitability (models) greater in grid cells with larger temporal differences in local climate (metrics); (2) are projected losses or gains of climatically suitable areas (models) greater for species in grid cells with climates that are projected to be less or more available in the future, respectively (metrics); and (3) are projected shifts in the position of climatically suitable areas (models) greater for species in grid cells with climates projected to move farther in space (metrics)?

Results

The changes in climatic suitability projected by the bioclimatic envelope models covaried with the climatic changes measured with the metrics. Agreement between the two approaches was found for all taxonomic groups, although it was stronger for species with a narrower climatic envelope breadth.

Main conclusions

For sub‐Saharan African vertebrates, projected patterns of exposure to climate change given by climate change metrics alone were qualitatively comparable to bioclimatic model projections of changes in areas of suitable climate for species. Assessments based on climate change metrics can thus be useful for making first‐cut inferences about the potential effects of climate change on regions with poorly known biodiversity.
Study of the effect of vitamin D supplementation on glycemic control in type 2 diabetic prevalent hemodialysis patients
Authors: Ibrahim Mohamed A. , Sarhan Iman I. , Halawa Mohamed R. , Afify Essam N. , Hebah Hayam A. , Al‐Gohary Eman A. , El‐Shazly Islam O.
Published: October 2015

Vitamin D is claimed to have an adjuvant effect on glycemic control by dual action on pancreatic β‐cells and insulin resistance. The aim of this study was to assess the possible effect of short‐term alfacalcidol supply on glycemic control in type 2 diabetic hemodialysis (HD) patients. Twenty type 2 diabetic HD patients (using diet and oral drugs but not insulin) were randomly selected from our dialysis unit as well as 20 non‐diabetic HD patients as control. A third group of 12 healthy subjects were studied as well. All three groups were similar in age, sex, and body mass index. Oral alfacalcidol therapy was administrated daily as recommended by Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for 12 weeks guided by monthly serum phosphorus and CaxPO4 product. Corrected total calcium, phosphorus, intact parathyroid hormone, 25‐hydroxy vitamin D (25[OH]D), and glucoparameters (fasting blood glucose, glycated hemoglobin [HbA1c%], insulin resistance by homeostatic model assessment, and β‐cell function by HOMA‐β%) were measured under basal conditions and after 3 months of therapy. 25(OH)D was non‐significantly lower in diabetic than non‐diabetic HD patients, but significantly lower than healthy subjects at the start of the study. However, vitamin D level increased significantly after 3 months of trial, although the levels did not reach normal values. This vitamin D rise was associated with highly significant improvement in concentrations of fasting blood sugar (FBS), fasting insulin, HbA1c%, and HOMA‐β‐cell function in diabetic and non‐diabetic controls. However, there was a significant rise in insulin resistance after treatment. The percentage of change was evident more in diabetics regarding FBS and 25(OH)D concentration. Adjustment of 25(OH)D level in type 2 diabetic prevalent HD patients may improve, at least with short‐term therapy, glycemic control mainly through improving β‐cell function.
Evaluation of solute penetration across the polysulfone membrane with vitamin E coating
Authors: Yamashita Akihiro C. , Masaki Hidenori , Kobayashi Eisuke , Sukegawa Takeshi
Published: October 2015

Vitamin E (vit E) is coated on polysulfone (PS) dialysis membrane for antioxidative purpose. The membrane, however, has not yet been evaluated from the mass transfer point of view. We investigated this PS membrane with and without vit E coating in vitro ultrafiltration experiments to identify whether or not the coating influences the mass transfer. Dialyzers that included PS membrane with and without vit E coating were investigated. Aqueous test solution of various solutes including vitamin B12 (VB12, MW1355), chymotrypsin (chymo, MW25000), and albumin (alb, MW66000) was prepared, and normal ultrafiltration experiments were performed at 310 K. Reverse ultrafiltration experiments in which test solution was filtered from outside to inside the hollow fiber were also performed. Sieving coefficients (SC) were computed for evaluation. SC for VB12 was the same regardless of vit E coating; however, chymo was 0.82 ± 0.01 and 0.86 ± 0.01, respectively, for the membrane with and without vit E. Thus, it would be understood that vit E coating reduces the pore size of the membrane, resulting the reduced transport of larger solutes. Like other PS membrane, SC for alb was decreased over time regardless of vit E coating. More importantly, although the steady‐state SC for alb was almost identical in two membranes, PS without vit E showed much greater decrease for the first 2 h, while that with vit E showed very little decrease over time, which suggested the reduced fouling effect due to vit E coating. All the SC values found in reverse ultrafiltration were higher than those found in normal ultrafiltration; moreover, the degree of increase with chymo was approximately 5%, whereas that with alb was approximately 430%, which may be explained by a new model in which wedge effect is taken into consideration for the membrane transport. Vit E coating not only has antioxidative effect but also reduces the fouling that is usually caused by various proteins.
Surgical site infection rates in dialysis patients undergoing endovascular procedures
Authors: Urbanes Aris Q. , Litchfield Terry , Graham Kevin , Hutyra Carolyn A.
Published: October 2015

A surgical site infection (SSI) is an infection related to surgery that develops within 30 days after an operation or within 1 year of implant placement. Postoperative SSIs are the most common health‐care‐associated infections, occurring in up to 5% of surgical patients. Endovascular surgical procedures related to vascular access are common in the dialysis population and may cause SSIs. A large outpatient vascular access system developed and implemented a surveillance program to measure and monitor SSIs in their population. The health‐care surveillance system extended to 76 ambulatory care centers across the United States and Puerto Rico. Based on a recorded 92,880 patient encounters, the surveillance system tabulated 12,541 valid patient survey responses documenting self‐reported symptoms of infection within a 30‐day postoperative period. The SSI rate was tabulated based on the presence of two or more specified indicators of infection: antibiotics, pus, dehiscence, pain, warmth, and swelling. Patients undergoing interventional procedures received surveys at discharge. Data were collected and analyzed using SPSS software. Survey analysis indicated a less than 3% superficial incisional SSI rate in hemodialysis patients undergoing endovascular procedures. The SSI rate for clean wound procedures is generally 2% or less. These data indicate that dialysis patients undergoing interventional procedures in vascular access centers may have a slightly greater risk of developing SSIs due to the presence of additional risk factors including obesity, diabetes, and age. This study was limited by a set of loose diagnostic criteria self‐reported by patients, which may have overestimated the prevalence of infection. SSIs are a serious medical problem associated with increased morbidity and mortality and increased medical care costs. All providers should consider an active surveillance program following endovascular procedures given the comorbidities associated with the dialysis population.
Hospital discharge summary scorecard: a quality improvement tool used in a tertiary hospital general medicine service
Authors: Singh G. , Harvey R. , Dyne A. , Said A. , Scott I.
Published: October 2015

We assessed the impact of completion and feedback of discharge summary scorecards on the quality of discharge summaries written by interns in a general medicine service of a tertiary hospital. The scorecards significantly improved summary quality in the first three rotations of the intern year and could be readily adopted by other units as a quality improvement intervention for optimizing clinical handover to primary care providers.
DNA–histone complexes as ligands amplify cell penetration and nuclear targeting of anti‐DNA antibodies via energy‐independent mechanisms
Authors: Zannikou Markella , Bellou Sofia , Eliades Petros , Hatzioannou Aikaterini , Mantzaris Michael D. , Carayanniotis George , Avrameas Stratis , Lymberi Peggy
Published: October 2015

We have generated three monoclonal cell‐penetrating antibodies (CPAbs) from a non‐immunized lupus‐prone (NZB × NZW)F1 mouse that exhibited high anti‐DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA–histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell‐entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis‐specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy‐independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant.
Analysts’ and Investors’ Reactions to Consistent Earnings Signals
Authors: Caylor Marcus L. , Christensen Theodore E. , Johnson Peter M. , Lopez Thomas J.
Published: October 2015

We investigate (1) whether the trajectory of the current‐quarter earnings expectation path (defined by the signs of the forecast revision and the earnings surprise) provides information about future firm performance, and (2) the extent to which analysts and investors react to that information. Our results indicate that analysts underreact more to earnings information revealed by consistent‐signal earnings expectation paths than to earnings information communicated by inconsistent‐signal expectation paths. We also find that the current earnings expectation path provides incremental explanatory power for future abnormal returns, even after controlling for the sign and magnitude of the earnings surprise. Overall, our evidence is consistent with underreaction stemming from analysts’ and investors’ bias in processing the information in consistent‐signal earnings expectation paths.
Student‐generated content in college teaching: content quality, behavioural pattern and learning performance
Authors: Yang X. , Guo X. , Yu S.
Published: October 2015

This study investigates the quality of course content, behavioural patterns of students and learning performance in teaching of student‐generated content (SGC). A total of 49 third‐year university students in educational technology participated in this study. By combining the methods of questionnaire, lag sequence analysis and interview, the study found that (1) SGC quality was acceptable, (2) SGC process has 14 significant behavioural sequences, and (3) students developed their knowledge and capability and were satisfied with SGC‐based teaching approach. In addition, this study revealed problems and proposed suggestions for SGC‐based course teaching. Finally, implications for course teaching in colleges, the limitations and future research plan were presented.
Factors affecting peri‐implant bone resorption in four Implant supported mandibular full‐arch restorations: a 3‐year prospective study
Authors: Krennmair Stefan , Weinländer Michael , Forstner Thomas , Krennmair Gerald , Stimmelmayr Michael
Published: October 2015

Background

Peri‐implant marginal bone‐level (MBL) alteration represents one of the parameters included in the criteria for determining implant health.

Objective

Factors affecting peri‐implant MBL alteration for 4‐implant‐supported fixed mandibular prostheses (4‐ISFMP) were assessed.

Material & Methods

A 3‐year prospective, cohort study was conducted on 44 mandibularly edentulous patients treated with 4‐ISFMP. Peri‐implant MBL alteration was evaluated radiographically at the 12‐, 24‐ and 36‐month follow‐ups considering to patient‐related risk factors [age, gender, diabetes mellitus, smoking, cardiovascular disease (CVD), rheumatic disorders (RD)] and implant/prosthesis‐related features (implant location, keratinized gingiva, denture cantilever length, prosthesis supporting zone, opposing dentition) as well as to peri‐implant biological parameters (plaque‐, bleeding‐, calculus index).

Results

148/176 implants (37 patients, drop‐out: 15%) were followed for 3 years showing significant (p < 0.001) annual differences of MBL alterations over time. The univariate analysis demonstrated differences of MBL alterations for smokers (p = 0.014), for patients with CVD (p = 0.001) and RD (p = 0.011). In the 3‐year multivariate analysis, MBL alteration was influenced by time (p < 0.001) and showed relationship with risk factors as smoking (p < 0.002; OR = 18.965), CVD (p < 0.021; OR = 5.172), RD (p < 0.006; OR = 50.171) and plaque‐index (p = 0.034; OR = 3.252).

Conclusions

Although peri‐implant MBL alteration increased annually, significant odds ratios, were found for patients‐related risk factors identifying them potentiating the alterations.
Is hidradenitis suppurativa associated with anaemia?: a population‐based and hospital‐based cross‐sectional study from Denmark
Authors: Miller I.M. , Johansen M.E. , Mogensen U.B. , Zarchi K. , Ellervik C. , Jemec G.B.
Published: October 2015

Background

Chronic inflammatory diseases may be associated with anaemia of inflammation. Hidradenitis suppurativa is a chronic inflammatory dermatological disease associated with metabolic comorbidities, low quality of life and fatigue. Anaemia may cause fatigue, and it has been hypothesized that HS‐related fatigue may be partly due to anaemia.

Objective

Our objective was to investigate a possible association between HS and anaemia.

Methods

We performed a hospital‐based and population‐based cross‐sectional study investigating the red blood cell profile, i.e. haemoglobin.

Results

We identified a total of 32 hospital HS individuals, 430 population HS individuals and 20,780 population non‐HS control individuals. The age‐sex‐smoking‐adjusted analyses showed no differences in the haemoglobin level of the HS groups vs. the control group. Analyses of the anaemic subgroup of HS individuals revealed that 60% had normocytic anaemia and 40% microcytic anaemia, in concordance with anaemia of inflammation.

Conclusion

In contrast to our hypothesis, this study showed that HS is not associated with anaemia. Thus, anaemia may not be the cause of the described fatigue in HS patients. Furthermore, the results indicate that if an HS patient does suffer from anaemia it is most likely to be normocytic or microcytic and thus compatible with anaemia seen in other chronic inflammatory disorders.
Cost–benefit of reflectance confocal microscopy in the diagnostic performance of melanoma
Authors: Pellacani G. , Witkowski A. , Cesinaro A.M. , Losi A. , Colombo G.L. , Campagna A. , Longo C. , Piana S. , De Carvalho N. , Giusti F. , Farnetani F.
Published: October 2015

Background

The sub‐optimal diagnostic accuracy for melanoma leads to excise a high number of benign lesions, with consequent costs. Reflectance confocal microscopy (RCM) improves diagnostic specificity, thus possibly inducing a reduction in unnecessary excisions and related costs.

Objective

To estimate the influence of RCM on number of benign lesions needed to excise (NNE) a melanoma, in term of clinical outcomes and costs per patient.

Patients and Methods

Skin neoplasms excised by the dermatology public service in the Province of Modena were retrieved form centralized pathology database. Differences in NNE between the territorial service (using dermoscopy only) and the University Hospital (adding also RCM to the patients’ workflow) were calculated and cost analysis was performed through a micro‐costing approach.

Results

A large reduction in benign lesions excised at University Hospital was evident, leading to NNE of 6.25 for University Hospital, compared to 19.41 for Territorial Dermatology. Since 4320 unnecessary excisions can be saved every million inhabitants, an overall yearly saving of over 280,000 Eur can be expected from the use of RCM.

Conclusions

The systematic use of RCM was dramatically affecting the number of benign lesions excised, and this can be translated in a significant cost–benefit advantage.
The role of clinical evidence in emergent therapies: an empirical study on femoropopliteal stent‐angioplasty in Europe
Authors: Bourdon Elmar , Schüller Katharina , Diehl Steffen
Published: October 2015

Rationale, aims and objective

A delayed availability of clinical evidence in rapidly emerging therapies is considered a major problem. In this study, we examined whether evidence from clinical studies has influenced the therapy of a major disease in industrial countries, peripheral arterial disease (PAD), using novel femoropopliteal stent‐angioplasty.

Method

This analysis of retrospective time series data uses multivariate linear regression to investigate associations between published clinical evidence on femoropopliteal stent‐angioplasty from Q3/2004 to Q4/2010 and the demand for femoropopliteal stents in Germany, France, Italy and the UK between Q1/2005 and Q4/2010, controlling for the prevalence of PAD risk factors, cardiovascular drug demand, reimbursement of health care providers for stent implantation, stent selling prices of manufacturers and economic indicators.

Results

We did not observe any association of published clinical evidence with femoropopliteal stent demand in Germany, France, Italy and the UK, while we observed such associations for varying control variables at different time lags respectively.

Conclusion

We observed no association between published clinical evidence of femoropopliteal stent‐angioplasty and its use in any of the four countries. The country‐specific context and practice‐related variables at a centre and individual doctor level may have limited the role of published clinical evidence in emerging femoropopliteal stent‐angioplasty. More research is needed at this context, centre and individual level.
Statin prescribing according to gender, age and indication: what about the benefit–risk balance?
Authors: Wallach‐Kildemoes Helle , Stovring Henrik , Holme Hansen Ebba , Howse Kenneth , Pétursson Hálfdán
Published: October 2015

Rationales, aims and objectives

The increasing dispensing of statins has raised concern about the appropriateness of prescribing to various population groups. We aimed to (1) investigate incident and prevalent statin prescribing according to indication, gender and age and (2) relate prescribing patterns to evidence on beneficial and adverse effects.

Methods

A cohort of Danish inhabitants (n = 4 424 818) was followed in nationwide registries for dispensed statin prescriptions and hospital discharge information. We calculated incidence rates (2005–2009), prevalence trends (2000–2010) and absolute numbers of statin users according to register proxies for indication, gender and age.

Results

In 2010, the prevalence became highest for ages 75–84 and was higher in men than women (37% and 33%, respectively). Indication‐specific incidences and prevalences peaked at ages around 65–70, but in myocardial infarction, the prevalence was about 80% at ages 45–80. Particularly, incidences tended to be lower in women until ages of about 60 where after gender differences were negligible. In asymptomatic individuals (hypercholesterolaemia, presumably only indication) aged 50+, dispensing was highest in women. The fraction of statin dispensing for primary prevention decreased with age: higher for incident than prevalent prescribing. Independent of age, this fraction was highest among women, e.g. 60% versus 45% at ages 55–64. The fraction for potential atherosclerotic condition (PAC, e.g. heart failure) increased with age.

Conclusion

Prevalence of statin utilization was highest for ages 75–84, although indication‐specific measures were relatively low. Despite inconclusive evidence for a favourable risk–benefit balance, statin prescribing was high among people aged 80+, asymptomatic women and PAC patients.
Responding to cough presentations: an interview study with Cambodian pharmacies participating in a National Tuberculosis Referral Program
Authors: Bell Carolyn A. , Pichenda Koeut , Ilomäki Jenni , Duncan Gregory J. , Eang Mao Tan , Saini Bandana
Published: October 2015

Rationale, aims and objectives

Asia‐Pacific carries a high burden of respiratory‐related mortality. Timely referral and detection of tuberculosis cases optimizes patient and public health outcomes. Registered private pharmacies in Cambodia participate in a National Tuberculosis Referral Program to refer clients with cough suggestive of tuberculosis to public sector clinics for diagnosis and care. The objective of this study was to investigate clinical intentions of pharmacy staff when presented with a hypothetical case of a client with prolonged cough suggestive of tuberculosis.

Method

A random sample of 180 pharmacies was selected. Trained interviewers administered a hypothetical case scenario to trained pharmacy staff. Participants provided ‘yes’/‘no’ responses to five clinical actions presented in the scenario. Actions were not mutually exclusive. Data were tabulated and compared using chi‐square tests or Fisher's exact tests.

Results

Overall, 156 (92%) participants would have referred the symptomatic client in the case scenario. Participants who would have referred the client were less likely to sell a cough medicine (42% vs. 100%, P < 0.001) and less likely to sell an antibiotic (19% vs. 79%, P < 0.001) than those who would not have referred the client.

Conclusion

Involving pharmacies in a Referral Program may have introduced concepts of appropriate clinical care when responding to clients presenting with cough suggestive of tuberculosis. However, results showed enhancing clinical competence among all referral programme participants particularly among non‐referring pharmacies and those making concurrent sales of cough‐related products would optimize pharmacy‐initiated referral. Further research into actual clinical practices at Referral Program pharmacies would be justified.
Induction of inducible nitric oxide synthase expression in ammonia‐exposed cultured astrocytes is coupled to increased arginine transport by upregulated y+LAT2 transporter
Authors: Zielińska Magdalena , Milewski Krzysztof , Skowrońska Marta , Gajos Anna , Ziemińska Elżbieta , Beręsewicz Andrzej , Albrecht Jan
Published: October 2015

One of the aspects of ammonia toxicity to brain cells is increased production of nitric oxide (NO) byNOsynthases (NOSs). Previously we showed that ammonia increases arginine (Arg) uptake in cultured rat cortical astrocytes specificallyviay+L amino acid transport system, by activation of its member, a heteromeric y+LAT2 transporter. Here, we tested the hypothesis that up‐regulation of y+LAT2 underlies ammonia‐dependent increase ofNOproductionviainducible NOS (iNOS) induction, and protein nitration. Treatment of rat cortical astrocytes for 48 with 5 mM ammonium chloride (‘ammonia’) (i) increased the y+L‐mediated Arg uptake, (ii) raised the expression of iNOS and endothelial NOS (eNOS), (iii) stimulatedNOproduction, as manifested by increased nitrite+nitrate (Griess) and/or nitrite alone (chemiluminescence), and consequently, (iv) evoked nitration of tyrosine residues of proteins in astrocytes. Except for the increase of eNOS, all the above described effects of ammonia were abrogated by pre‐treatment of astrocytes with either siRNAsilencing of the Slc7a6 gene coding for y+LAT2 protein, or antibody to y+LAT2, indicating their strict coupling to y+LAT2 activity. Moreover, induction of y+LAT2 expression by ammonia was sensitive to Nf‐κB inhibitor,BAY11‐7085, linking y+LAT2 upregulation to the Nf‐κB activation in this experimental setting as reported earlier and here confirmed. Importantly, ammonia did not affect y+LAT2 expression nor y+L‐mediated Arg uptake activity in the cultured cerebellar neurons, suggesting astroglia‐specificity of the above described mechanism. The described coupling of up‐regulation of y+LAT2 transporter with iNOS in ammonia‐exposed astrocytes may be considered as a mechanism to ensureNOsupply for protein nitration.

image

Ammonia (NH4+) increases the expression and activity of the L‐arginine (Arg) transporter (Arg/neutral amino acids [NAA] exchanger) y+LAT2 in cultured rat cortical astrocytes by a mechanism involving activation (nuclear translocation) of the transcription factor nuclear factor‐Nuclear factor‐κB (Nf‐κB‐p65). Up‐regulation of y+LAT2 transporter is coupled with increased inducible nitric oxide synthase (iNOS) expression, which leads to increase nitric oxide (NO) synthesis and protein nitration.
Progesterone receptor signalling in retinal photoreceptor neuroprotection
Authors: Wyse Jackson Alice C. , Roche Sarah L. , Byrne Ashleigh M. , Ruiz‐Lopez Ana M. , Cotter Thomas G.
Published: October 2015

‘Norgestrel’, a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of progesterone receptors present in the C57 wild type and rd10 mouse model of retinitis pigmentosa. Classical progesterone receptors A and B (PR A/B), progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane progesterone receptors α, β and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up‐regulated in the degenerating rd10 mouse retina. Activated by Norgestrel through nuclear trafficking, siRNA knock down of PGRMC1 abrogated the protective properties of Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by AG205 blocked Norgestrel‐induced protection in stressed retinal explants. Therefore, we conclude that PGRMC1 is crucial to the neuroprotective effects of Norgestrel on stressed photoreceptors.

image

The synthetic progestin ‘Norgestrel’ has been identified as a potential therapeutic for the treatment of Retinitis Pigmentosa, a degenerative eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify ‘Progesterone Receptor Membrane Component 1’ as the major progesterone receptor eliciting the protective effects of Norgestrel, both in vitro and ex vivo. This furthers our understanding of Norgestrel's molecular mechanism, which we hope will help bring Norgestrel one step closer to the clinic.
The Effect of Fingolimod on Conversion of Acute Gadolinium‐Enhancing Lesions to Chronic T1 Hypointensities in Multiple Sclerosis
Authors: Oommen Vinit V. , Tauhid Shahamat , Healy Brian C. , Chua Alicia S. , Malik Muhammad T. , Diaz‐Cruz Camilo , Dupuy Sheena L. , Weiner Howard L. , Chitnis Tanuja , Bakshi Rohit
Published: October 2015

BACKGROUND

Brain lesions converting to chronic T1 hypointensities (“chronic black holes” [CBH]), indicate severe tissue destruction (axonal loss and irreversible demyelination) in multiple sclerosis (MS). Two mechanisms by which fingolimod could limit MS lesion evolution include sequestration of lymphocytes in the periphery or direct neuroprotective effects. We investigated the effect of fingolimod on the evolution of acute gadolinium‐enhancing (Gd+) brain lesions to CBH in patients with MS.

METHODS

This was a retrospective nonrandomized comparison of patients with Gd+ brain lesions at the time of starting oral fingolimod [.5 mg/day,n= 26, age (mean ± SD) 39.2 ± 10.6 years, Expanded Disability Status Scale (EDSS) score ‐ median (range): 1.75 (0, 6.5)] to those on no therapy [n= 30, age 41.7 ± 9.3 years; EDSS 1.0 (0, 6)]. Each lesion was classified by whether it converted to a CBH in the year following treatment.

RESULTS

In the fingolimod group, 99 Gd+ baseline lesions (mean ± SD, range: 3.8 ± 5.1; 1, 21 per patient) were identified of which 25 (25%) evolved to CBH (1.0 ± 2.0; 0, 10 per patient). The untreated group had 62 baseline Gd+ lesions (2.1 ± 2.3; 1, 13), 26 (42%) of which evolved to CBH (.9 ± 1.4; 0, 7) (P= .063). Thirteen patients (50%) receiving fingolimod and 17 untreated patients (57%) developed CBH (P= .79).

CONCLUSION

This pilot study shows a trend of fingolimod on reducing the conversion rate from acute to chronic destructive MS lesions. Such an effect awaits verification in larger randomized prospective studies.
Different Intraorbital Implant Situations and Ocular Prosthetic Rehabilitation
Authors: Aggarwal Himanshi , Kumar Pradeep , Eachempati Prashanti , Alvi Habib A.
Published: October 2015

Enucleation is the removal of the entire globe of the eye and a portion of the optic nerve, while evisceration involves the removal of the contents of the globe leaving the sclera, extraocular muscles, and optic nerve. Following enucleation or evisceration, intraorbital implants are routinely placed to enhance the prosthetic outcome in addition to restoring the lost orbital volume. Current practice employs intraorbital implants made of nonporous silicone, hydroxyapatite, or porous polyethylene. Intraorbital implant selection and placement, being a highly demanding procedure in terms of knowledge, skill, and expertise, may be associated with a multiplicity of technical and surgical errors. Complications are usually minimal with these implants, but they do occur. The literature reveals many articles related to intraorbital implants, their benefits, and complications; however, the literature regarding the effect of various intraorbital implant situations on the subsequent prosthetic rehabilitation is markedly scarce. Moreover, the need for interdisciplinary surgical and prosthetic interventions required for successful rehabilitation in cases of compromised implant situations has been underemphasized. Hence, this review aimed to evaluate the effect of different intraorbital implant situations on ocular rehabilitation and the required interdisciplinary surgical and prosthetic treatment approach for rehabilitation of enucleated/eviscerated sockets with compromised implant situations, to provide a critical appraisal, and to present a simplified management strategy.
L1 and L2 Distance Effects in Learning L3 Dutch
Authors: Schepens Job J. , van der Slik Frans , van Hout Roeland
Published: October 2015

Many people speak more than two languages. How do languages acquired earlier affect the learnability of additional languages? We show that linguistic distances between speakers’ first (L1) and second (L2) languages and their third (L3) language play a role. Larger distances from the L1 to the L3 and from the L2 to the L3 correlate with lower degrees of L3 learnability. The evidence comes from L3 Dutch speaking proficiency test scores obtained by candidates who speak a diverse set of L1s and L2s. Lexical and morphological distances between the L1s of the learners and Dutch explained 47.7% of the variation in proficiency scores. Lexical and morphological distances between the L2s of the learners and Dutch explained 32.4% of the variation in proficiency scores in multilingual learners. Cross‐linguistic differences require language learners to bridge varying linguistic gaps between their L1 and L2 competences and the target language.
Lower levels of human milk adiponectin predict offspring weight for age: a study in a lean population of Filipinos
Authors: Anderson Justine , McKinley Kassielle , Onugha Jason , Duazo Paulita , Chernoff Meytal , Quinn Elizabeth A.
Published: October 2015

Prior studies have reported a significant, inverse association between adiponectin in human milk and offspring growth velocity. Less is known about this association in populations characterised by a loss of weight for age z‐scores (WAZs) in early life. We investigated the association between maternal body composition and milk adiponectin in a sample of Filipino mothers. We then tested for an association between milk adiponectin and size for age in their infants. A total of 117 Filipino mothers nursing infants from 0 to 24 months were recruited from Cebu, Philippines. Anthropometrics, interviews and milk samples were collected and analysed using standard protocols. Mean milk adiponectin in this sample was 7.47 ± 5.75 ng mL−1. Mean infant WAZ and weight for length (WLZ) decreased with age. Maternal body composition was not associated with milk adiponectin content. Milk adiponectin had a significant, positive association with infant WAZ and WLZ. Prior reports have found an inverse association between milk adiponectin and infant WAZ. Here, we report that in lean populations with lower milk adiponectin, there is a positive association with infant WAZ, possibly reflecting pleiotropic biological functions of adiponectin for post‐natal growth. This study increases the understanding of normal biological variation in milk adiponectin and the consequences of low levels of milk adiponectin for offspring growth.
Motility in cyanobacteria: polysaccharide tracks and Type IV pilus motors
Authors: Wilde Annegret , Mullineaux Conrad W.
Published: October 2015

Motility in cyanobacteria is useful for purposes that range from seeking out favourable light environments to establishing symbioses with plants and fungi. No known cyanobacterium is equipped with flagella, but a diverse range of species is able to ‘glide’ or ‘twitch’ across surfaces. Cyanobacteria with this capacity range from unicellular species to complex filamentous forms, including species such as Nostoc punctiforme, which can generate specialised motile filaments called hormogonia. Recent work on the model unicellular cyanobacterium Synechocystis sp. PCC 6803 has shown that its means of propulsion has much in common with the twitching motility of heterotrophs such as Pseudomonas and Myxococcus. Movement depends on Type IV pili, which are extended, adhere to the substrate and then retract to pull the cell across the surface. Previous work on filamentous cyanobacteria suggested a very different mechanism, with movement powered by the directional extrusion of polysaccharide from pores close to the cell junctions. Now a new report by Khayatan and colleagues in this issue of Molecular Microbiology suggests that the motility of Nostoc hormogonia has much more in common with Synechocystis than was previously thought. In both cases, polysaccharide secretion is important for preparing the surface, but the directional motive force comes from Type IV pili.
The EutQ and EutP proteins are novel acetate kinases involved in ethanolamine catabolism: physiological implications for the function of the ethanolamine metabolosome in Salmonella enterica
Authors: Moore Theodore C. , Escalante‐Semerena Jorge C.
Published: October 2015

Salmonella enterica catabolizes ethanolamine inside a compartment known as the metabolosome. The ethanolamine utilization (eut) operon of this bacterium encodes all functions needed for the assembly and function of this structure. To date, the roles of EutQ and EutP were not known. Herein we show that both proteins have acetate kinase activity and that EutQ is required during anoxic growth of S. enterica on ethanolamine and tetrathionate. EutP and EutQ‐dependent ATP synthesis occurred when enzymes were incubated with ADP, Mg(II) ions and acetyl‐phosphate. EutQ and EutP also synthesized acetyl‐phosphate from ATP and acetate. Although EutP had acetate kinase activity, ΔeutP strains lacked discernible phenotypes under the conditions where ΔeutQ strains displayed clear phenotypes. The kinetic parameters indicate that EutP is a faster enzyme than EutQ. Our evidence supports the conclusion that EutQ and EutP represent novel classes of acetate kinases. We propose that EutQ is necessary to drive flux through the pathway under physiological conditions, preventing a buildup of acetaldehyde. We also suggest that ATP generated by these enzymes may be used as a substrate for EutT, the ATP‐dependent corrinoid adenosyltransferase and for the EutA ethanolamine ammonia‐lyase reactivase.
The zinc cluster proteins Upc2 and Ecm22 promote filamentation in Saccharomyces cerevisiae by sterol biosynthesis‐dependent and ‐independent pathways
Authors: Woods Kelly , Höfken Thomas
Published: October 2015

The transition between a unicellular yeast form to multicellular filaments is crucial for budding yeast foraging and the pathogenesis of many fungal pathogens such as Candida albicans. Here, we examine the role of the related transcription factors Ecm22 and Upc2 in Saccharomyces cerevisiae filamentation. Overexpression of either ECM22 or UPC2 leads to increased filamentation, whereas cells lacking both ECM22 and UPC2 do not exhibit filamentous growth. Ecm22 and Upc2 positively control the expression of FHN1, NPR1, PRR2 and sterol biosynthesis genes. These genes all play a positive role in filamentous growth, and their expression is upregulated during filamentation in an Ecm22/Upc2‐dependent manner. Furthermore, ergosterol content increases during filamentous growth. UPC2 expression also increases during filamentation and is inhibited by the transcription factors Sut1 and Sut2. The expression of SUT1 and SUT2 in turn is under negative control of the transcription factor Ste12. We suggest that during filamentation Ste12 becomes activated and reduces SUT1/SUT2 expression levels. This would result in increased UPC2 levels and as a consequence to transcriptional activation of FHN1, NPR1, PRR2 and sterol biosynthesis genes. Higher ergosterol levels in combination with the proteins Fhn1, Npr1 and Prr2 would then mediate the transition to filamentous growth.
cyp51A gene silencing using RNA interference in azole‐resistant Aspergillus fumigatus
Authors: Mousavi Bita , Hedayati Mohammad T. , Teimoori‐Toolabi Ladan , Guillot Jacques , Alizadeh Ahad , Badali Hamid
Published: October 2015

An increasing number of reports have described the emergence of acquired resistance of Aspergillus fumigatus to azole compounds. The primary mechanism of resistance in clinical isolates is the mutation of the azole drug target enzyme, which is encoded by the cyp51A gene. The aim of this study was to evaluate the impact of silencing the cyp51A gene in azole‐resistant A. fumigatus isolates. A 21‐nucleotide small‐interfering RNA (siRNA) was designed based on the cDNA sequence of the A. fumigatus cyp51A gene. After silencing the cyp51A gene in germinated conidia (15, 20, 25 and 50 nM), azole‐resistant A. fumigatus was cultured on broth media and gene expression was analysed by measuring the cyp51A mRNA level using RT‐PCR assay. Hyphae were successfully transfected by siRNA and expression of the cyp51A gene was significantly reduced by siRNA at the concentration of 50 nM (P ≤ 0.05). In addition, at this siRNA concentration, the minimum inhibitory concentration of itraconazole for the treated cells was decreased, compared with that for untreated control cells, from 16 to 4 μg/ml.
Escherichia coli Urinary Infection as a Cause of Acute Hemorrhagic Edema in Infancy
Authors: Breda Luciana , Franchini Simone , Marzetti Valentina , Chiarelli Francesco
Published: October 2015

Acute hemorrhagic edema of infancy (AHEI) is a benign leukocytoclastic small‐vessel vasculitis that affects infants, presenting with a classic clinical triad. Because of the self‐limited progression, conservative management is the most common approach. We describe a case of AHEI apparently triggered by an Escherichia coli urinary tract infection.
Hoyeraal–Hreidarsson Syndrome: An Extremely Rare Dyskeratosis Congenita Phenotype
Authors: Bakar Özgür , Işik Ugˇur , Canpolat Cengiz , Alanay Yasemin
Published: October 2015

Hoyeraal–Hreidarsson syndrome is a rare telomere biology disorder that is recognized as a severe variant of dyskeratosis congenita. We present a Libyan boy with hematologic and neurologic abnormalities with typical dermatologic manifestations of dyskeratosis congenita. Death usually occurs before the age of 4 years as a result of pancytopenia or malignant transformation of mucocutaneous lesions. The boy presented survived longer than 5 years. Early recognition and appropriate genetic counseling are crucial because of the high mortality of this genetic disorder.
Genetic variation and evolutionary forces shaping Cucumber vein yellowing virus populations: risk of emergence of virulent isolates in Europe
Authors: Velasco L. , Salem N. , Willemsen A. , Lapidot M. , Mansour A. N. , Rubio L. , Galipienso L.
Published: October 2015

The genetic variation and evolutionary mechanisms shaping Cucumber vein yellowing virus (CVYV) populations were investigated by analysis of nucleotide sequences coding for P1b, P1b/P3 and coat proteins (CP) from isolates collected in different countries. The complete genome sequence of isolate ISM from Israel was also determined and compared to those of isolates Jor from Jordan and ALM32 from Spain. This isolate had overall nucleotide identities of 94·23 and 94·96% with ALM32 and Jor, respectively. Nucleotide variation among isolates was not homogeneously distributed, with the 5′ half of the genome being more variable than the 3′ half. A Bayesian phylogenetic tree of the CP showed that CVYV isolates clustered into two main clades: isolates from the Middle East region (Lebanon, Israel and Jordan) clustered in both clades whereas the isolate from Tunisia clustered in clade I and the European isolates clustered as a homogeneous phylogroup in Clade II. A similar topology was observed for P1b but with incongruences with respect to the CP, suggesting genetic exchange among virus isolates, which were confirmed with recombination algorithms. The low genetic diversity within the European phylogroup with respect to the other isolates, neutralist tests and genetic differentiation analyses suggest that the Middle East region is the cradle of CVYV and that a unique virus introduction event occurred in Europe, where the virus spread rapidly. Taken together, these findings indicate a risk of emergence of virulent CVYV isolates in Europe either through migration from the Middle East or by genetic changes of the European isolates.
Bacteria from the citrus phylloplane can disrupt cell–cell signalling in Xanthomonas citri and reduce citrus canker disease severity
Authors: Caicedo J. C. , Villamizar S. , Ferro M. I. T. , Kupper K. C. , Ferro J. A.
Published: October 2015

Xanthomonas citri subsp. citri (Xcc) is the causal agent of citrus canker, a disease that affects almost all types of citrus crops. Production of particular Xcc pathogenicity factors is controlled by a gene cluster rpf, which encodes elements of a cell–cell communication system called quorum sensing (QS), mediated by molecules of the diffusible signal factor (DSF) family. Interference with cell–cell signalling, also termed quorum quenching, either by signal degradation or over‐production, has been suggested as a strategy to control bacterial disease. In this study, three bacterial strains were isolated from citrus leaves that displayed the ability to disrupt QS signalling in Xcc. Pathogenicity assays in sweet orange (Citrus sinensis) showed that bacteria of the genera Pseudomonas and Bacillus also have a strong ability to reduce the severity of citrus canker disease. These effects were associated with alteration in bacterial attachment and biofilm formation, factors that are known to contribute to Xcc virulence. These quorum‐quenching bacteria may represent a highly valuable tool in the process of biological control and offer an alternative to the traditional copper treatment currently used to treat citrus canker disease.