bluuebunny/crossref_metadata_2025 huggingface dataset:
Light chain amyloidosis 2012: a new era
Authors: Gatt Moshe E. , Palladini Giovanni
Published: January 2013

AL amyloidosis patients with multi‐organ and particularly cardiac involvement have historically been considered to have a bad prognosis. The introduction of autologous stem cell transplantation was associated with unacceptable toxicity in high‐risk patients, but responding patients have prolonged overall survival. Toxicities can be decreased by careful patient selection, but this reduces the applicability of this treatment modality to a limited number of patients. Efforts are therefore needed to design novel more effective regimens, with the use of new medications, such as thalidomide, lenalidomide and bortezomib, next generation immunomodulatory drugs and proteasome inhibitors. Their combination with dexamethasone and alkylating agents show promising results, allowing a high percentage of remission and subsequent event‐free and overall survival, even in a significant proportion of high risk, poor prognosis populations. This review includes the state‐of‐the‐art treatment for AL amyloidosis patients as of 2012, in light of the progress in management of this disease during recent years.
Next‐generation sequencing – feasibility and practicality in haematology
Authors: Kohlmann Alexander , Grossmann Vera , Nadarajah Niroshan , Haferlach Torsten
Published: January 2013

Next‐generation sequencing platforms have evolved to provide an accurate and comprehensive means for the detection of molecular mutations in heterogeneous tumour specimens. Here, we review the feasibility and practicality of this novel laboratory technology. In particular, we focus on the utility of next‐generation sequencing technology in characterizing haematological neoplasms and the landmark findings in key haematological malignancies. We also discuss deep‐sequencing strategies to analyse the constantly increasing number of molecular markers applied for disease classification, patient stratification and individualized monitoring of minimal residual disease. Although many facets of this assay need to be taken into account, amplicon deep‐sequencing has already demonstrated a promising technical performance and is being continuously developed towards routine application in diagnostic laboratories so that an impact on clinical practice can be achieved.
Mesenchymal stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia‐bearing mice
Authors: Pessina Augusto , Coccè Valentina , Pascucci Luisa , Bonomi Arianna , Cavicchini Loredana , Sisto Francesca , Ferrari Maura , Ciusani Emilio , Crovace Antonio , Falchetti Maria Laura , Zicari Sonia , Caruso Arnaldo , Navone Stefania , Marfia Giovanni , Benetti Anna , Ceccarelli Piero , Parati Eugenio , Alessandri Giulio
Published: January 2013

Current leukaemia therapy focuses on increasing chemotherapy efficacy. Mesenchymal stromal cells (MSCs) have been proposed for carrying and delivery drugs to improve killing of cancer cells. We have shown that MSCs loaded with Paclitaxel (PTX) acquire a potent anti‐tumour activity. We investigated the effect of human MSCs (hMSCs) and mouse SR4987 loaded with PTX (hMSCsPTX and SR4987PTX) on MOLT‐4 and L1210, two leukaemia cell (LCs) lines of human and mouse origin, respectively. SR4987PTX and hMSCsPTX showed strong anti‐LC activity. hMSCsPTX, co‐injected with MOLT‐4 cells or intra‐tumour injected into established subcutaneous MOLT‐4 nodules, strongly inhibited growth and angiogenesis. In BDF1‐mice‐bearing L1210, the intraperitoneal administration of SR4987PTX doubled mouse survival time. In vitro, both hMSCs and hMSCsPTX released chemotactic factors, bound and formed rosettes with LCs. In ultrastructural analysis of rosettes, hMSCsPTX showed no morphological alterations while the attached LCs were apoptotic and necrotic. hMSCs and hMSCsPTX released molecules that reduced LC adhesion to microvascular endothelium (hMECs) and down‐modulated ICAM1 and VCAM1 on hMECs. Priming hMSCs with PTX is a simple procedure that does not require any genetic cell manipulation. Once the effectiveness of hMSCsPTX on established cancers in mice is proven, this procedure could be proposed for leukaemia therapy in humans.
Risk‐stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukaemia
Authors: Richardson Simon E. , Khan Iftekhar , Rawstron Andrew , Sudak Jagoda , Edwards Noha , Verfuerth Stephanie , Fielding Adele K. , Goldstone Anthony , Kottaridis Panagiotis , Morris Emma , Benjamin Reuben , Peggs Karl S. , Thomson Kirsty J. , Vandenberghe Elisabeth , Mackinnon Stephen , Chakraverty Ronjon
Published: January 2013

Following reduced intensity‐conditioned allogeneic stem cell transplantation (RIC allo‐SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft‐versus‐host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab‐based RIC allo‐SCT and pre‐emptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high‐risk disease, including 30% with 17p deletion (17p−). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD‐negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD‐negative CR. With a median follow‐up of 4·3 years, 4‐year current progression‐free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p−). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6·4%. At last follow‐up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high‐risk CLL without incurring excessive GVHD.
A new Middle Pleistocene interglacial record from Denmark: Chronostratigraphic correlation, palaeovegetation and fire dynamics
Authors: Kuneš Petr , Kjærsgaard Sørensen Malene , Buylaert Jan‐Pieter , Murray Andrew S. , Houmark‐Nielsen Michael , Odgaard Bent Vad
Published: January 2013

Previously only three terrestrial interglacial periods were known from southern Scandinavia, all of which could be relatively easily correlated within the central European stratigraphical framework. Here, we present a new interglacial–interstadial pollen, plant macrofossil and charcoal record from Trelde Klint, Denmark, and analyse its biostratigraphy, correlation with other European records, vegetation development, fire dynamics and absolute dating. Except for a slight truncation of the early part of the record, the pollen stratigraphy exhibits a full interglacial succession, including temperate trees (Quercus, Ulmus and Tilia) during its mesocratic stage. Macrofossil analysis allowed identification to species level for Quercus robur, Picea abies and two mosses. Conifers (Pinus and Picea) dominate the pollen record of the interglacial sequence, and the occurrence of Larix pollen in the top part of the interglacial record as well as in the interstadial sediments is especially indicative of this interglacial. The overall diversity of tree genera is rather low. These biostratigraphical features suggest that Trelde Klint is unique among Danish records, but it is similar to records from northern Germany. Numerical analyses (REVEALS and DCA) indicate that forests during the temperate stage were dense and that vegetation openness increased only towards the end of the interglacial, accompanied by increased fire occurrence. A short interstadial sequence with a dominance of Pinus and Betula and the presence of Larix is present above the interglacial deposit. We argue that lack of attention to differences in fire regimes may hamper understanding of between‐site correlations of interglacial pollen records. OSL dating, using a novel feldspar technique, yields an average age of 350±20 ka for the sandy sediments above the interglacial layers at Trelde Klint, suggesting that the whole interglacial–interstadial succession belongs to Marine Isotope Stage 11.
Immediately Loaded Implants with or without Abutments Supporting Fixed Partial Dentures: 1‐Year Results from a Prospective, Randomized, Clinical Trial
Authors: Göthberg Catharina , André Ulrika , Gröndahl Kerstin , Ljungquist Birgit , Thomsen Peter , Slotte Christer
Published: January 2013

Purpose

To evaluate 1‐year implant survival and marginal bone loss around implants that support fixed partial dentures loaded immediately or after 3 months, and effects from abutment usage.

Materials and Methods

In this 2005 to 2009 randomized, parallel‐group, clinical trial, 50 partially edentulous patients each received three Brånemark TiUnite™ implants (Nobel Biocare®, Göteborg, Sweden), mostly in the posterior maxilla. Two implants were fitted with abutments: a TiUnite™ surface and a machine‐milled surface; the suprastructure was attached directly at implant level for the third implant. After randomized allocation, implants were immediately loaded with a fixed temporary bridge (test group) or left unloaded for 3 months (control group). A permanent fixed suprastructure replaced the temporary bridge after 6 months (test). Hard and soft tissues were examined during pretreatment and surgery plus 2 days, 14 days, 4 weeks, 3 months, and 1 year after surgery.

Results

After 1 year, four implants were lost in the test and two in the control groups (1‐year survival rates of 94.9% [test] and 97.2% [control], with no significant intergroup difference). Resonance frequency analysis values indicated a similar pattern in both groups, with implant stability quotient (ISQ) reduction between 2 and 4 weeks. The test group had a significantly lower ISQ than the control group at these appointments. After 1 year, marginal bone losses around the implants were, on average, 1.32 mm (test, standard error of the mean [SEM] 0.08) and 1.24 mm (control, SEM 0.08), with no significant intergroup difference. Significantly larger marginal bone loss was observed at implants without abutment compared with implants with abutment.

Conclusions

For both groups, this study showed similar implant survival rates and marginal bone loss. Larger bone loss was found at implants loaded without attached abutments.
Facial alveolar bone wall width – a cone‐beam computed tomography study inAsians
Authors: Zekry Ahmed , Wang Ren , Chau Anson C. M. , Lang Niklaus P.
Published: January 2013

Background

The width of the facial alveolar bone wall is crucial for long‐term successful esthetic outcomes of implants immediately placed into extraction sockets. A threshold of 2 mm is recommended to minimize buccal vertical bone resorption.

Aim

To assess the width of the facial alveolar bone wall using cone‐beam computed tomography images (CBCT).

Material and methods

RetrospectiveCBCTimages were acquired from a representative sample of Asians using the i‐CAT®classic system with a 0.4‐mm voxel size. At random, 200CBCTimages were selected according to predefined criteria. TheDICOMfile was imported into the i‐CAT Vision®software. In the panoramic screen, the middle of each tooth was selected, and in the sagittal window, the middle cross section was selected for performing the measurements using a computer. The vertical distance from the alveolar crest (BC) – cemento‐enamel junction (CEJ) was measured. The width of the facial alveolar bone wall was measured at three locations: 1, 3, and 5 mm apical toBC. Descriptive statistics, frequency analyses, and multi‐level comparisons were performed.

Results

The sample consisted of 74 men and 126 women (mean age of 37.2 years; range 17–82years). A total of 3618 teeth were assessed. There was no significant difference between the values of right and left sides, or between genders. However, statistically significant differences were observed between age groups at all levels. The distance fromCEJtoBCvaried from 0.4 to 4 mm, with an overall tendency to increase with age. The mean width of the facial alveolar bone wall at anterior teeth was 0.9 mm and increased toward posterior regions. Rarely, a width of 2 mm was yielded (0.6–1.8% for anterior teeth, 0.7–30.8% for posterior teeth). At a 5‐mm distance fromBC, minimal widths of facial alveolar bone were identified for the anterior teeth. The frequency of dehiscence ranged from 9.9% to 51.6% for anterior and 3.1% to 53.6% for posterior teeth, respectively.

Conclusion

A thin facial alveolar bone wall was usually present in both jaws. Hence, for most patients, adjunctive bone augmentation may be needed when installing implants in areas of esthetic concern.
The influence of bone marrow aspirates and concentrates on the early volume stability of maxillary sinus grafts with deproteinized bovine bone mineral – first results of a RCT
Authors: Kühl S. , Payer M. , Kirmeier R. , Wildburger A. , Wegscheider W. , Jakse N.
Published: January 2013

Objectives

The aim of the study was to investigate whether bone marrow aspirates (BMA) and concentrates (BMAC) influence the grafts' stability when added to deproteinized bovine bone mineral (DBBM) within the first 6 months after maxillary sinus augmentation.

Material and methods

26 CT data of 13 patients undergoing bilateral maxillary sinus augmentation in a split‐mouth design were evaluated using the Voxim® software by comparing the graft volumes 2 weeks after the sinus lift procedure with CT data obtained 6 months later. DBBM with (N = 6) or without tibial BMA (N = 6) and DBBM with (N = 7) and without adding iliac BMAC® (N = 7) were used as grafts. Absolute and percentage changes in the graft volumes were evaluated, and the nonparametric Mann–Whitney U‐test and the nonparametric Wilcoxon test were performed to determine significant differences between the graft volumes within each single split‐mouth group and between the two groups.

Results

Overall, the volumes decreased between 15% and 21%. All single groups showed statistically significant decreases over 6 months of healing. The time‐dependent changes in volumes between the different groups were not statistically significant (P = 0.818).

Conclusions

An evident decrease in graft volume over the first 6 months of healing has to be expected irrespectively of graft composite. Neither BMA nor BMAC seem to have an evident impact. Overaugmentation seems recommendable in two‐stage maxillary sinus surgery.
Predicting Recovery Criteria for Threatened and Endangered Plant Species on the Basis of Past Abundances and Biological Traits
Authors: NEEL MAILE C. , CHE‐CASTALDO JUDY P.
Published: January 2013

Recovery plans for species listed under the U.S. Endangered Species Act are required to specify measurable criteria that can be used to determine when the species can be delisted. For the 642 listed endangered and threatened plant species that have recovery plans, we applied recursive partitioning methods to test whether the number of individuals or populations required for delisting can be predicted on the basis of distributional and biological traits, previous abundance at multiple time steps, or a combination of traits and previous abundances. We also tested listing status (threatened or endangered) and the year the recovery plan was written as predictors of recovery criteria. We analyzed separately recovery criteria that were stated as number of populations and as number of individuals (population‐based and individual‐based criteria, respectively). Previous abundances alone were relatively good predictors of population‐based recovery criteria. Fewer populations, but a greater proportion of historically known populations, were required to delist species that had few populations at listing compared with species that had more populations at listing. Previous abundances were also good predictors of individual‐based delisting criteria when models included both abundances and traits. The physiographic division in which the species occur was also a good predictor of individual‐based criteria. Our results suggest managers are relying on previous abundances and patterns of decline as guidelines for setting recovery criteria. This may be justifiable in that previous abundances inform managers of the effects of both intrinsic traits and extrinsic threats that interact and determine extinction risk.

Predicción de Criterios de Recuperación para Especies de Plantas en Peligro y Amenazadas con Base en Abundancias Pasadas y Atributos Biológicos
Contact allergy from disperse dyes in textiles–a review
Authors: Malinauskiene Laura , Bruze Magnus , Ryberg Kristina , Zimerson Erik , Isaksson Marléne
Published: January 2013

Several disperse dyes (DDs) are still considered to be the most important allergens in textile dermatitis, but there are sparse data about their current use in textiles. The aim of this review was to evaluate published studies and reports on contact allergy to DDs published in PubMed during the last 22 years (1990–2012). Prevalence data are provided by study and by dye, as well as by the described clinical peculiarities of DD dermatitis. We reviewed 54 studies. In total, 26 DDs were tested. The average prevalence in screening studies was >1% for Disperse Blue 106, Disperse Blue 124, and Disperse Orange 3. There is a lack of data on patch testing with Disperse Blue 26, Disperse Blue 102, Disperse Orange 37, Disperse Orange 149, Disperse Yellow 23 and Disperse Yellow 49, which are listed as allergens by the EU Commission. It is necessary to check the purity and identity of dyes used for patch testing, confirm the clinical relevance of positive reactions by patch testing with suspected textiles, and, if the results are positive, determine the culprit dye.
The Influence of Activation Level on Belief Bias in Relational Reasoning
Authors: Banks Adrian P.
Published: January 2013

A novel explanation of belief bias in relational reasoning is presented based on the role of working memory and retrieval in deductive reasoning, and the influence of prior knowledge on this process. It is proposed that belief bias is caused by the believability of a conclusion in working memory which influences its activation level, determining its likelihood of retrieval and therefore its effect on the reasoning process. This theory explores two main influences of belief on the activation levels of these conclusions. First, believable conclusions have higher activation levels and so are more likely to be recalled during the evaluation of reasoning problems than unbelievable conclusions, and therefore, they have a greater influence on the reasoning process. Secondly, prior beliefs about the conclusion have a base level of activation and may be retrieved when logically irrelevant, influencing the evaluation of the problem. The theory of activation and memory is derived from the Atomic Components of Thought‐Rational (ACT‐R) cognitive architecture and so this account is formalized in an ACT‐R cognitive model. Two experiments were conducted to test predictions of this model. Experiment 1 tested strength of belief and Experiment 2 tested the impact of a concurrent working memory load. Both of these manipulations increased the main effect of belief overall and in particular raised belief‐based responding in indeterminately invalid problems. These effects support the idea that the activation level of conclusions formed during reasoning influences belief bias. This theory adds to current explanations of belief bias by providing a detailed specification of the role of working memory and how it is influenced by prior knowledge.
Metaphase arrest and delay in cell cycle kinetics of root apical meristems and mouse bone marrow cells treated with leaf aqueous extract of Clerodendrum viscosum Vent
Authors: Ray S. , Kundu L. M. , Goswami S. , Roy G. C. , Chatterjee S. , Dutta S. , Chaudhuri A. , Chakrabarti C. S.
Published: January 2013

Objectives

To study cell cycle delay and metaphase arresting activity of leaf aqueous extract of Clerodendrum viscosum Vent. (LAECV) in root apical meristems and mouse bone marrow cells.

Materials and methods

Cell cycle delay and metaphase arresting activities of LAECV were analysed, in root apical meristems of onion and wheat, and in mouse bone marrow cells, by scoring mitotic index, metaphase frequency and transition of cells from metaphase to anaphase. Colchicine was used as the standard metaphase arresting drug. Phytochemicals present in LAECV were detected and their phytotoxic activity was evaluated by analysing green‐gram (Vigna radiata) seedling's root growth retardation and branch root swelling phenomenon.

Results

LAECV treatment resulted in dose‐dependent root growth retardation of green‐gram seedling root length (P < 0.01) and half maximal growth inhibitory concentration (IC50) of LAECV was 0.87 mg/ml at 144 h. In onion and wheat root meristem cells the mitotic index decreased, metaphase frequency increased and transition from metaphase to anaphase reduced. Experimentation with mouse bone marrow cells indicated that LAECV induced metaphase arrest (164.3% increase in arrested metaphases per 300 mg/kg body weight, over 2.5 h). Phytochemicals like carbohydrates, glycosides, saponins, terpenoids, triterpenoids, tannins and trace amounts of alkaloids were detected in LAECV.

Conclusion

It may be said that LAECV contains mitostatic and metaphase arresting components that are able to induce significant metaphase arrest in root apical meristems and also in mouse bone marrow cells.
Influence of larger graft weight to recipient weight on the post‐liver transplantation course
Authors: Levesque Eric , Duclos Julie , Ciacio Oriana , Adam Rene , Castaing Denis , Vibert Eric
Published: January 2013

Size matching between recipient and donor livers is an important factor in organ allocation in the context of liver transplantation (LT). The aim of this study was to determine whether a large graft for recipient size influenced the post‐transplant course. One hundred and sixty‐two successive LT recipients were included and retrospectively divided into two groups: 25 (15%) had a graft‐to‐recipient weight ratio (GWRW) ≥2.5% and 137 (85%) had a GWRW <2.5%. Postoperative complications and outcomes were recorded. In the GWRW >2.5% group, more end‐to‐end caval replacement (72% vs. 38%, p = 0.003) and veno‐venous bypass (48% vs. 23%, p = 0.01) were used. Peak AST/ALT values were higher in the GWRW >2.5% group (AST: 596 [70–5876] vs. 453 [29–5132] IU/l, p = 0.03; ALT: 773 [101–5025] vs. 383 [36–4921] IU/l, p = 0.02). Among postoperative complications, the rate of respiratory failure was higher in the GWRW >2.5% group (32% vs. 14%, p = 0.04). The rates of other complications did not differ between the two groups. Both groups had similar graft and patient survival rates at one yr. Using large grafts for recipient size did not impair liver function and did not modify graft and patient outcomes at one yr. However, a GWRW >2.5% appeared to be a determining factor for respiratory morbidity following LT.
Native kidney function following liver transplantation using calcineurin inhibitors: single‐center analysis with 20 years of follow‐up
Authors: LaMattina John C. , Mezrich Joshua D. , Fernandez Luis A. , D'Alessandro Anthony M. , Djamali Arjang , Musat Alexandru I. , Pirsch John D. , Foley David P.
Published: January 2013

Introduction

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long‐term native kidney function in these recipients becomes more critical to patient survival.

Methods

We analyzed 1151 adult, deceased‐donor, single‐organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr.

Results

Kaplan–Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end‐stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non‐Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor‐based regimen.

Conclusion

Close, long‐term follow‐up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long‐term outcomes despite a calcineurin inhibitor‐based immunosuppressive regimen.
Adverse drug interactions as a high‐risk factor for lethal post‐transplant complications in Chinese population
Authors: Yang Ting , Wu Xue Mei , Qiu Hong Qiang , Fu Dan Hui , Hu Jian Da , Li Jian , Zheng Xiao Yun , Luo Xiao Feng , Yuan Xiao Hong , Chen Ru Ling , Chen Zhi Zhe
Published: January 2013

Metabolism of triazole antifungal agents is highly competitive to conventional post‐transplant immunosuppressants like cyclosporine A (CsA) via the cytochrome P450‐dependent pathway. We present the first report on lethal complications that may arise due to this type of drug interaction. A retrospective survey identified 10 of 104 cases (9.62%) that suffered life‐threatening complications associated with the interaction between CsA and itraconazole or voriconazole following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at our center. According to the close drug monitoring, all 10 patients experienced supratherapeutic levels of CsA even with a preemptive CsA dosage reduction and prompt dose adjustment. Six patients developed grade I to III acute graft‐versus‐host disease (aGVHD) and eventually died from either idiopathic pneumonia syndrome or diffuse alveolar hemorrhage; another four patients died from CSA‐associated neurological complications. Impaired hepatic and renal function was noted in only one of these 10 cases. The high frequency as well as the unpredictability of severe complications lead us to suggest that triazole should always be replaced by another antifungal medication (e.g., amphotericin B or Echincandins) while patients receive CsA after HSCT, especially in the Chinese population.
Impaired muscle growth in spastic cerebral palsy
Authors: Barrett Rod S , Barber Lee
Published: January 2013

This commentary is on the original article by Smith et al on pages 264–270 of this issue.
Pathological mandibular fractures: a review of the literature of the last two decades
Authors: Boffano Paolo , Roccia Fabio , Gallesio Cesare , Berrone Sid
Published: January 2013

Pathological mandibular fractures are rare, accounting for fewer than 2% of all fractures of the mandible. They could be defined as fractures that occur in regions where bone has been weakened by an underlying pathological process. Pathological fractures usually may follow surgical interventions such as third molar removal or implant placement, result from regions of osteomyelitis, osteoradionecrosis, and bisphosphonate‐related osteonecrosis of the jaw, occur because of idiopathic reasons or be facilitated by cystic lesions, benign, malignant, or metastatic tumors. Pathological mandibular fractures may be challenging to treat because of their different etiology and peculiar local and general conditions, often requiring a more rigid fixation. In patients with poor medical conditions, simpler and more limited options may be preferred.
Replication and meta‐analysis of common variants identifies a genome‐wide significant locus in migraine
Authors: Esserlind A.‐L. , Christensen A. F. , Le H. , Kirchmann M. , Hauge A. W. , Toyserkani N. M. , Hansen T. , Grarup N. , Werge T. , Steinberg S. , Bettella F. , Stefansson H. , Olesen J.
Published: January 2013

Background and purpose

Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population‐based genome‐wide association study by Chasman et al. (Nat Genet 2011: 43: 695–698), three common variants were found to confer risk of migraine at a genome‐wide significant level (P < 5 × 10−8). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic‐based Danish and Icelandic cohort.

Methods

The top association SNPs were assessed in 2523 cases and 38 170 controls, and a meta‐analysis was performed, combining the discovery set with all the follow‐up studies. Finally the confirmed SNPs were assessed in a genotype–phenotype analysis.

Results

Two out of three SNPs that showed genome‐wide significant associations in the previous study: rs10166942 (near TRPM8) and rs11172113 (in LRP1) were significantly associated with migraine in the present study. The meta‐analysis confirmed the previous three genome‐wide significant associated SNPs (rs2651899, rs10166942 and rs11172113) to confer risk of migraine. In addition, the C‐allele of rs2078371 (near TSPAN‐2) also reached genome‐wide significance for association with migraine [OR = 1.14; CI = (1.09–1.20); P = 2.55 × 10−8].

Conclusion

TSPAN‐2 encodes an integral membrane protein involved in oligodendrogenesis. This new finding supports the plausible implication of neuroglia in the pathophysiology of MO and MTA.
Do systolic BP and pulse pressure relate to ventricular enlargement?
Authors: Graff‐Radford N. R. , Knopman D. S. , Penman A. D. , Coker L. H. , Mosley T. H.
Published: January 2013

Background and purpose

To evaluate the association between systolic, diastolic and pulse pressure, and increase in ventricular size (VS). Observations in laboratory animals suggest intraventricular pulse pressure (systolic–diastolic) may play a role in ventricular enlargement.

Methods

Initial magnetic resonance (MR) scans and vascular risk factors evaluation were performed in 1812 Atherosclerosis Risk in Communities participants in 1994–1995. In 2004–2006, 1130 participants underwent repeat MR. VS was rated using a validated nine‐point scale. Multiple logistic regression analysis assessed association between blood pressure measures and pulse pressure, and the change between the MR scans of VS controlling for age, sex and race.

Results

At baseline 1112 participants (385 black women, 200 black men, 304 white women and 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models pulse pressure at baseline was associated with an increase in VS [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01–1.40], as was systolic pressure (OR 1.28, 95% CI 1.03–1.58).

Conclusions

Systolic pressure and pulse pressure are associated with future development of increased VS. The findings are consistent with the animal literature that increased pulse pressure predisposes to risk of future increased VS. High pulse pressure might play a role in the pathogenesis of normal pressure hydrocephalus.
Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system
Authors: Banati M. , Csecsei P. , Koszegi E. , Nielsen H. H. , Suto G. , Bors L. , Trauninger A. , Csepany T. , Rozsa C. , Jakab G. , Molnar T. , Berthele A. , Kalluri S. R. , Berki T. , Illes Z.
Published: January 2013

Background

Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity.

Methods

Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4‐seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO‐SD), 17 patients with AQP4‐seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC).

Results

Thirty‐seven percentages of patients with AQP4‐seropositive NMO/NMO‐SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4‐seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti‐gliadin and ASCA were more frequent in the AQP4‐seropositive NMO‐spectrum compared to controls (P = 0.01 and P < 0.05, respectively).

Conclusion

Antibody responses against gastrointestinal antigens are common in MS and AQP4‐seropositive NMO/NMO‐SD, especially in longitudinally extensive myelitis.
The epileptic aura in literature: Aesthetic and philosophical dimensions. An essay
Authors: Wolf Peter
Published: January 2013

In literary accounts of epilepsy the aura has a prominent place as the subjective aspect of the seizure experience. Descriptions by authors with their own aura experiences stand out by their precision and authenticity. Many different aura types are mentioned, but the ecstatic aura described by Dostoyevsky has received particular attention and is echoed in many later works. Some authors are interested primarily in the possibilities provided by auras to react, for example, by hiding, seeking help, counteracting the oncoming seizure, or taking measures to prevent damage. Others by their unique aura experiences are inspired to create specific literary flavors like oxymora, spectacular metaphors, or the depiction of complex perceptions and states of mind. Some authors, adding a philosophical dimension, proceed to analyze the consequences of patients’ subjective seizure experiences for their identity and their self‐perception as creative or religious persons. To sum up, the works discussed herein strongly support that literary texts provide valuable insights beyond those of medical texts.
Reduced default mode network connectivity in treatment‐resistant idiopathic generalized epilepsy
Authors: Kay Benjamin P. , DiFrancesco Mark W. , Privitera Michael D. , Gotman Jean , Holland Scott K. , Szaflarski Jerzy P.
Published: January 2013

Purpose

Idiopathic generalized epilepsy (IGE) resistant to treatment is common, but its neuronal correlates are not entirely understood. Therefore, the aim of this study was to examine resting‐state default mode network (DMN) functional connectivity in patients with treatment‐resistant IGE.

Methods

Treatment resistance was defined as continuing seizures despite an adequate dose of valproic acid (valproate, VPA). Data from 60 epilepsy patients and 38 healthy controls who underwent simultaneous electroencephalography (EEG) and resting‐state functional magnetic resonance imaging (fMRI) were included (EEG/fMRI). Independent component analysis (ICA) and dual regression were used to quantify DMN connectivity. Confirmatory analysis using seed‐based voxel correlation was performed.

Key Findings

There was a significant reduction of DMN connectivity in patients with treatment‐resistant epilepsy when compared to patients who were treatment responsive and healthy controls. Connectivity was negatively correlated with duration of epilepsy.

Significance

Our findings in this large sample of patients with IGE indicate the presence of reduced DMN connectivity in IGE and show that connectivity is further reduced in treatment‐resistant epilepsy. DMN connectivity may be useful as a biomarker for treatment resistance.
Increased excitability and molecular changes in adult rats after a febrile seizure
Authors: Reid Aylin Y. , Riazi Kiarash , Campbell Teskey G. , Pittman Quentin J.
Published: January 2013

Both early life inflammation and prolonged febrile seizures have been associated with increased excitation in the adult brain. We hypothesized this may be due in part to changes in the cation‐chloride cotransporter system. Rat pups received saline or lipopolysaccharide/kainic acid (LPS/KA) resulting in inflammation, followed by a behavioral febrile seizure (FS) in approximately 50% of rats. Adult animals from the saline, inflammation, or inflammation + FS groups underwent the following: (1) in vitro electrophysiologic studies; (2) Western blotting or polymerase chain reaction; or (3) application of the Na‐K‐Cl cotransporter 1 (NKCC1) blocker bumetanide to determine its effect on reversing increased excitability in vitro. The inflammation and inflammation + FS groups demonstrated increased excitability in vitro and increased hippocampal protein expression of NR2B and GABAA α5 receptor subunits and mRNA expression of NKCC1. The inflammation + FS group also had decreased protein expression of GluR2 and GABAA α1 receptor subunits and mRNA and protein expression of KCC2. Bumetanide decreased in vitro 4‐aminopyridine‐induced inter‐ictal activity in the inflammation and inflammation + FS groups. The results demonstrate early‐life inflammation with or without a behavioral FS can lead to long‐lasting molecular changes and increased excitability in the adult rat hippocampus, although some changes are more extensive when inflammation is accompanied by behavioral seizure activity. Bumetanide is effective in reversing increased excitability in vitro, providing evidence for a causal role for cation‐chloride cotransporters and suggesting this drug may prove useful for treating epilepsy that develops after a FS.
Down‐regulation of gephyrin and GABAA receptor subunits during epileptogenesis in the CA1 region of hippocampus
Authors: González Marco I. , Cruz Del Angel Yasmin , Brooks‐Kayal Amy
Published: January 2013

Purpose

Epileptogenesis is the process by which a brain becomes hyperexcitable and capable of generating recurrent spontaneous seizures. In humans, it has been hypothesized that following a brain insult there are a number of molecular and cellular changes that underlie the development of spontaneous seizures. Studies in animal models have shown that an injured brain may develop epileptiform activity before appearance of epileptic seizures and that the pathophysiology accompanying spontaneous seizures is associated with a dysfunction of γ‐aminobutyric acid (GABA)ergic neurotransmission. Here, we analyzed the effects of status epilepticus on the expression of GABAA receptors (GABAARs) and scaffolding proteins involved in the regulation of GABAAR trafficking and anchoring.

Methods

Western blot analysis was used to determine the levels of proteins involved in GABAAR trafficking and anchoring in adult rats subjected to pilocarpine‐induced status epilepticus (SE) and controls. Cell surface biotinylation using a cell membrane–impermeable reagent was used to assay for changes in the expression of receptors at the plasma membrane. Finally, immunoprecipitation experiments were used to evaluate the composition of GABAARs. We examined for a correlation between total GABAAR subunit expression, plasma membrane expression, and receptor composition.

Key Findings

Analysis of tissue samples from the CA1 region of hippocampus show that SE promotes a loss of GABAAR subunits and of the scaffolding proteins associated with them. We also found a decrease in the levels of receptors located at the plasma membrane and alterations in GABAAR composition.

Significance

The changes in protein expression of GABAARs and scaffolding proteins detected in these studies provide a potential mechanism to explain the deficits in GABAergic neurotransmission observed during the epileptogenic period. Our current observations represent an additional step toward the elucidation of the molecular mechanisms underlying GABAAR dysfunction during epileptogenesis.
Cognitive impairment and cortical reorganization in children with benign epilepsy with centrotemporal spikes
Authors: Datta Alexandre N. , Oser Nadine , Bauder Florian , Maier Oliver , Martin Florence , Ramelli Gian Paolo , Steinlin Maja , Weber Peter , Penner Iris‐Katharina
Published: January 2013

Purpose

Benign epilepsy with centrotemporal spikes (BECTS) is associated with mild cognitive deficits, especially language impairment. This study aimed to clarify whether children withBECTSwith left‐ or right‐hemispheric, or bilateral focus have specific neuropsychological language deficits when compared to healthy controls, whether these deficits correlate functionally with language network organization (typical vs. atypical), and whether cofactors such as duration, handedness, and medication have a relevant impact on language reorganization processes.

Methods

Twenty‐seven patients and 19 healthy controls were examined with several neuropsychological tests (German version of theWechsler Intelligence Scale for Children [WISC‐IV], Regensburger verbal fluency test [RWT], Corsiblock forward and backward andHand‐Dominanz‐Test [HDT]) and with two language paradigms on functional magnetic resonance imaging (fMRI):silent reading of word‐pairsandsilent generation of simple sentences.

Key Findings

Although neuropsychological test results only differed by trend betweenBECTSpatients and controls, language laterality indices (LIs) in fMRIwere significantly lower in patients than in controls. In particular, the anterior language network withBroca's area and the supplementary motor area (SMA) revealed the lowestLIs and showed the most bilateral or right hemispheric activations in the sentence generation task. Medication and duration of epilepsy did not have any significant effect on language reorganization and patients' performances.

Significance

Language reorganization inBECTSpatients takes place in bilateral or right hemispheric language networks, with a strong focus in anterior language regions. These functional changes can be interpreted as important compensatory strategies of the central nervous system (CNS) to stabilize cognitive, especially language performance.
Use of the modified Atkins diet for treatment of refractory childhood epilepsy: A randomized controlled trial
Authors: Sharma Suvasini , Sankhyan Naveen , Gulati Sheffali , Agarwala Anuja
Published: January 2013

Purpose

The aim of this study was to evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with refractory epilepsy.

Methods

Children aged 2–14 years who had daily seizures despite the appropriate use of at least three anticonvulsant drugs were enrolled. Children were randomized to receive either the modified Atkins diet or no dietary intervention for a period of 3 months. The ongoing anticonvulsant medications were continued unchanged in both the groups. Seizure control at 3 months was the primary end point. Analysis was intention to treat. Adverse effects of the diet were assessed by parental reports (ClinicalTrials.gov Identifier: NCT00836836).

Key Findings

Among a total of 102 children, 50 were in the diet group and 52 in the control group. Four children discontinued the diet before the study end point, and three children in the control group were lost to follow‐up. The mean seizure frequency at 3 months, expressed as a percentage of the baseline, was significantly less in the diet group: 59 ± 54 (95% confidence interval [CI] 44–74.5) versus 95.5 ± 48 (95% CI 82–109), p = 0.003. The proportion of children with >90% seizure reduction (30% vs. 7.7%, p = 0.005) and >50% seizure reduction was significantly higher in the diet group (52% vs. 11.5%, p < 0.001). Constipation was the most common adverse effect among children on the diet (23, 46%).

Significance

The modified Atkins diet was found to be effective and well tolerated in children with drug‐refractory epilepsy.
High‐frequency oscillations, extent of surgical resection, and surgical outcome in drug‐resistant focal epilepsy
Authors: Haegelen Claire , Perucca Piero , Châtillon Claude‐Edouard , Andrade‐Valença Luciana , Zelmann Rina , Jacobs Julia , Collins D. Louis , Dubeau François , Olivier André , Gotman Jean
Published: January 2013

Purpose

Removal of areas generating high‐frequency oscillations (HFOs) recorded from the intracerebral electroencephalography (iEEG) of patients with medically intractable epilepsy has been found to be correlated with improved surgical outcome. However, whether differences exist according to the type of epilepsy is largely unknown. We performed a comparative assessment of the impact of removing HFO‐generating tissue on surgical outcome between temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE). We also assessed the relationship between the extent of surgical resection and surgical outcome.

Methods

We studied 30 patients with drug‐resistant focal epilepsy, 21 with TLE and 9 with ETLE. Two thirds of the patients were included in a previous report and for these, clinical and imaging data were updated and follow‐up was extended. All patients underwent iEEG investigations (500 Hz high‐pass filter and 2,000 Hz sampling rate), surgical resection, and postoperative magnetic resonance imaging (MRI). HFOs (ripples, 80–250 Hz; fast ripples, >250 Hz) were identified visually on a 5–10 min interictal iEEG sample. HFO rates inside versus outside the seizure‐onset zone (SOZ), in resected versus nonresected tissue, and their association with surgical outcome (ILAE classification) were assessed in the entire cohort, and in the TLE and ETLE subgroups. We also tested the correlation of resected brain hippocampal and amygdala volumes (as measured on postoperative MRIs) with surgical outcome.

Key Findings

HFO rates were significantly higher inside the SOZ than outside in the entire cohort and TLE subgroup, but not in the ETLE subgroup. In all groups, HFO rates did not differ significantly between resected and nonresected tissue. Surgical outcome was better when higher HFO rates were included in the surgical resection in the entire cohort and TLE subgroup, but not in the ETLE subgroup. Resected brain hippocampal and amygdala volumes were not correlated with surgical outcome.

Significance

In TLE, removal of HFO‐generating areas may lead to improved surgical outcome. Less consistent findings emerge from ETLE, but these may be related to sample size limitations of this study. Size of resection, a factor that was ignored and that could have affected results of earlier studies did not influence results.
Siblings with refractory occipital epilepsy showing localized network activity on EEG‐fMRI
Authors: Carney Patrick W. , Harvey A. Simon , Berkovic Samuel F. , Jackson Graeme D. , Scheffer Ingrid E.
Published: January 2013

The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes; a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging (MRI). Electroencephalography (EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants.
Progressive fiber tract affections after temporal lobe surgery
Authors: Faber Jennifer , Schoene‐Bake Jan‐Christoph , Trautner Peter , von Lehe Marec , Elger Christian E. , Weber Bernd
Published: January 2013

Several studies reported changes in white matter architecture following temporal lobe surgery in patients with temporal lobe epilepsy (TLE) at short intervals after surgery. We investigated 20 patients with left‐sided TLE using diffusion‐imaging at two time points, that is, at 3–6 months and 12 months after surgery, to investigate postsurgical plasticity. We observed a loss of fiber tract integrity mainly in fiber tracts of the ipsilateral temporal lobe. Our data show that the remodeling of brain connectivity after surgical interventions continues for longer time periods. The functional implications of these plastic changes will have to be explored.