bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitrification procedure decreases inositol 1,4,5‐trisphophate receptor expression, resulting in low fertility of pig oocytes
Authors: Hirose Masahiko , Kamoshita Maki , Fujiwara Katsuyoshi , Kato Tsubasa , Nakamura Ayaka , Wojcikiewicz Richard J. H. , Parys Jan B. , Ito Junya , Kashiwazaki Naomi
Published: April 2013

Although cryopreservation of mammalian oocytes is an important technology, it is well known that unfertilized oocytes, especially in pigs, are highly sensitive to low temperature and that cryopreserved oocytes show low fertility and developmental ability. The aim of the present study was to clarify why porcine in vitro matured (IVM) oocytes at the metaphase II (MII) stage showed low fertility and developmental ability after vitrification. In vitro matured cumulus oocyte complexes (COCs) were vitrified with Cryotop and then evaluated for fertility through in vitro fertilization (IVF). Although sperm‐penetrated oocytes were observed to some extent (30–40%), the rate of pronuclear formation was low (9%) and none of them progressed to the two‐cell stage. The results suggest that activation ability of cryopreserved oocytes was decreased by vitrification. We examined the localization and expression level of the type 1 inositol 1,4,5 trisphosphate receptor (IP3R1), the channel responsible for Ca2+ release during IVF in porcine oocytes. Localization of IP3R1 close to the plasma membrane and total expression level of IP3R1 protein were both decreased by vitrification. In conclusion, our present study indicates that vitrified‐warmed porcine COCs showed a high survival rate but low fertility after IVF. This low fertility seems to be due to the decrease in IP3R1 by the vitrification procedure.
Genome‐wide association study for fatty acid composition in Japanese Black cattle
Authors: Ishii Atsushi , Yamaji Keita , Uemoto Yoshinobu , Sasago Nanae , Kobayashi Eiji , Kobayashi Naohiko , Matsuhashi Tamako , Maruyama Shin , Matsumoto Hirokazu , Sasazaki Shinji , Mannen Hideyuki
Published: April 2013

Fatty acid composition is one of the important traits in beef. The aim of this study was to identify candidate genomic regions for fatty acid composition by genome‐wide association study with 50 K single nucleotide polymorphism (SNP) array in Japanese Black cattle. A total of 461 individuals and 40 657 SNPs were used in this study. We applied genome‐wide rapid association using mixed model and regression (GRAMMAR) and genomic control approaches to estimate the associations between genotypes and fatty acid composition. In addition, two SNPs in fatty acid synthase (FASN) (T1952A) and stearoyl‐CoA desaturase (SCD) (V293A) genes were also genotyped. Association analysis revealed that 30 significant SNPs for several fatty acids (C14:0, C14:1, C16:1 and C18:1) were located in the BTA19 FASN gene located within this region but the FASN mutation had no significant effect on any traits. We also detected one significant SNP for C18:1 on BTA23 and two SNPs for C16:0 on BTA25. The region around 17 Mb on BTA26 harbored two significant SNPs for C14:1 and SNP in SCD in this region showed the strongest association with C14:1. This study demonstrated novel candidate regions in BTA19, 23 and 25 for fatty acid composition.
Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses
Authors: Ferraz Karina C. , Sousa‐Santos Ozélia , Neto‐Neves Evandro M. , Rizzi Elen , Muniz Jaqueline J. , Gerlach Raquel F. , Tanus‐Santos Jose E.
Published: April 2013

Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP‐2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP‐2 may affect the vascular tone and impair β‐adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP‐2. We examined the effects of recombinant human MMP‐2 (rhMMP‐2) administered intravenously to anaesthetized lambs at baseline conditions and during β1‐adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP‐2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 μg/kg/min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP‐2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP‐2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP‐2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/dtmax, and these effects were attenuated by rhMMP‐2. The previous administration of doxycycline blunted rhMMP‐2‐induced changes in dobutamine responses. While the infusion of rhMMP‐2 did not increase plasma and cardiac MMP‐2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP‐2 exerts no major haemodynamic effects in lambs. However, rhMMP‐2 impairs the responses elicited by activation of β‐adrenoreceptors.
A Human Experimental Bone Pain Model
Authors: Andresen Trine , Pfeiffer‐Jensen Mogens , Brock Christina , Drewes Asbjørn M. , Arendt‐Nielsen Lars
Published: April 2013

The aim of this study was to develop a human experimental bone pain model. Fourteen healthy men were included in two study sessions. Pressure pain threshold (PPT) was estimated using probes of different sizes. Computer‐controlled and hand‐held algometry were applied to the skin area covering right and left medial tibia before and after local anaesthesia (LA) of the skin and reproducibility was evaluated. Pain experience (McGill questionnaire) was compared between healthy volunteers and 12 patients with vertebral fractures. Computer‐controlled algometer: No differences in PPT between study sessions for 6 and 8‐mm probes (p = 0.43 and 0.32) were seen. There was a difference in PPT before and after LA for the 6‐mm probe (p = 0.008), but not for the 8‐mm probe (p = 0.26). Hand‐held algometer: A difference in PPT between study sessions was observed for 4‐ and 8‐mm probes (p = 0.03 and 0.007), but not for 2, 6 and 10‐mm probes (p = 0.19, 0.05 and 0.25). No differences in PPT were seen before and after LA for 2, 4, 8 and 10‐mm probes (p = 0.35, 0.15, 0.08 and 0.53), but LA significantly influenced PPT with the 6‐mm probe (p = 0.01). Similar words were chosen in the McGill pain questionnaire by healthy volunteers and patients, qualitatively describing the deep pain sensation. The pain evoked by hand‐held algometer and the 2‐mm probe was not influenced by LA, and PPT was reproducible between sessions and is recommended for studies of experimentally evoked bone‐associated pain.
Bringing ‘patient voice’ into psychological formulations of in‐patients with intellectual disabilities, autism spectrum disorder and severe challenging behaviours: report of a service improvement pilot
Authors: Rowe Gareth , Nevin Helen
Published: April 2013

Accessible summary

It is important to listen to patients' views when they are in hospital.

Sometimes it is difficult for staff to understand what people with intellectual disabilities are saying.

This project tried to include the views of all the patients on an autism services ward.

Some people were easier to understand than others but we managed to listen to everybody.

This is a report of a service improvement pilot project undertaken at an inpatient autism service for adults with intellectual disabilities and severe challenging behaviours. Within the service, a key facet of the care pathway was the use of a biopsychosocial case formulation. Formulation meetings were led by psychology and involved a full multidisciplinary team and external representation. However, routine invitation of patients was not appropriate due to anxiety and complex communication difficulties. Therefore, the service was looking for alternative ways to incorporate the voices of patients into formulation. This report presents the case studies of four individual patients who were chosen because together they were indicative of the patient profile across the service. The study has demonstrated that it is possible to include patients' voices in their psychological formulation. For those with mild intellectual disabilities and mild autism spectrum disorder, this has been simple and extremely fruitful. For those with severe intellectual disability and severe autism spectrum disorder this has been more resource intensive and the results have been more tentative. Despite this, it has been demonstrated that it is possible to include the voices of all patients to some extent.
The impact of cognitive assessment on the identity of people with learning disabilities
Authors: Davidson Terence , Smith Hilary , Burns Jan
Published: April 2013

Accessible summary

People with learning disabilities often have cognitive assessments (IQ tests) carried out by psychologists.

A cognitive assessment is a range of tests which help find out what people are good at and where they have difficulties.

Five people who had been given a cognitive assessment by a psychologist were interviewed.

They said it helped them to find out new things about themselves but they weren't sure why they had performed it.

Psychologists could explain more to people about why they were doing a cognitive assessment and what would happen afterwards.

Researchers and clinicians have hypothesised that cognitive assessments have the power to influence the self‐identity of people with learning disabilities. This research aimed to explore the experience of a sample of people who had been given a cognitive assessment by a psychologist based in a team for people with learning disabilities. Five people who had undergone these assessments participated in semi‐structured interviews, and interpretative phenomenological analysis (IPA) was used to analyse the transcripts. The analysis identified that despite the participants not understanding the purpose of the assessment, they trusted the clinicians and felt they benefitted from the experience of doing the actual assessment. However, the term ‘learning disability’ was not used by the participants who also described experiencing little agency in the process, and being dependent on the actions of others for the assessment to bring about change.
Diffusion pattern of low dose rate brachytherapy for prostate cancer in Japan
Authors: Nakamura Katsumasa , Ohga Saiji , Yorozu Atsunori , Dokiya Takushi , Saito Shiro , Yamanaka Hidetoshi
Published: April 2013

Permanent implant brachytherapy for prostate cancer using iodine‐125 seeds was adopted in Japan in 2003. Here, we report on the diffusion pattern of this treatment in Japan since 2003. We examined the annual numbers of prostate cancer patients per hospital in Japan, who were treated with iodine‐125 seed implant brachytherapy with or without external beam radiation therapy between 2003 and 2011. The hospitals were excluded from the count if brachytherapy was begun in a hospital within the given year, and thus was only available for part of the year. In 2004, 269 patients were treated by brachytherapy at only two hospitals. However, the numbers increased rapidly. A total of 1412 patients were treated at 23 hospitals in 2005, 2783 patients were treated at 83 hospitals in 2008, and 3793 patients were treated at 109 hospitals in 2011. The mean/median numbers of patients treated per hospital were 61.4/42 in 2005, 33.5/25 in 2008, and 35.0/24 in 2011. The number of hospitals where 24 or fewer patients were treated in a year increased. On the other hand, the number of hospitals with a volume of >48 patients per year was stable. Because a relationship between provider volume and outcomes following oncological procedures was shown, a careful evaluation of the effectiveness of permanent implant brachytherapy for prostate cancer is needed.
Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: a prospective randomized controlled clinical trial
Authors: Ronda Marco , Rebaudi Alberto , Torelli Lucio , Stacchi Claudio
Published: April 2013

Objective

This prospective randomized controlled trial was designed to test the performance of titanium‐reinforced dense polytetrafluoroethylene (d‐PTFE) membrane vs. titanium‐reinforced expanded polytetrafluoroethylene (e‐PTFE) membrane in achieving vertical bone regeneration, both associated with a composite grafting material.

Material and methods

The study enrolled 23 patients requiring bone augmentation with guided bone regeneration (GBR) procedures for placing implants in atrophic posterior mandibles (available bone height <7 mm). Implants were inserted and left to protrude from the bone level to achieve the programmed amount of vertical regeneration. Defects were filled with a composite bone graft (50% autologous bone and 50% mineralized bone allograft) and randomly covered with either an e‐PTFE membrane (control) or a d‐PTFE membrane (test). Membrane removal was performed after 6 months, and changes in bone height were recorded.

Results

Seventy‐eight implants were inserted in 26 mandibular sites contextually to vertical ridge augmentation procedures. The healing period was uneventful in all sites, and the vertical defects were satisfactorily filled with a newly formed hard tissue. Mean defect fill after 6 months was 5.49 mm (SD ± 1.58) at test sites and 4.91 mm (SD ± 1.78) at control sites. The normalized data (percentage changes against baseline) did not show any statistically significant difference between test and control groups (P = NS).

Conclusions

Based on the data from this study, both d‐PTFE and e‐PTFE membranes showed identical clinical results in the treatment of vertical bone defects around implants, using the GBR technique. The membrane removal procedure was easier to perform in the d‐PTFE group than in the e‐PTFE group.
Use of a self‐curing resorbable polymer in vertical ridge augmentations – a pilot study in dogs
Authors: Schliephake Henning , Drewes Mona , Mihatovic Ilja , Schwarz Frank , Becker Jürgen , Iglhaut Gerhard
Published: April 2013

Aim

The aim of the present study was to evaluate bone formation in vertical ridge augmentations using particulate bone grafting material stabilized by a resorbable polymer.

Material and methods

Three vertical defects were created in the maxillary alveolar ridge of six Beagle dogs 3 months after the removal of all premolars. One defect in each dog was filled with tricalciumphosphate/hydroxylapatite (TCP/HA) grafting material and stabilized using a poloxamer hydrogel (test group). Defects filled with grafting material only and covered with a collagen membrane as well as empty defects served as controls (controls 1 & 2). Bone formation in the defects was evaluated after 14 weeks of healing using histomorphometry on undecalcified thick‐section specimens.

Results

There was no difference between the test group and the controls with respect to the amount of newly formed bone, percentage of bone fill, and bone density. The mean maximum bone height within the augmented area was the only parameter that was significantly higher in the test group compared with empty defects. The use of the poloxamer gel did not result in a better preservation of ridge shape compared with the group of augmentations covered with a collagen membrane.

Conclusions

The use of a poloxamer gel for the stabilization of particulate bone grafting material in vertical ridge augmentations had no advantage compared with coverage of grafting materials with a collagen membrane.
Six Common Mistakes in Conservation Priority Setting
Authors: GAME EDWARD T. , KAREIVA PETER , POSSINGHAM HUGH P.
Published: April 2013

A vast number of prioritization schemes have been developed to help conservation navigate tough decisions about the allocation of finite resources. However, the application of quantitative approaches to setting priorities in conservation frequently includes mistakes that can undermine their authors’ intention to be more rigorous and scientific in the way priorities are established and resources allocated. Drawing on well‐established principles of decision science, we highlight 6 mistakes commonly associated with setting priorities for conservation: not acknowledging conservation plans are prioritizations; trying to solve an ill‐defined problem; not prioritizing actions; arbitrariness; hidden value judgments; and not acknowledging risk of failure. We explain these mistakes and offer a path to help conservation planners avoid making the same mistakes in future prioritizations.

Seis Errores Comunes en la Definición de Prioridades de Conservación
Regional Ontogeny of New England Salt Marsh Die‐Off
Authors: COVERDALE TYLER C. , BERTNESS MARK D. , ALTIERI ANDREW H.
Published: April 2013

Coastal areas are among the world's most productive and highly affected ecosystems. Centuries of human activity on coastlines have led to overexploitation of marine predators, which in turn has led to cascading ecosystem‐level effects. Human effects and approaches to mediating them, however, differ regionally due to gradients in biotic and abiotic factors. Salt marsh die‐off on Cape Cod, Massachusetts (U.S.A.), triggered by a recreational‐fishing‐induced trophic cascade that has released herbivorous crabs from predator control, has been ongoing since 1976. Similar salt marsh die‐offs have been reported in Long Island Sound and Narragansett Bay (U.S.A.), but the driving mechanism of these die‐offs has not been examined. We used field experiments to assess trophic interactions and historical reconstructions of 24 New England marshes to test the hypotheses that recreational fishing and predator depletion are a regional trigger of salt marsh die‐off in New England and that die‐offs in Long Island Sound and Narragansett Bay are more recent than those on Cape Cod. Predator depletion was the general trigger of marsh die‐off and explained differences in herbivorous crab abundance and the severity of die‐off across regions. Die‐offs in Long Island Sound and Narragansett Bay are following a trajectory similar to die‐off on Cape Cod, but are approximately 20 years behind those on Cape Cod. As a result, die‐off currently affects 31.2% (SE 2.2) of low‐marsh areas in Long Island Sound and Narragansett Bay, less than half the severity of die‐off on Cape Cod. Our results contribute to the growing evidence that recreational fishing is an increasing threat to coastal ecosystems and that studying the effects of human activity at regional scales can provide insight into local effects and aid in early detection and potential remediation.

Ontogenia Regional de un Incremento en la Mortandad en una Marisma Salada de Nueva Inglaterra
Exhaled nitric oxide indicates poorly athlete's asthma
Authors: Voutilainen Mikko , Malmberg Leo Pekka , Vasankari Tommi , Haahtela Tari
Published: April 2013

Introduction

In athletes, exercise‐induced respiratory symptoms are common and their assessment is time and resource consuming.

Objective

The objective was to evaluate fractional concentration of exhaled nitric oxide (FENO) as a predictor of bronchial hyperresponsiveness (BHR) and of asthma.

Materials and Methods

Eighty‐seven elite athletes and a control group of 87 sedentary patients with symptoms suggesting asthma underwent measurements of FENO and of BHR by using methacholine provocation test (MCH) and eucapnic voluntary hyperpnoea (EVH) (athletes) or histamine provocation test (HIST) (controls).

Results

In athletes, elevated FENO (>30 ppb) was not associated with lung function‐confirmed asthma or with MCH positivity, but receiver operating characteristics (ROC) analysis showed some predictive value for EVH positivity [Area Under Curve (AUC) 0.652, 95% confidence interval (CI): 0.53 to 0.78, P = 0.020]. However, the sensitivity (55%) and the specificity (71%) were poor. In sedentary patients, FENO was significantly associated with both confirmed asthma and HIST positivity, ROC analysis showing FENO to be significantly predictive for HIST positivity (AUC 0.83, 95% CI: 0.70 to 0.96, P = 0.001) and for asthma (AUC 0.74, 95% CI: 0.63 to 0.85, P < 0.001).

Conclusion

The results suggest that in contrast to sedentary patients, FENO seems to be a poor predictor of BHR and of clinical asthma in elite athletes. We find it unlikely that FENO could be a useful screening tool in athletes with exercise‐induced respiratory symptoms.
Endoscopic stapling in comparison to laparoscopic fundoplication for the treatment of gastroesophageal reflux disease
Authors: Danalioglu Ahmet , Cipe Gokhan , Toydemir Toygar , Kocaman Orhan , Ince Ali Tuzun , Muslumanoglu Mahmut , Senturk Hakan
Published: April 2013

Background

The SRSTM Endoscopic Stapling System (Medigus Ltd, Omer, Israel) is a novel method for the treatment of gastroesophageal reflux disease (GERD). The present study assessed the safety and efficacy of SRS compared with laparoscopic anti‐reflux surgery (LARS).

Patients and Methods

Of 27 participants, 11 underwent SRS and 16 LARS. Symptoms were assessed using Velanovich GERD–health‐related quality of life (GERD‐HRQL) scores. The groups were compared in reference to operation time, improvement in GERD‐HRQL scores, and postoperative course. Chi‐squared and Mann–Whitney‐U‐tests were used for statistical analysis.

Results

Of 16 (59.3%) male and 11 (40.7%) female patients, mean age was 39.6 (range: 24–60) years and mean body mass index was 26.2 kg/m2. Both groups were statistically similar. An esophageal perforation observed in the SRS group completely recovered after over‐the‐scope clipping. Procedure times for SRSand LARS were 89 and 47 min, respectively (P < 0.05). Mean discharge time was longer for SRS than LARS (3 days vs 1.2 days, P < 0.05). However, this difference disappeared with the exclusion of a complicated patient with long hospitalization in the SRS group. During 6 months mean follow up, proton‐pump inhibitor use was insignificantly higher in the SRS group (P > 0.05). Mean GERD‐HRQL scores dropped in 87% and in 64% of patients (P > 0.05) from 29.3 to 4.1 and from 24.8 to 8.9 (P = 0.016) in LARS and SRS groups, respectively.

Conclusion

The short‐term results of SRS are promising. The forthcoming new‐generation devices and increasing experience may further improve efficacy and decrease untoward effects.
Image processing and recognition for biological images
Authors: Uchida Seiichi
Published: April 2013

This paper reviews image processing and pattern recognition techniques, which will be useful to analyze bioimages. Although this paper does not provide their technical details, it will be possible to grasp their main tasks and typical tools to handle the tasks. Image processing is a large research area to improve the visibility of an input image and acquire some valuable information from it. As the main tasks of image processing, this paper introduces gray‐level transformation, binarization, image filtering, image segmentation, visual object tracking, optical flow and image registration. Image pattern recognition is the technique to classify an input image into one of the predefined classes and also has a large research area. This paper overviews its two main modules, that is, feature extraction module and classification module. Throughout the paper, it will be emphasized that bioimage is a very difficult target for even state‐of‐the‐art image processing and pattern recognition techniques due to noises, deformations, etc. This paper is expected to be one tutorial guide to bridge biology and image processing researchers for their further collaboration to tackle such a difficult target.
Early developmental outcomes in children following convulsive status epilepticus: A longitudinal study
Authors: Martinos Marina M. , Yoong Michael , Patil Shekhar , Chong Wui K. , Mardari Rodica , Chin Richard F. M. , Neville Brian G. R. , de Haan Michelle , Scott Rod C.
Published: April 2013

Purpose

Convulsive status epilepticus (CSE) is the most common pediatric neurologic emergency and is often associated with unfavorable neurodevelopmental outcomes. The early developmental trajectory of children following CSE has not been previously investigated, leaving a gap in our understanding of how these adverse long‐term outcomes emerge.

Methods

We prospectively recruited children aged between 1 and 42 months from a predefined geographic region of North London who had at least one episode of CSE and classified them as prolonged febrile seizures (PFS) or nonfebrile CSE. Neuropsychological and imaging investigations were conducted within 6 weeks of CSE (baseline) and were repeated a year later (follow‐up). Neurodevelopment was assessed using the Bayley Scales of Infant Development III and compared to normally developing children. Predictors of neurodevelopmental scores at baseline and follow‐up were investigated using regression analyses.

Key Findings

Of the 54 children that underwent investigations a mean of 38 days following CSE, 27 had PFS (mean age 18.4 months) and 27 had nonfebrile CSE (mean age 15.5 months). In addition, 17 healthy controls were assessed (mean age 20.49 months). Children with nonfebrile CSE had a worse developmental outcome than children with PFS (p < 0.002), despite there being no differences in seizure characteristics. In contrast to expectations, the PFS group had a worse developmental outcome than controls (p = 0.002). There were no significant differences in performance from baseline to 1‐year follow‐up for the 70.4% of children who provided data. Seizure characteristics were not shown to be significant predictors of performance.

Significance

CSE is associated with developmental impairments within 6 weeks of the acute event that continue to be present a year onward. This is also true of PFS cases that under‐perform relative to controls despite mean scores within the clinically normal range. The absence of a change in performance from baseline to follow‐up as well as the lack of a relationship between seizure characteristics and developmental outcomes supports the notion that premorbid abilities may be overshadowing any direct effects of CSE itself on outcome.
Mutations in PRRT2 are not a common cause of infantile epileptic encephalopathies
Authors: Heron Sarah E. , Ong Yeh Sze , Yendle Simone C. , McMahon Jacinta M. , Berkovic Samuel F. , Scheffer Ingrid E. , Dibbens Leanne M.
Published: April 2013

Heterozygous mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Homozygous mutations in PRRT2 have also been reported in two families with intellectual disability (ID) and seizures. Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal‐infantile epilepsy. Mutations in KCNQ2 and SCN2A also contribute to severe infantile epileptic encephalopathies (IEEs) in which seizures and intellectual disability co‐occur. We therefore hypothesized that PRRT2 mutations may also underlie cases of IEE. We examined PRRT2 for heterozygous, compound heterozygous or homozygous mutations to determine their frequency in causing epileptic encephalopathies (EEs). Two hundred twenty patients with EEs with onset by 2 years were phenotyped. An assay for the common PRRT2 c.649‐650insC mutation and high resolution‐melt analysis for mutations in the remaining exons of PRRT2 were performed. Neither the common mutation nor any other pathogenic variants in PRRT2 were detected in the 220 patients. Our findings suggest that mutations in PRRT2 are not a common cause of IEEs.
Network‐specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin
Authors: Thomas Evan A. , Petrou Steven
Published: April 2013

Purpose

A common notion of the mechanism by which the antiepileptic drugs (AEDs) carbamazepine and phenytoin act is that they block sodium channels by binding preferentially to the inactivated state, thereby allowing normal neuronal firing while blocking ictal activity. However, these drugs have unpredictable efficacy and, in some cases, may exacerbate seizures. Previous studies have suggested that reducing sodium channel availability in the dentate gyrus (DG) paradoxically increases excitability. We used a biophysically detailed computer model of the DG to test the hypothesis that AEDs increase excitability by disproportionately reducing negative feedback mechanisms.

Methods

We built a Markov model of sodium channel gating that reproduces responses to voltage clamp experiments in the presence of carbamazepine and phenytoin. We incorporated this validated Markov model into a biophysically realistic computer model of DG neurons and networks. Simulated drug concentrations were similar to those measured in cerebral spinal fluid in medicated patients. Single neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. In the network model, environmental effects were studied by introducing mossy fiber sprouting.

Key Findings

As expected, drugs reduced sodium channel availability, which in turn reduced action potential amplitude. This had only a small effect on action potential (AP) firing rate during brief (100 msec) current injections. Paradoxically, long current injections (2,500 msec) increased AP firing rates. This was caused by reduced calcium entry and consequently reduced activation of calcium activated potassium channels. It is important to note that the main determinant of drug effect was resting membrane potential (RMP) and not action potential firing rate. Binding of phenytoin and carbamazepine is slow and, thus drug effects are largely determined by the long term state of the RMP. This paradoxical AP firing increase was dependent on the unusually large calcium‐activated potassium conductances expressed by DG granule cells. This predicts that drug efficacy in a given network will depend on the precise makeup of conductances in the network. RMP is expected to vary with the level of activity in the network. We simulated the effects of drugs on single shot stimulus responses in networks with mossy fiber sprouting and varied the RMP in all neurons as a model for network activity. For an RMP of −50 mV, representing an active network, drugs had no effect, or in some cases, increased excitability. Drugs had an increasingly larger inhibitory effect on network responses as RMP decreased. An important prediction is that drugs will be unable to block ictal activity invading an active network.

Significance

Our key findings are that drug effects depend on both intrinsic properties of the network and its behavioral state. This may explain the paradoxical and unpredictable effects of some AEDs on seizure control in some patients.
Nanoscale infrared (IR) spectroscopy and imaging of structural lipids in human stratum corneum using an atomic force microscope to directly detect absorbed light from a tunable IR laser source
Authors: Marcott Curtis , Lo Michael , Kjoller Kevin , Domanov Yegor , Balooch Guive , Luengo Gustavo S.
Published: April 2013

An atomic force microscope (AFM) and a tunable infrared (IR) laser source have been combined in a single instrument (AFM‐IR) capable of producing ~200‐nm spatial resolution IR spectra and absorption images. This new capability enables IR spectroscopic characterization of human stratum corneum at unprecendented levels. Samples of normal and delipidized stratum corneum were embedded, cross‐sectioned and mounted on ZnSe prisms. A pulsed tunable IR laser source produces thermomechanical expansion upon absorption, which is detected through excitation of contact resonance modes in the AFM cantilever. In addition to reducing the total lipid content, the delipidization process damages the stratum corneum morphological structure. The delipidized stratum corneum shows substantially less long‐chain CH2‐stretching IR absorption band intensity than normal skin. AFM‐IR images that compare absorbances at 2930/cm (lipid) and 3290/cm (keratin) suggest that regions of higher lipid concentration are located at the perimeter of corneocytes in the normal stratum corneum.
Postnatal regulation of X,K‐ATPases in rat skin and conserved lateroapical polarization of Na,K‐ATPase in vertebrate epidermis
Authors: Pestov Nikolay B. , Korneenko Tatyana V. , Shakhparonov Mikhail I. , Modyanov Nikolai N.
Published: April 2013

Development of epidermis creates stratified epithelium with different sets of ion‐transporting enzymes in its layers. We have characterized expression of Na,K‐ and H,K‐ATPase α and β subunits and FXYD isoforms in rat skin. Maturation of rat skin from newborn to adult is associated with an increase in FXYD4 and a decrease of Na,K‐ATPase α1‐isoform, ATP1B4 and FXYD6 transcripts. Na,K‐ATPase of rat epidermis is represented predominantly by α1 and β3 isoforms. Keratinization is associated with the loss of the Na,K‐ATPase α‐subunit and an enrichment of αng. Na,K‐ATPase α1 is abundant in the innermost layer, stratum basale, where it is lacking in basal membranes, thus indicating lateroapical polarization of Na,K‐ATPase. Immunocytochemical detection of Na,K‐ATPase in Xenopus laevis skin shows that cellular and subcellular localization of the enzyme has a pattern highly similar to that of mammals: basolateral in glandular epithelium and lateroapical in epidermis.
Donor, Dad, or…? Young Adults with Lesbian Parents’ Experiences with Known Donors
Authors: Goldberg Abbie E. , Allen Katherine R.
Published: April 2013

In this exploratory qualitative study of 11 young adults, ages 19–29 years, we examine how young people who were raised by lesbian parents make meaning out of and construct their relationships with known donors. In‐depth interviews were conducted to examine how participants defined their family composition, how they perceived the role of their donors in their lives, and how they negotiated their relationships with their donors. Findings indicate that mothers typically chose known donors who were family friends, that the majority of participants always knew who their donors were, and that their contact with donors ranged from minimal to involved. Further, participants perceived their donors in one of three ways: as strictly donors and not members of their family; as extended family members but not as parents; and as fathers. The more limited role of donors in participants' construction of family relationships sheds light on how children raised in lesbian, gay, and bisexual families are contributing to the redefinition and reconstruction of complex kinship arrangements. Our findings hold implications for clinicians who work with lesbian‐mother families, and suggest that young adulthood is an important developmental phase during which interest in and contact with the donor may shift, warranting a transfer of responsibility from mother to offspring in terms of managing the donor‐child relationship.
The Quote Exception Rule: Giving High Frequency Traders an Unintended Advantage
Authors: McInish Thomas H. , Upson James
Published: April 2013

Under the Securities and Exchange Commission (SEC) Rule 611 exchanges that have not matched a new National Best Bid and Offer (NBBO) can trade at the old NBBO for one second. In 2008, this rule allowed fast traders to earn estimated revenues of $233 million at the expense of slow traders. Furthermore, we find that when the NYSE decreased latency by 600 milliseconds on March 10, 2008, execution quality improved markedly for fast liquidity demanders, but improved only minimally for slow liquidity demanders. However, we find a decrease in volume executed at adverse prices under the faster market conditions.
Corporate Payout Policy, Cash Savings, and the Cost of Consistency: Evidence from a Structural Estimation
Authors: Mahmudi Hamed , Pavlin Michael
Published: April 2013

We develop a dynamic structural model to better understand how corporate payout policy is determined in conjunction with other corporate decisions. In a first‐best model, a manager maximizes equity value by choosing the firm's optimal financing, investment, dividends, and cash holdings. By using simulated method of moments, we show that, on average, firms excessively smooth their payout while making corporate savings overly volatile and retaining excess cash. We then extend the model to capture the effect of a manager, who perceives a cost to cutting payouts. Estimating the model, we infer the magnitude of this cost. We find that a managerial preference for consistent payout explains the smooth payout and high volatility of cash holdings.
Temperature and precipitation drive temporal variability in aquatic carbon and GHG concentrations and fluxes in a peatland catchment
Authors: Dinsmore K. J. , Billett M. F. , Dyson K. E.
Published: April 2013

The aquatic pathway is increasingly being recognized as an important component of catchment carbon and greenhouse gas (GHG) budgets, particularly in peatland systems due to their large carbon store and strong hydrological connectivity. In this study, we present a complete 5‐year data set of all aquatic carbon and GHG species from an ombrotrophic Scottish peatland. Measured species include particulate and dissolved forms of organic carbon (POC, DOC), dissolved inorganic carbon (DIC), CO2, CH4 and N2O. We show that short‐term variability in concentrations exists across all species and this is strongly linked to discharge. Seasonal cyclicity was only evident in DOC, CO2 and CH4 concentration; however, temperature correlated with monthly means in all species except DIC. Although the temperature correlation with monthly DOC and POC concentrations appeared to be related to biological productivity in the terrestrial system, we suggest the temperature correlation with CO2 and CH4 was primarily due to in‐stream temperature‐dependent solubility. Interannual variability in total aquatic carbon concentration was strongly correlated with catchment gross primary productivity (GPP) indicating a strong potential terrestrial aquatic linkage. DOC represented the largest aquatic carbon flux term (19.3 ± 4.59 g C m−2 yr−1), followed by CO2 evasion (10.0 g C m−2 yr−1). Despite an estimated contribution to the total aquatic carbon flux of between 8 and 48%, evasion estimates had the greatest uncertainty. Interannual variability in total aquatic carbon export was low in comparison with variability in terrestrial biosphere–atmosphere exchange, and could be explained primarily by temperature and precipitation. Our results therefore suggest that climatic change is likely to have a significant impact on annual carbon losses through the aquatic pathway, and as such, aquatic exports are fundamental to the understanding of whole catchment responses to climate change.
Changes in atmospheric CO2 influence the allergenicity of Aspergillus fumigatus
Authors: Lang‐Yona Naama , Levin Yishai , Dannemiller Karen C. , Yarden Oded , Peccia Jordan , Rudich Yinon
Published: April 2013

Increased susceptibility to allergies has been documented in the Western world in recent decades. However, a comprehensive understanding of its causes is not yet available. It is therefore essential to understand trends and mechanisms of allergy‐inducing agents, such as fungal conidia. In this study, we investigated the hypothesis that environmental conditions linked to global atmospheric changes can affect the allergenicity of Aspergillus fumigatus, a common allergenic fungal species in indoor and outdoor environments and in airborne particulate matter. We show that fungi grown under present‐day CO2 levels (392 ppm) exhibit 8.5 and 3.5 fold higher allergenicity compared to fungi grown at preindustrial (280 ppm) and double (560 ppm) CO2 levels, respectively. A corresponding trend is observed in the expression of genes encoding for known allergenic proteins and in the major allergen Asp f1 concentrations, possibly due to physiological changes such as respiration rates and the nitrogen content of the fungus, influenced by the CO2 concentrations. Increased carbon and nitrogen levels in the growth medium also lead to a significant increase in the allergenicity. We propose that climatic changes such as increasing atmospheric CO2 levels and changes in the fungal growth medium may impact the ability of allergenic fungi such as A. fumigatus to induce allergies.
The effect of labour on the coagulation system in the term neonate
Authors: Kulkarni A. A. , Osmond M. , Bapir M. , Riddell A. , Smith C. , Lee C. A. , Kadir R. A.
Published: April 2013

The coagulation system of the foetus is markedly different from that of adults. To assess the influence of maternal age, mode of delivery and intrapartum events, and foetal gender and weight on the foetal coagulation system. Cord blood was collected from 154 healthy pregnant women, with gestational age 37 – 42 weeks at birth. Mann–Whitney test was used for analysis of binary data and continuous variables were analysed using Pearson's correlation coefficient. Mean cord blood levels of FVIII:C, VWF:Ag, VWF:CB, FIX, FXI, FXII and plasminogen were significantly higher in babies delivered after labour, compared to those delivered after an elective caesarean. Mean cord blood levels of FII (P = 0.003), FV (P = 0.009), FVII (P = 0.0004) and FX (P = 0.0009) were significantly lower in the babies with meconium stained liquor in labour, compared with those with clear liquor. Augmentation with oxytocin, instrumental delivery, did not affect any of the factor levels and duration of labour did not have an effect on the level of coagulation proteins in cord blood. This study provides valuable information about effect of labour on the coagulation system of the foetus. It is concluded that, in cord blood, the results of coagulation parameters in the newborn baby should be considered in light of mode of delivery and events of labour.
Molecular basis of quantitative fibrinogen disorders in 27 patients from India
Authors: Sumitha E. , Jayandharan G. R. , Arora N. , Abraham A. , David S. , Devi G. S. , Shenbagapriya P. , Nair S. C. , George B. , Mathews V. , Chandy M. , Viswabandya A. , Srivastava A.
Published: April 2013

Congenital fibrinogen deficiency is an extremely rare (1:1 000 000) hereditary bleeding disorder caused by defects in genes coding for fibrinogen Aα‐, Bβ‐ and γ‐chains, respectively. We report here the molecular basis of fibrinogen deficiency in a large series of patients from India. Twenty‐seven patients with clinical features suggestive of fibrinogen deficiency and with prolonged plasma clotting times and low fibrinogen levels were studied. Genomic DNA was screened for mutations in the fibrinogen alpha (FGA), beta (FGB), gamma (FGG) genes by PCR and conformation sensitive gel electrophoresis. Fourteen different disease‐causing mutations including frameshifts (51.9%), splice site (22.2%), missense (18.5%) and nonsense mutation (7.4%) were identified in 27 patients. Thirteen of them were novel, including seven frameshifts (fibrinogen Aα: p.Asp296 fs*59, p.Thr466 fs*17 and p.Lys575 fs*74; fibrinogen Bβ: p.Gly414 fs*2 and fibrinogen γ: p.Ser81 fs*5, p.Lys185 fs*13 and p.Asp278_279 fs*17), three splice site mutations (FGA gene c.364+1G>A; c.510+2 T>G; FGB gene c.851+1G>A), two missense substitutions (fibrinogen Bβ: p.Gly288Ser; p.Arg445Thr) and a nonsense mutation in fibrinogen Aα (p.Tyr127*). Two common mutations (FGA: c.364+1G>A, n = 6, FGG: p.Lys185 fs*13, n = 7) affecting 13 patients were identified in this series, suggesting that these mutations could be screened first in Indian patients with fibrinogen deficiency. The molecular data presented here is the largest series of patients with fibrinogen deficiency reported so far, adding significantly to the mutation database of this condition. It also helps create an algorithm for its genetic diagnosis in India.
Inhibition of Glutaminyl Cyclases alleviates CCL2‐mediated inflammation of non‐alcoholic fatty liver disease in mice
Authors: Cynis Holger , Kehlen Astrid , Haegele Monique , Hoffmann Torsten , Heiser Ulrich , Fujii Masato , Shibazaki Yuichiro , Yoneyama Hiroyuki , Schilling Stephan , Demuth Hans‐Ulrich
Published: April 2013

Inflammation is an integral part of non‐alcoholic fatty liver disease (NAFLD), the most prevalent form of hepatic pathology found in the general population. In this context, recently we have examined the potential role of Glutaminyl Cyclases (QC and isoQC), and their inhibitors, in the maturation of chemokines, for example, monocyte chemoattractant protein 1 (MCP‐1, CCL2), to generate their bioactive conformation. Catalysis by isoQC leads to the formation of an N‐terminal pyroglutamate residue protecting CCL2 against degradation by aminopeptidases. This is of importance because truncated forms possess a reduced potential to attract immune cells. Since liver inflammation is characterized by the up‐regulation of different chemokine pathways, and within this CCL2 is known to be a prominent example, we hypothesised that application of QC/isoQC inhibitors may alleviate liver inflammation by destabilizing CCL2. Therefore, we investigated the role of QC/isoQC inhibition, in comparison with the angiotensin receptor blocker Telmisartan, during development of pathology in a mouse model of non‐alcoholic fatty liver disease. Application of a QC/isoQC inhibitor led to a significant reduction in circulating alanine aminotransferase and NAFLD activity score accompanied by an inhibitory effect on hepatocyte ballooning. Further analysis revealed a specific reduction of inflammation by decreasing the number of F4/80‐positive macrophages, which is in agreement with the proposed CCL2‐related mechanism of action of QC/isoQC inhibitors. Finally, QC/isoQC inhibitor application attenuated liver fibrosis as characterized by reduced collagen deposition in the liver parenchyma. Thus in conclusion, QC/isoQC inhibitors are a promising novel class of anti‐non‐alcoholic steatohepatitis drugs which have a comparable disease‐modifying effect to that of Telmisartan, which is probably mediated via specific interference with a comparable monocyte/macrophage infiltration that occurs under inflammatory conditions.
A Simple Way to Prepare C/SiC Spring
Authors: Chen Si'an , Zhang Yudi , Zhang Changrui , Xiong Xin , Li Guangde , Hu Haifeng
Published: April 2013

A new method to form helical C/SiC spring is proposed. Using paraffin mold as a sacrificial core, unidirectional carbon fiber bundles (infiltrated with resin) are wrapped around the mold to form helical spring, and after resin curing, the mold is removed, leaving a preform of C/SiC spring. Following densification is finished with precursor infiltration and pyrolysis (PIP) process. The spring constant of C/SiC spring reaches 7.88 N/mm and could be regulated by varying composite density and carbon fiber content. The spring properties could be improved by twisting the carbon fibers at 35–50 twist/m. The restoration ratio reaches 100%, but energy dissipation happens during unloading process. After oxidation in air at 1200°C for 10 min, the spring has an 82.4% spring constant remaining ratio.
Influence of Oxygen Substoichiometry on the Dielectric Properties of BaTiO3‐δ Nanoceramics Obtained by Spark Plasma Sintering
Authors: Voisin Christophe , Guillemet‐Fritsch Sophie , Dufour Pascal , Tenailleau Christophe , Han Hyuksu , Nino Juan C.
Published: April 2013

Oxygen‐deficient BaTiO3‐δ nanoceramics were prepared by spark plasma sintering. Partially reduced raw nanopowders led to unusual dielectric properties. A short postsintering treatment was performed to reach a high εr/tan δ, which makes them attractive for industrial applications such as low‐frequency capacitors. Surprisingly, our ceramics also remained black even after annealing for 5 days at 850°C in air, indicating the presence of barriers against oxygen diffusion. This exceptional behavior in pure barium titanate was consistent with a core–shell structure made of semiconductive grains and insulating grain boundaries, due to the presence of Ti3+/Ti4+ and oxygen vacancies.