bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of different regimens for initiating anagrelide in patients with essential thrombocythemia who are intolerant or refractory to their current cytoreductive therapy: results from the multicenter FOX study of 177 patients in France
Authors: Rey Jérôme , Viallard Jean‐François , Keddad Karim , Smith Jonathan , Wilde Paul , Kiladjian Jean‐Jacques
Published: October 2013

Objectives

To identify switch modalities used when initiating second‐ or third‐line anagrelide for essential thrombocythemia (ET), assess whether anagrelide is initiated consistently with Summary of Product Characteristics (SPC) recommendations, and determine whether different observed switch regimens have any relationship with maintenance, platelet response, or tolerability.

Methods

This observational study was conducted across 43 centers in France. High‐risk patients (>60 yr of age and/or history of thrombosis and/or platelet count >1000 × 109/L) with ET starting second‐ or third‐line anagrelide therapy were identified and monitored for 6 months.

Results

A total of 177 patients were enrolled. The SPC‐recommended starting dose (1 mg/d) was used in 52.6% of patients; 0.5 mg/d was used in 41.1%. 77.1% of patients underwent an anagrelide dose increase during the study. At 6‐month follow‐up, 84.7% of patients (n = 144/170) were still receiving anagrelide; 70.6% (n = 120/170) achieved a platelet response. A higher proportion of patients who discontinued previous cytoreductive therapy (CRT) after initiating anagrelide achieved a platelet response (n = 34/39, 87.2%) vs. patients who discontinued their previous CRT before anagrelide initiation (n = 77/115, 67.0%). Platelet response rates were higher in patients whose anagrelide initiation was consistent (n = 100/133, 75.2%) vs. inconsistent (n = 20/37, 54.1%) with the SPC. The incidence of adverse drug reactions was lower in patients whose anagrelide treatment was consistent (n = 52/133, 39.1%) vs. inconsistent (n = 25/37, 67.6%) with the SPC.

Conclusions

To our knowledge, the FOX study provides the first comprehensive real‐world data on the modalities used when switching from previous CRT to anagrelide. Highest platelet responses were observed when previous CRT was discontinued after anagrelide initiation or when anagrelide was initiated consistently with the SPC. Safety data corresponded with the SPC.
Electrical stimulation accelerates nerve regeneration and functional recovery in delayed peripheral nerve injury in rats
Authors: Huang Jinghui , Zhang Yongguang , Lu Lei , Hu Xueyu , Luo Zhuojing
Published: October 2013

The present study aims to investigate the potential of brief electrical stimulation (ES; 3 V, 20 Hz, 20 min) in improving functional recovery in delayed nerve injury repair (DNIR). The sciatic nerve of Sprague Dawley rats was transected, and the repair of nerve injury was delayed for different time durations (2, 4, 12 and 24 weeks). Brief depolarizing ES was applied to the proximal nerve stump when the transected nerve stumps were bridged with a hollow nerve conduit (5 mm in length) after delayed periods. We found that the diameter and number of regenerated axons, the thickness of myelin sheath, as well as the number of Fluoro‐Gold retrograde‐labeled motoneurons and sensory neurons were significantly increased by ES, suggesting that brief ES to proximal nerve stumps is capable of promoting nerve regeneration in DNIR with different delayed durations, with the longest duration of 24 weeks. In addition, the amplitude of compound muscle action potential (gastrocnemius muscle) and nerve conduction velocity were also enhanced, and gastrocnemius muscle atrophy was partially reversed by brief ES, indicating that brief ES to proximal nerve stump was able to improve functional recovery in DNIR. Furthermore, brief ES was capable of increasing brain‐derived neurotrophic factor (BDNF) expression in the spinal cord in DNIR, suggesting that BDNF‐mediated neurotrophin signaling might be one of the contributing factors to the beneficial effect of brief ES on DNIR. In conclusion, the present findings indicate the potential of using brief ES as a useful method to improve functional recovery for delayed repair of peripheral nerve lesions.
Parallelism in the brain's visual form system
Authors: Shigihara Yoshihito , Zeki Semir
Published: October 2013

We used magnetoencephalography (MEG) to determine whether increasingly complex forms constituted from the same elements (lines) activate visual cortex with the same or different latencies. Twenty right‐handed healthy adult volunteers viewed two different forms, lines and rhomboids, representing two levels of complexity. Our results showed that the earliest responses produced by lines and rhomboids in both striate and prestriate cortex had similar peak latencies (40 ms) although lines produced stronger responses than rhomboids. Dynamic causal modeling (DCM) showed that a parallel multiple input model to striate and prestriate cortex accounts best for the MEG response data. These results lead us to conclude that the perceptual hierarchy between lines and rhomboids is not mirrored by a temporal hierarchy in latency of activation and thus that a strategy of parallel processing appears to be used to construct forms, without implying that a hierarchical strategy may not be used in separate visual areas, in parallel.
The effect of task‐irrelevant visual backgrounds on human transcranial magnetic stimulation‐evoked electroencephalography responses and cortical alpha activity
Authors: Rutiku Renate , Einberg Anu , Imanaka Kuniyasu , Bachmann Talis
Published: October 2013

Brain responses evoked by transcranial magnetic stimulation (TMS) in task‐free experimental contexts are known to depend on psychophysiological states such as sleep, vegetative state and caffeine‐induced arousal. Much less is known about how TMS‐evoked responses depend on task‐irrelevant steady perceptual input. Here, we examined ongoing alpha activity and the mean amplitude of EEG potentials in response to occipitally applied TMS as a function of task‐irrelevant visual backgrounds. Responses to TMS were robustly modulated by photographs of natural scenes and man‐made environments. These effects began as early as during the N100 and continued for several hundred milliseconds after the stimulation. There was also a more general effect of background along with other stimuli, such as blank backgrounds, sinusoidal gratings and moving dot‐patterns. This effect was observable from ongoing alpha activity as well. Based on these results we conclude that different types of steady perceptual input modulate visual cortex reactivity and/or connectivity and it is possible to measure these modulations by combining TMS with electroencephalography.
Predicting evolutionary responses to climate change in the sea
Authors: Munday Philip L. , Warner Robert R. , Monro Keyne , Pandolfi John M. , Marshall Dustin J.
Published: October 2013

An increasing number of short‐term experimental studies show significant effects of projected ocean warming and ocean acidification on the performance on marine organisms. Yet, it remains unclear if we can reliably predict the impact of climate change on marine populations and ecosystems, because we lack sufficient understanding of the capacity for marine organisms to adapt to rapid climate change. In this review, we emphasise why an evolutionary perspective is crucial to understanding climate change impacts in the sea and examine the approaches that may be useful for addressing this challenge. We first consider what the geological record and present‐day analogues of future climate conditions can tell us about the potential for adaptation to climate change. We also examine evidence that phenotypic plasticity may assist marine species to persist in a rapidly changing climate. We then outline the various experimental approaches that can be used to estimate evolutionary potential, focusing on molecular tools, quantitative genetics, and experimental evolution, and we describe the benefits of combining different approaches to gain a deeper understanding of evolutionary potential. Our goal is to provide a platform for future research addressing the evolutionary potential for marine organisms to cope with climate change.
Gray matter differences contribute to variation in cognitive performance in Parkinson's disease
Authors: Gerrits N. J. H. M. , van der Werf Y. D. , Hofman M. , Foncke E. M. J. , Klein M. , Berendse H. W. , van den Heuvel O. A.
Published: October 2013

Background and purpose

A substantial proportion of patients with Parkinson's disease (PD) suffer from cognitive deficits, although there is a large variability in the severity of these impairments. Whilst the cognitive deficits are often attributed to monoaminergic changes, there is evidence that alterations in structural brain volume also play a role. The aim of our study was to gain more insight into the variability of cognitive performance amongst PD patients by examining the relation between regional gray matter (GM) volume and cognitive performance.

Methods

Linear regression analyses were performed between task performance and GM volume for six neuropsychological tasks within a group of 93 PD patients; they were additionally compared at a group level with matched healthy controls, using voxel‐based morphometry.

Results

Our most important findings were positive correlations between GM volume and cognitive performance for (i) parahippocampal gyrus and verbal memory, (ii) medial temporal lobe and putamen and visuospatial memory, and (iii) middle temporal gyrus and frontal lobe and verbal fluency. In addition, decreased GM volume was found in the frontal, parietal and temporal cortices of PD patients compared with matched healthy controls.

Conclusions

It is argued that the large variability in cognitive function across PD patients is partly mediated by GM volume differences in the implicated areas. Volume differences in these brain regions do not discriminate between patients and controls but explain cognitive variation within the patient population.
Sex‐related and non‐sex‐related comorbidity subtypes of tic disorders: a latent class approach
Authors: Rodgers S. , Müller M. , Kawohl W. , Knöpfli D. , Rössler W. , Castelao E. , Preisig M. , Ajdacic‐Gross V.
Published: October 2013

Background and purpose

Recent evidence suggests that there may be more than one Gilles de la Tourette syndrome (GTS)/tic disorder phenotype. However, little is known about the common patterns of these GTS/tic disorder‐related comorbidities. In addition, sex‐specific phenomenological data of GTS/tic disorder‐affected adults are rare. Therefore, this community‐based study used latent class analyses (LCA) to investigate sex‐related and non‐sex‐related subtypes of GTS/tic disorders and their most common comorbidities.

Methods

The data were drawn from the PsyCoLaus study (n = 3691), a population‐based survey conducted in Lausanne, Switzerland. LCA were performed on the data of 80 subjects manifesting motor/vocal tics during their childhood/adolescence. Comorbid attention‐deficit hyperactivity disorder (ADHD), obsessive‐compulsive disorder, depressive, phobia and panic symptoms/syndromes comprised the selected indicators. The resultant classes were characterized by psychosocial correlates.

Results

In LCA, four latent classes provided the best fit to the data. We identified two male‐related classes. The first class exhibited both ADHD and depression. The second class comprised males with only depression. Class three was a female‐related class depicting obsessive thoughts/compulsive acts, phobias and panic attacks. This class manifested high psychosocial impairment. Class four had a balanced sex proportion and comorbid symptoms/syndromes such as phobias and panic attacks. The complementary occurrence of comorbid obsessive thoughts/compulsive acts and ADHD impulsivity was remarkable.

Conclusions

To the best of our knowledge, this is the first study applying LCA to community data of GTS symptoms/tic disorder‐affected persons. Our findings support the utility of differentiating GTS/tic disorder subphenotypes on the basis of comorbid syndromes.
Effect of aminotriazole on antioxidant defense system of tasar silkworm Antheraea mylitta
Authors: Patra Bamadeb , Sahu Smaranika , Dandapat Jagneshwar
Published: October 2013

This study was designed to find out the metabolic consequences of H2O2 following catalase inhibition by aminotriazole in the fat body of an Antheraea mylitta pupa. H2O2 content in the pupal fat body exhibited a decreasing trend over the experimental period (up to 48 h). However, a substantial decrease in its level was marked after 12, 24 and 48 h of treatment. The level of lipid peroxidation was elevated within 4 h of aminotriazole injection. Nevertheless, its level significantly decreased after 12, 24 and 48 h of treatment. Superoxide dismutase activity was elevated within 4 h, followed by a transient decrease in its activity at 12 h of treatment and again increased over the experimental period. Catalase activity was found to decline in the fat body within 4 h of aminotriazole treatment compared to the control. However, it was surprising to observe that there was a two‐fold increase in catalase activity compared to its previous experimental group after 12 h, followed by a rapid decline in its activity at 24 h of aminotriazole injection and non‐detectable catalase activity at 48 h. Ascorbic acid content was found to be elevated after 12 h of injection and maintained an increasing trend over the rest of the experimental period compared to the respective control. Despite the progressive inhibition of catalase activity beyond 12 h of treatment, H2O2 accumulation was not observed as a consequence of catalase inhibition. Hence, catalase depletion by aminotriazole involves compensatory changes in other components of the antioxidant system for the efficient removal of H2O2.
Failure to process dentin sialophosphoprotein into fragments leads to periodontal defects in mice
Authors: Gibson Monica P. , Jani Priyam , Liu Ying , Wang Xiaofang , Lu Yongbo , Feng Jian Q. , Qin Chunlin
Published: October 2013

Dentin sialophosphoprotein (DSPP) plays a vital role in dentinogenesis. Previously, we showed that, in addition to dentin, DSPP is also highly expressed in alveolar bone and cellular cementum, and plays a crucial role in maintaining periodontal integrity; Dspp‐deficient mice demonstrate severe periodontal defects, including alveolar bone loss, decreased cementum deposition, abnormal osteocyte morphology in the alveolar bone, and apical migration of periodontal ligament. Dentin sialophosphoprotein in dentin and bone is cleaved into NH2‐terminal and COOH‐terminal fragments. Whilst our previous study showed that the proteolytic processing of DSPP is critical for dentinogenesis, it is unclear whether the post‐translational cleavage of DSPP also plays an essential role in maintaining a healthy periodontium. In this study, we analyzed the periodontal tissues from transgenic mice expressing the uncleavable full‐length DSPP in the Dspp knockout (Dspp‐KO) background (named ‘Dspp‐KO/D452A‐Tg mice’), in comparison with those from wild‐type mice, Dspp‐KO mice, and mice expressing the normal Dspp transgene in the Dspp‐KO background (designated ‘Dspp‐KO/normal‐Tg mice’). We found that transgenic expression of the normal DSPP fully rescued the periodontal defects of the Dspp‐KO mice, whereas this was not the case in Dspp‐KO/D452A‐Tg mice. These results indicate that proteolytic processing of DSPP is essential to periodontal integrity.
Epilepsy surgery, vision, and driving: What has surgery taught us and could modern imaging reduce the risk of visual deficits?
Authors: Winston Gavin P.
Published: October 2013

Up to 40% of patients with temporal lobe epilepsy (TLE) are refractory to medication. Surgery is an effective treatment but may cause new neurologic deficits including visual field deficits (VFDs). The ability to drive after surgery is a key goal, but a postoperative VFD precludes driving in 4–50% of patients even if seizure‐free. VFDs are a consequence of damage to the most anterior portion of the optic radiation, Meyer's loop. Anatomic dissection reveals that the anterior extent of Meyer's loop is highly variable and may clothe the temporal horn, a key landmark entered during temporal lobe epilepsy surgery. Experience from surgery since the 1940s has shown that VFDs are common (48–100%) and that the degree of resection affects the frequency or severity of the deficit. The pseudowedge shape of the deficit has led to a revised retinotopic model of the organization of the optic radiation. Evidence suggests that the left optic radiation is more anterior and thus at greater risk. Alternative surgical approaches, such as selective amygdalo‐hippocampectomy, may reduce this risk, but evidence is conflicting or lacking. The optic radiation can be delineated in vivo using diffusion tensor imaging tractography, which has been shown to be useful in predicting the postoperative VFDs and in surgical planning. These data are now being used for surgical guidance with the aim of reducing the severity of VFDs. Compensation for brain shift occurring during surgery can be performed using intraoperative magnetic resonance imaging (MRI), but the additional utility of this expensive technique remains unproven.
Getting a scientific paper published in Epilepsia: An editor's perspective
Authors: Schwartzkroin Philip A.
Published: October 2013

Getting a paper published in Epilepsia depends first and foremost on the quality of the work reported, and on the clarity and convincingness of the presentation. Papers should focus on important and interesting topics with clearly stated objectives and goals. The observations and findings are of greatest interest when they are novel and change our views on the mechanisms and/or treatment of an epileptic disease. Studies should be carefully designed to include adequate sample size, comparison groups, and statistical analyses. Critically, the data must be clearly presented and appropriately interpreted. If followed, these recommendations will improve an author's chances of having his/her paper accepted in a high quality journal like Epilepsia.
Neuroimaging characteristics of MRI‐negative orbitofrontal epilepsy with focus on voxel‐based morphometricMRIpostprocessing
Authors: Wang Z. Irene , Ristic Aleksandar J. , Wong Chong H. , Jones Stephen E. , Najm Imad M. , Schneider Felix , Wang Shuang , Gonzalez‐Martinez Jorge A. , Bingaman W. , Alexopoulos Andreas V.
Published: October 2013

Purpose

The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmedOFepilepsy and a negative magnetic resonance imaging (MRI) study. We aimed to examine the neuroimaging characteristics ofMRI‐negativeOFepilepsy with the focus on a voxel‐based morphometricMRIpostprocessing technique.

Methods

We included six patients withOFepilepsy, who met the following criteria: surgical resection of theOFlobe with/without adjacent cortex, seizure‐free for ≥12 months, invasive video–electroencephalography (EEG) monitoring showing ictal onset from theOFarea, and preoperativeMRIregarded as negative. Patients were investigated in terms of their image postprocessing and functional neuroimaging characteristics, electroclinical characteristics obtained from noninvasive and invasive evaluations, and surgical pathology.MRIpostprocessing on T1‐weighted high‐resolution scans was implemented with a morphometric analysis program (MAP) inMATLAB.

Key Findings

SingleMAP+ abnormalities were found in four patients; three were in theOFregion and one in the ipsilateral mesial frontal area. These abnormalities were included in the resection. One patient had bilateralMAP+ abnormalities in theOFregion, with the ipsilateral one completely removed. TheMAP+ foci were concordant with invasive electrophysiologic data in the majority ofMAP+ patients (four of five). The localization value of 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and ictal single‐photon emission computed tomography (SPECT) is low in this cohort. Surgical pathology included focal cortical dysplasia, remote infarct, Rosenthal fiber formation and gliosis.

Significance

Our study highlights the importance ofMRIpostprocessing in the process of presurgical evaluation of patients with suspected orbitofrontal epilepsy and “normal”MRI. UsingMAP, we were able to positively identify subtle focal abnormalities in the majority of the patients.MAPresults need to be interpreted in the context of their electroclinical findings and can provide valuable targets in the process of planning invasive evaluation.
Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double‐blind, randomized, placebo‐controlled, flexible‐dose trial
Authors: Kwan Patrick , Trinka Eugen , Van Paesschen Wim , Rektor Ivan , Johnson Martin E. , Lu Sarah
Published: October 2013

Purpose

To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high‐affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures.

Methods

This was a phase III, randomized, double‐blind, placebo (PBO)‐controlled flexible dose trial (N01254/NCT00504881) in adults (16–70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4‐week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8‐week dose‐finding period. This was followed by an 8‐week stable‐dose maintenance period. The treatment period comprised the dose‐finding period plus the maintenance period (16 weeks).

Key Findings

A total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV‐ and 91.7% PBO‐treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV‐ and PBO‐treated patients, respectively. The incidence of AEs declined from the dose‐finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline‐adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline‐adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV‐treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO‐treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV‐treated and PBO‐treated patients, respectively.

Significance

Adjunctive BRV given at individualized tailored doses (20–150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.
Lennox‐Gastaut syndrome of unknown cause: Phenotypic characteristics of patients in theEpilepsyPhenome/GenomeProject
Authors: Widdess‐Walsh Peter , Dlugos Dennis , Fahlstrom Robyn , Joshi Sucheta , Shellhaas Renée , Boro Alex , Sullivan Joseph , Geller Eric ,   the EPGP Investigators
Published: October 2013

Purpose

Lennox‐Gastaut syndrome (LGS) is a devastating childhood‐onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features ofLGSof unknown or genetic cause (LGSu). TheEpilepsyPhenome/GenomeProject (EPGP) aims to characterizeLGSuby phenotypic analysis of patients withLGSuand their parents.

Methods

One hundred thirty‐five patients withLGSwith no known etiology and their parents were enrolled from 19EPGPcenters in the United States andAustralia. Clinical data from medical records, standardized questionnaires, imaging, andEEGwere collected with use of online informatics systems developed forEPGP.

Key Findings

LGSuin theEPGPcohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients withLGSucompleted secondary school. Parents were cognitively normal. All subjects hadEEGrecordings with generalized epileptiform abnormalities with a spike wave frequency range of 1–5 Hz (median 2 Hz), whereas 8.1% of subjects hadEEGstudies with a normal posterior dominant rhythm. Almost 12% of patients evolved fromWest syndrome.

Significance

LGSuhas distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description ofLGSucoupled with future genetic studies will advance our understanding of this epilepsy syndrome.
Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature rat brain
Authors: Auvin Stéphane , Lecointe Cécile , Dupuis Nina , Desnous Béatrice , Lebon Sophie , Gressens Pierre , Dournaud Pascal
Published: October 2013

Purpose

After the first positive experimental data in rodents in the early 1970s demonstrating the anticonvulsant effect of stiripentol (STP), in vitro studies showed that STP acts directly on γ‐aminobutyric acid A (GABAA) receptors. Chloride influx is higher when these receptors contain an α3 subunit, leading to the hypothesis that STP might exhibit higher efficacy in the immature brain.

Methods

We explored this issue by studying the efficacy of STP in P21 and P75 rats using the pentylenetetrazol model of acute seizures or the lithium‐pilocarpine status epilepticus model. P21 and adult rats received vehicle, 150, 250, or 350 mg/kg of STP, i.p., 1 h before evaluating the anticonvulsant. We also studied the blood and brain levels of STP as well as the expression and the messenger RNA (mRNA) levels of the α3 subunit of the GABAA receptors at both ages.

Keys Findings

STP exhibited anticonvulsant properties in both models at both ages, but STP was more effective in P21 than in P75 rats. This was shown by the significant suppression of seizure or status epilepticus occurrence in P21 with 350 mg/kg STP, whereas the same dose had no significant effect at P75. The blood level, brain level, and blood/brain ratio of STP did not explain these differences between the two age groups. Moreover, the higher anticonvulsant properties in the immature brain were not explained by the mRNA level or protein expression of the GABAA α3 subunit at either age.

Significance

Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature brain. These findings require further investigation because it might lead to new clinical developments.
The Influence of Family Goals, Governance, and Resources on Firm Outcomes
Authors: Chrisman James J. , Sharma Pramodita , Steier Lloyd P. , Chua Jess H.
Published: October 2013

We briefly reflect on the theoretical contributions of the ongoing series of special issues on theories of family enterprise and discuss the contributions of each article and commentary in the current special issue. We observe that the meta–themes—the unique goals, governance, and resources of family firms—are not only primary sources of heterogeneity but key determinants of outcomes such as the continuation of family involvement, firm survival and renewal, and financial performance. We conclude that the importance and interrelationships of goals, governance, and resources suggest that a configuration approach to studying their interactions in family firms might be useful.
Goal Setting in Family Firms: Goal Diversity, Social Interactions, and Collective Commitment to Family–Centered Goals
Authors: Kotlar Josip , De Massis Alfredo
Published: October 2013

Goal setting in family firms is very complex due to the interplay between family and business systems. However, this topic is largely overlooked in family business research. In this qualitative study of goals and goal formulation processes among 76 organizational members across 19 family firms, we identify goal diversity as a direct consequence of the overlap between the family, ownership, and business systems. We found that goal diversity is expressed more strongly in the proximity of generational transitions, triggering social interaction processes through which organizational members contrast their goals. Our findings suggest that different types of social interactions lead to different behaviors, with familial social interactions being more effective than professional social interactions in managing goal diversity toward the formation of collective commitment to family–centered goals.
Explaining Performance Differences between Family Firms with Family and Nonfamily CEOs: It's the Nature of the Tie to the Family that Counts!
Authors: Jaskiewicz Peter , Luchak Andrew A.
Published: October 2013

Drawing on regulatory focus theory, we advance a microtheory for Naldi, Cennamo, Corbetta, and Gómez–Mejía's findings suggesting that family ties as well as the career aspirations that derive from them trigger relatively higher prevention and relatively lower promotion goal orientations of family when compared with nonfamily chief executive officers (CEOs). Our conceptualization offers an alternative theory for why family firms with family CEOs outperform those with nonfamily CEOs in contexts such as industrial districts where conservation strategies are more valuable, but underperform in contexts such as publicly listed firms where market–driven strategies are more valuable. Our commentary highlights the need for future research to examine variance in the self–regulatory mindsets of family and nonfamily CEOs, and to link these differences to firm strategies and performance.
Familiness and Innovation: Resource Bundling as the Missing Link
Authors: Carnes Christina Matz , Ireland R. Duane
Published: October 2013

Using resource–based logic, we integrate and extend theory and research on familiness and innovation in family firms. Supporting our efforts to do this is the suggestion that recent mixed results regarding the ability of family firms to innovate are at least partially accounted for by the failure to fully consider the importance of resource bundling processes as a mediator of the relationship between familiness as a unique organizational resource and innovation. Specifically, we suggest that the individual components of the resource bundling process—stabilizing, enriching, and pioneering—each mediate the relationship between familiness and innovation, and that these mediation effects account for at least part of the previously reported inconsistent results. Using theory and by integrating insights about familiness, innovation, and resource bundling, we seek to provide a more complete model of conditions affecting family firms’ ability to innovate.
‘Playing the Judicial Card’: Litigation Strategies during the Process of Ratification of the Lisbon Treaty
Authors: Castillo Ortiz Pablo José
Published: October 2013

During the process of ratification of the Lisbon Treaty, a number of constitutional jurisdictions were activated by political actors. In playing ‘the judicial card’, opponents of ratification decided to seek political goals through judicial means, and thus they were obliged to develop litigation strategies. This article explores such strategies and the responses that courts gave them. It shows that constitutional proceedings with regards to the Lisbon Treaty became a political battleground governed by legal logics, in which the interpretation of European clauses, the democratic deficit of the Union and the tensions underlying the European judicial dialogue were privileged objects of discussion between claimants and courts in which law and politics intertwined.
Endometrial tissue and blood plasma concentration of ceftiofur and metabolites following intramuscular administration of ceftiofur crystalline free acid to mares
Authors: Scofield D. , Black J. , Wittenburg L. , Gustafson D. , Ferris R. , Hatzel J. , Traub‐Dargatz J. , McCue P.
Published: October 2013

Reasons for performing study

Systemic administration of ceftiofur crystalline free acid (CCFA) may be a potential treatment for infectious endometritis caused byStreptococcus equissp.zooepidemicus(S. zooepidemicus) and other susceptible bacterial organisms in the mare.

Objective

To determine if i.m. administration ofCCFAat the label dose will exceed the minimum inhibitory concentration (MIC) ofS. zooepidemicusin the endometrium following single administration and multiple administration protocols.

Study design

Experimental pharmacokinetic study.

Methods

Three mares (Group 1) were administered a single i.m. dose ofCCFA(6.6 mg/kg bwt) and blood and endometrial biopsies were collected at selected intervals for 144 h. Six additional mares (Groups 2and3) receivedCCFAat times 0, 4, 11 and 18 days, and were sampled at predetermined times for 25 or 49 days, respectively. Plasma and tissue samples were analysed by high‐pressure liquid chromatography with tandem mass spectrometry for desfuroylceftiofur acetamide concentration, which is a direct measure of all ceftofur and ceftiofur metabolites in the sample.

Results

A mean plasma desfuroylceftiofur acetamide concentration of 0.367 ± 0.0162 μg/ml (mean ± s.e.) was detected at 96 h following administration. Mean endometrial tissue concentration was 0.510 ± 0.0418 μg/g at 96 h and exceeded theMICforS. zooepidemicus(0.25 μg/ml) throughout the 144 h monitoring period forGroup 1. Mares inGroups 2and3, given multiple doses ofCCFA, maintained plasma concentrations above theMICforS. zooepidemicusfor 25 days. Endometrial tissue levels remained above theMICat most data collection points for 25 days.

Conclusions

Ceftiofur crystalline free acid reaches appropriate endometrial tissue values to exceed theMICofS. zooepidemicus, a common cause of bacterial endometritis. Therefore,CCFAshould be effective in the treatment of equine bacterial endometritis caused byS. zooepidemicusand other susceptible bacterial pathogens in the mare.
Hair miR‐29a levels are decreased in patients with scleroderma
Authors: Takemoto Risa , Jinnin Masatoshi , Wang Zhongzhi , Kudo Hideo , Inoue Kuniko , Nakayama Wakana , Ichihara Asako , Igata Toshikatsu , Kajihara Ikko , Fukushima Satoshi , Ihn Hironobu
Published: October 2013

In the present study, we evaluated the possibility that we can utilize hair shaft miR‐29a levels as disease marker of scleroderma. Hair samples were obtained from 20 scleroderma patients, five dermatomyositis patients and 13 controls. microRNAs were purified from hairs as well as skins or sera, and miR‐29a levels were measured with quantitative real‐time polymerase chain reaction. Mean hair miR‐29a levels in scleroderma patients were significantly lower than those in control subjects or dermatomyositis, while expression levels of hair shaft marker keratin 34 were similar among them. There was no strong correlation among the miR‐29a levels in the hair, skin and serum of each patient, suggesting that hair microRNAs can be independent biomarkers. We found scleroderma patients with decreased miR‐29a levels had contracture of the phalanges at a significantly higher prevalence than those without. To confirm the clinical usefulness of hair microRNAs, large‐scale researches are needed in the future.
Canonical Wnt signalling as a key regulator of fibrogenesis – implications for targeted therapies?
Authors: Dees Clara , Distler Jörg H. W.
Published: October 2013

Canonical Wnt signalling belongs to the so‐called morphogen pathways and plays essential roles in development and tissue homeostasis. Being such a crucial regulatory pathway, Wnt signalling is tightly controlled at different levels. However, uncontrolled activation of canonical Wnt signalling has been implicated into the pathogenesis of various human disorders. In the last years, aberrant Wnt signalling has been demonstrated in fibrotic diseases including systemic sclerosis (SSc). In this review, we will discuss the current state of research on canonical Wnt signalling in SSc. Activation of canonical Wnt signalling induces fibroblast activation with subsequent myofibroblast differentiation and excessive collagen release resulting in tissue fibrosis. Genetic or pharmacological blockade of Wnt activation ameliorates experimental fibrosis in different preclinical models. These findings have direct translational implications because several small molecule inhibitors of Wnt signalling are currently evaluated in clinical trials and some already showed first promising results.
Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through TGF‐β1
Authors: Ohgo Shiro , Hasegawa Seiji , Hasebe Yuichi , Mizutani Hiroshi , Nakata Satoru , Akamatsu Hirohiko
Published: October 2013

Systemic sclerosis [scleroderma (SSc)]‐associated skin fibrosis is characterized by increased fibrosis in the dermis and a reduction in the thickness of the subcutaneous adipose tissue layer. Although many studies have examined fibrosis in SSc, only a few studies have focused on the associated reduction in the thickness of the subcutaneous adipose tissue layer. In this study, we investigated the effects of SSc‐induced fibrosis on adipose tissue. We found that bleomycin suppresses adipogenesis in adipose‐derived stem cells (ASCs) and stimulates ASCs to express transforming growth factor β1 (TGF‐β1), which suppresses adipogenesis and promotes fibrosis. Furthermore, we found that adipocyte‐conditioned medium suppressed collagen synthesis by fibroblasts in fibrosis‐like conditions. We concluded that in the skin affected by bleomycin‐induced fibrosis, increased TGF‐β1 expression suppresses adipogenesis and promotes adipocyte fibrosis. It was also suggested that adipocytes have an inhibitory effect on the progression of fibrosis.
Gentian Violet: a 19th century drug re‐emerges in the 21st century
Authors: Maley Alexander M. , Arbiser Jack L.
Published: October 2013

Gentian violet (GV) has a long and varied history as a medicinal agent. Historically used as an antibacterial and antifungal, recent reports have shown its utility as an antitypranosomal, antiviral and anti‐angiogenic agent. The objective of this article is to summarize evidence regarding the efficacy and safety ofGVuse in dermatology. Recent discoveries have found novel targets ofGV, namelyNADPHoxidase in mammalian cells and thioredoxin reductase 2 in bacterial, fungal and parasitic cells. These discoveries have expanded the use ofGVin the 21st century. Given thatGVis well tolerated, effective and inexpensive, its use in dermatology is predicted to increase.
Characterization of tryptophan aminotransferase 1 of Malassezia furfur, the key enzyme in the production of indolic compounds by M. furfur
Authors: Preuss Janina , Hort Wiebke , Lang Sarah , Netsch Anette , Rahlfs Stefan , Lochnit Günter , Jortzik Esther , Becker Katja , Mayser Peter A.
Published: October 2013

Malassezia yeasts are responsible for the widely distributed skin disease Pityriasis versicolor (PV), which is characterized by a hyper‐ or hypopigmentation of affected skin areas. For Malassezia furfur, it has been shown that pigment production relies on tryptophan metabolism. A tryptophan aminotransferase was found to catalyse the initial catalytic step in pigment formation in the model organism Ustilago maydis. Here, we describe the sequence determination, recombinant production and biochemical characterization of tryptophan aminotransferase MfTam1 from M. furfur. The enzyme catalyses the transamination from l‐tryptophan to keto acids such as α‐ketoglutarate with Km values for both substrates in the low millimolar range. Furthermore, MfTam1 presents a temperature optimum at 40°C and a pH optimum at 8.0. MfTam1 activity is highly dependent on pyridoxal phosphate (PLP), whereas compounds interfering with PLP, such as cycloserine (CS) and aminooxyacetate, inhibit the MfTam1 reaction. CS is known to reverse hyperpigmentation in PV. Thus, the results of the present study give a deeper insight into the role of MfTam1 in PV pathogenesis and as potential target for the development of novel PV therapeutics.
Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model
Authors: Mudnakudu Nagaraju Kiran Kumar , Babina Magda , Worm Margitta
Published: October 2013

Proteasome inhibition (PI) has been reported to interfere with antibody‐driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen‐driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen‐specific plasma cells/antibody‐secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase‐1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti‐inflammatory effects are detectable in the skin, counter‐regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.
A new KRT16 mutation associated with a phenotype of pachyonychia congenita
Authors: Paris Francesc , Hurtado Cristina , Azón Antoni , Aguado Leyre , Vizmanos José L.
Published: October 2013

Pachyonychia congenita is a rare, autosomal dominant genetic disease characterized by painful palmoplantar keratoderma and hypertrophic nail dystrophy. This disorder is caused by mutations in any one of five cytoskeletal keratin proteins, K6a, K6b, K6c, K16 and K17. Here, we describe a new p.Leu421Pro (c.1262T>C) mutation in the highly conserved helix termination motif of K16 in a large Spanish family. Bioinformatic analyses as well as previous descriptions in the literature of homologous mutations in other keratin‐coding genes show that this mutation is probably causative of the disease.
Overlooked impacts and challenges of the new European discard ban
Authors: Sardà Francesc , Coll Marta , Heymans Johanna J , Stergiou Konstantinos I
Published: October 2013

Discards are the portion of animal and plant material in the catch that is dumped back at sea. The Common Fisheries Policy plan proposed by the European Commission for 2014–2020 presents a controversial goal: to enforce the landing of fishing discards as a measure to encourage their reduction. This historical and political decision will shape the future of the fishing exploitation in European Seas. Discards generated by European fleets are not negligible, and its reduction is an ecological, socioeconomical and moral imperative. However, it must be achieved through the reduction in discards at source and the promotion of selective and non‐destructive gears. We argue it is doubtful that this discard ban will result in an effective reduction of discards. The proposed measure may, in fact, negatively affect ecosystems at all levels of biological hierarchy by disregarding the Ecosystem‐Based Approach to Fisheries and the Precautionary Principle. It could negatively impact several species by increasing fishing mortality, also commercial species if discards are not accounted in the total allowable catch. Communities preying on discards will likely be affected. The role discards currently play in the energy turnover of current ecosystems will be modified and should be fully evaluated. The landing of discards will likely generate new markets of fishmeal due to the growing demands for marine living resources. The ban will require substantial public investment to deal with technical problems on board and to control and enforce. Therefore, this measure should be only implemented after rigorous scientific and technical studies have been developed.
miRNA expression is modulated over time after focal ischaemia: up‐regulation of miR–347 promotes neuronal apoptosis
Authors: Gubern Carme , Camós Susanna , Ballesteros Iván , Rodríguez Rocío , Romera Víctor G. , Cañadas Roberto , Lizasoain Ignacio , Moro María A. , Serena Joaquín , Mallolas Judith , Castellanos Mar
Published: October 2013

Despite the large number of molecules reported as being over‐expressed after ischaemia, little is known regarding their regulation. miRNAs are potent post‐transcriptional regulators of gene expression, and reports have shown differentially miRNA expression in response to focal cerebral ischaemia. The present study analysed miRNA expression from acute to late phases of ischaemia to identify specific ischaemia‐related miRNAs, elucidate their role, and identify potential targets involved in stroke pathophysiology. Of 112 miRNAs, 32 showed significant changes and different expression profiles. In addition to the previously reported differentially expressed miRNAs, new ischaemia‐regulated miRNAs have been found, including miR‐347. Forty‐seven genes involved in brain functions or related to ischaemia are predicted to be potential targets of the differentially expressed miRNAs after middle cerebral artery occlusion. Analysis of four of these targets (Acsl4, Arf3, Btg2 and Dpysl5) showed them to be differentially regulated by ischaemia at the transcriptional or post‐transcriptional level. Acsl4, Bnip3l and Phyhip, potential targets of miR‐347, were up‐regulated after miR‐347 over‐expression, inducing neuronal apoptotic death. Our findings suggest that miR‐347 plays an important role in regulating neuronal cell death, identify Acsl4 as a new protein requiring study in ischaemia, and provide an important resource for future functional studies of miRNAs after ischaemia.
Bridge fatigue life prediction using Mittag–Leffler distribution
Authors: Liang Y. J. , Chen W.
Published: October 2013

This paper is aimed at developing a statistical approach for fatigue life prediction of steel bridges with structural health monitoring data. The present approach obtains the static cumulative damage index by using the Mittag–Leffler distribution in conjunction with the statistical form of Miner's rule and investigates the influence of annual traffic increase on the evolution of the dynamic service life by a modified statistical formula of Miner's rule, which includes the relationship between the levels of stress range and the annual traffic increase rate. The proposed method is exemplified to specifically predict the static fatigue life of the Neville Island Bridge and the dynamic fatigue life of the Birmingham Bridge.