bluuebunny/crossref_metadata_2025 huggingface dataset:
Stalled replication fork repair and misrepair during thymineless death in Escherichia coli
Authors: Kuong Kawai J , Kuzminov Andrei
Published: May 2010

Starvation for DNA precursor dTTP, known as ‘thymineless death’ (TLD), kills bacterial and eukaryotic cells alike. Despite numerous investigations, toxic mechanisms behind TLD remain unknown, although wrong nucleotide incorporation with subsequent excision dominates the explanations. We show that kinetics of TLD in Escherichia coli is not affected by mutations in DNA repair, ruling out excision after massive misincorporation as the cause of TLD. We found that the rate of DNA synthesis in thymine‐starved cells decreases exponentially, indicating replication fork stalling. Processing of stalled replication forks by recombinational repair is known to fragment the chromosome, and we detect significant chromosomal fragmentation during TLD. Moreover, we report that, out of major recombinational repair functions, only inactivation of recF and recO relieves TLD, identifying the poisoning mechanism. Inactivation of recJ and rep has slight effect, while the recA, recBC, ruvABC, recG and uvrD mutations all accelerate TLD, identifying the protection mechanisms. Our epistatic analysis argues for two distinct pathways protecting against TLD: RecABCD/Ruv repairs the double‐strand breaks, whereas UvrD counteracts RecAFO‐catalyzed toxic single‐strand gap processing.
Salicylic acid treatment via the rooting medium interferes with stomatal response, CO2 fixation rate and carbohydrate metabolism in tomato, and decreases harmful effects of subsequent salt stress
Authors: Poór P. , Gémes K. , Horváth F. , Szepesi Á. , Simon M. L. , Tari I.
Published: May 2010

Salicylic acid (SA) applied at 10−3 m in hydroponic culture decreased stomatal conductance (gs), maximal CO2 fixation rate (Amax) and initial slopes of the CO2 (A/Ci) and light response (A/PPFD) curves, carboxylation efficiency of Rubisco (CE) and photosynthetic quantum efficiency (Q), resulting in the death of tomato plants. However, plants could acclimate to lower concentrations of SA (10−7−10−4 m) and, after 3 weeks, returned to control levels of gs, photosynthetic performance and soluble sugar content. In response to high salinity (100 mm NaCl), the pre‐treated plants exhibited higher Amax as a function of internal CO2 concentration (Ci) or photosynthetic photon flux density (PPFD), and higher CE and Q values than salt‐treated controls, suggesting more effective photosynthesis after SA treatment. Growth in 10−7 or 10−4 m SA‐containing solution led to accumulation of soluble sugars in both leaf and root tissues, which remained higher in both plant parts during salt stress at 10−4 m SA. The activity of hexokinase (HXK) with glucose, but not fructose, as substrate was reduced by SA treatment in leaf and root samples, leading to accumulation of glucose and fructose in leaf tissues. HXK activity decreased further under high salinity in both plant organs. The accumulation of soluble sugars and sucrose in roots of plants growing in the presence of 10−4 m SA contributed to osmotic adjustment and improved tolerance to subsequent salt stress. Apart from its putative role in delaying senescence, decreased HXK activity may divert hexoses from catabolic reactions to osmotic adaptation.
Expression and Activity of Matrix Metalloproteinases in the Uterus of Bitches After Spontaneous and Induced Abortion
Authors: Kanca H , Walter I , Miller I , Schäfer‐Somi S , Izgur H. , Aslan S
Published: May 2010

Contents

Aim of this study was to determine the intrauterine activity of matrix metalloproteinases (MMP)‐2 and ‐9 after cessation of the local effect of progesterone. For this purpose, pregnancy was terminated in 10 bitches at mid‐gestation with the progesterone receptor antagonist aglepristone (10 mg/kg body weight, sc, Alizine®; Virbac, France) at two subsequent days (group IRA = induced resorption/abortion). The IRA group was divided into two subgroups (Group I, n = 5, days 25–35 of pregnancy; group II, n = 5, days 36–45). Five further bitches were introduced with beginning abortion (group SRA = spontaneous resorption/abortion). Seven healthy bitches between day 25 and 45 of gestation served as controls. After ovariohysterectomy at the end of abortion and between days 25 and 45 of gestation, respectively, the distribution and activity of collagenases were investigated by immunohistochemistry and gelatin zymography. At placental sites, MMP‐2 activity in the endometrium was significantly lower in IRA groups than in the SRA group (33.7 ± 11.8% and 39.3 ± 5.4% vs 52.2 ± 10.2%, p < 0.05); however, MMP‐2 expression was lowest in the control group (control: 21.4 ± 6.3%; p < 0.01) and similarly in the myometrium (controls: 13.1 ± 2.5%; p < 0.05). MMP‐9 activity was also lower in the endometrium and myometrium of the control group in comparison to SRA and IRA groups (11.8 ± 3.2%; p < 0.01 and 28.4 ± 32.8%; p < 0.05). At interplacental sites, the amount of active collagenases in the myometrium was significantly lower in the control group. It is concluded that the blockade of the biological progesterone effect was associated with an increase in activity of both collagenases.
Assessment of Actin Cytoskeleton and Nuclei in Bovine Blastocysts Developed Under Different Culture Conditions Using a Novel Computer Program
Authors: Kuzmany A , Havlicek V , Brem G , Walter I , Besenfelder U
Published: May 2010

Contents

This study was performed to investigate the effects, in terms of nuclear material and actin cytoskeleton quantities (fluorescent pixel counts), of four different bovine blastocyst culturing techniques (in vitro, stepwise in vitro‐to‐in vivo, or purely in vivo). Cumulus oocyte complexes from abattoir‐sourced ovaries were matured in vitro and allocated to four groups: IVP‐group embryos developed up to blastocyst stage in vitro. Gamete intra‐fallopian transfer (GIFT)‐group oocytes were co‐incubated with semen for 4 h before transfer to oviducts of heifers. Following in vitro fertilization, cleaved embryos (day 2 of embryo development, day 2–7 group) were transferred into oviducts on day 2. Multiple ovulation embryo transfer (MOET)‐group embryos were obtained by superovulating and inseminating heifers; the heifers’ genital tracts were flushed at day 7 of blastocyst development. Within each group, ten blastocysts were selected to be differentially dyed (for nuclei and actin cytoskeleton) with fluorescent stains. A novel computer program (ColorAnalyzer) provided differential pixel counts representing organelle quantities. Blastocysts developed only in vivo (MOET group) showed significantly more nuclear material than did blastocysts produced by any other technique. In terms of actin cytoskeleton quantity, blastocysts produced by IVP and by day 2–7 transfer did not differ significantly from each other. Gamete intra‐fallopian transfer‐ and MOET‐group embryos showed significantly larger quantities of actin cytoskeleton when compared with any other group and differed significantly from each other. The results of this study indicate that culturing under in vitro conditions, even with part time in vivo techniques, may adversely affect the quantity of blastocyst nuclear material and actin cytoskeleton. The software employed may be useful for culture environment evaluation/developmental competence assessment.
Early Development and Putative Primordial Germ Cells Characterization in Dogs
Authors: Martins DS , Ambrósio CE , Saraiva NZ , Wenceslau CV , Morini AC , Kerkis I , Garcia JM , Miglino MA
Published: May 2010

Contents

Previously, three distinct populations of putative primordial germ cells (PGCs), namely gonocytes, intermediate cells and pre‐spermatogonia, have been described in the human foetal testis. According to our knowledge, these PGCs have not been studied in any other species. The aim of our study was to identify similar PGC populations in canine embryos. First, we develop a protocol for canine embryo isolation. Following our protocol, 15 canine embryos at 21–25 days of pregnancy were isolated by ovaryhysterectomy surgery. Our data indicate that dramatic changes occur in canine embryo development and PGCs specification between 21 to 25 days of gestation. At that moment, only two PGC populations with distinct morphology can be identified by histological analyses. Cell population 1 presented round nuclei with prominent nucleolus and a high nuclear to cytoplasm ratio, showing gonocyte morphology. Cell population 2 was often localized at the periphery of the testicular cords and presented typical features of PGC. Both germ cell populations were positively immunostained with anti‐human OCT‐4 antibody. However, at day 25, all cells of population 1 reacted positively with OCT‐4, whereas in population 2, fewer cells were positive for this marker. These two PGCs populations present morphological features similar to gonocytes and intermediate cells from human foetal testis. It is expected that a population of pre‐spermatogonia would be observed at later stages of canine foetus development. We also showed that anti‐human OCT‐4 antibody can be useful to identify canine PGC in vivo.
Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone‐releasing hormone‐agonist therapy for prostate cancer
Authors: Taxel Pamela , Dowsett Robert , Richter Lee , Fall Pamela , Klepinger Alison , Albertsen Peter
Published: May 2010

Study Type – Therapy (RCT) Level of Evidence 1b

OBJECTIVE

To determine whether increased bone loss and bone turnover during the first 6 months of therapy for prostate cancer with luteinizing hormone‐releasing hormone (LHRH)‐agonist therapy could be prevented by bisphosphonate therapy with risedronate 35 mg/week, as prostate cancer is commonly treated with LHRH agonists and this often leads to rapid bone loss within the first 6 months of therapy.

PATIENTS AND METHODS

A 6‐month randomized, double‐blind, placebo‐controlled trial was conducted, including 40 men aged ≥55 years receiving LHRH‐agonist treatment for 6 months for locally advanced prostate cancer. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip was measured every 6 months. In addition, bone turnover markers including N‐telopeptide, serum C‐telopeptide and procollagen peptide, and 25‐OH vitamin D and intact parathyroid hormone were measured at baseline and at 6 months.

RESULTS

After 6 months of LHRH‐agonist therapy, the control group had a significant decline at the spine and hip BMD sites; however, the risedronate group had no bone loss at the hip and an increase at the lumber spine. Markers of bone turnover were increased significantly in the control group but unchanged in the risedronate group.

CONCLUSIONS

LHRH‐agonist treatment for locally advanced prostate cancer produces increased bone turnover and rapid bone loss within the initial 6 months of therapy, and this can be prevented by weekly risedronate treatment.
Changes in pulse pressure, heart rate and the pulse pressure × heart rate product during squatting in Type 1 diabetes according to age
Authors: Philips J.‐C. , Marchand M. , Scheen A. J.
Published: May 2010

Diabet. Med. 27, 753–761 (2010)

Aims  We assessed changes in pulse pressure and heart rate during a squatting test, as indirect markers of arterial stiffness and cardiovascular autonomic neuropathy, respectively, according to age and sex in patients with Type 1 diabetes mellitus.

Methods  We evaluated 160 diabetic patients, divided into four groups of 20 men and 20 women according to age (G1, 20–30 years old; G2, 31–40 years old; G3, 41–50 years old; and G4, 51–60 years old), and 160 non‐diabetic matched control subjects. Each subject underwent a 3 min posture test (standing–squatting–standing) with continuous measurement of arterial blood pressure and heart rate by a Finapres® device. Overall values throughout the test, baseline levels in initial standing position and squatting‐induced changes in pulse pressure, heart rate and the pulse pressure × heart rate product were compared between diabetic patients and healthy control subjects.

Results  In the standing position, a greater increase in pulse pressure and lower reduction in heart rate with age led to a significantly higher pulse pressure × heart rate product in diabetic patients compared with control subjects. In the squatting position, a more marked pulse pressure increase in the absence of appropriate reduction in heart rate resulted in a greater rise in the pulse pressure × heart rate product in diabetic patients than in healthy subjects. No major differences were noted between the sexes, with the exception of a stronger relationship between pulse pressure and age in the female population with diabetes. Squatting‐derived indices of cardiovascular autonomic neuropathy were also noted with increasing age in diabetic patients.

Conclusions  The marked increase in the pulse pressure × heart rate product (‘pulsatile stress’) according to age, combined with cardiovascular autonomic neuropathy, may contribute to the higher cardiovascular risk of patients with Type 1 diabetes.
Triggering mechanisms of neuroarthropathy following conservative surgery for osteomyelitis
Authors: Aragón‐Sánchez J. , Lázaro‐Martínez J. L. , Hernández‐Herrero M. J.
Published: May 2010

Diabet. Med. 27, 844–847 (2010)

Background  The purpose of this study was to raise awareness and stimulate discussion of the possible triggering factors of Charcot neuroarthropathy by presenting the case of one patient who had both undergone surgery and was suffering from osteomyelitis.

Case report  We have extracted one case from our data set for a patient who underwent conservative surgery for osteomyelitis and subsequently developed acute Charcot in the midfoot. We present the clinical findings, photographs and X‐ray studies. Preoperative X‐ray showed irregular severe bone destruction in the fourth metatarsal head and a fracture of the fourth metatarsal bone. No signs of midfoot Charcot neuroarthropathy were found in this preoperative X‐ray. The third and fourth metatarsal bones were both removed and the surgical wound was left open to heal by second intention. Histopathological study confirmed osteomyelitis in the bone sample. Twenty‐five days after surgery, the surgical wound showed no signs of infection and healing progressed in a satisfactory way. However, the foot was swollen, erythematous and warm. Skin temperature was two degrees higher than the contralateral foot. X‐ray was taken and acute neuroarthropathy of the tarso‐metatarsal joints was diagnosed.

Conclusions  Charcot neuroarthropathy appears to have been triggered by bone infection and/or surgery. We believe that the pivotal factor in the development of acute Charcot neuroarthropathy in this case was the weight bearing in the deformed foot so soon after the operation. Immobilization of the foot is critical as it serves to decrease the inflammation which has a key role in the development of Charcot neuroarthropathy.
The New Political Role of Business in a Globalized World: A Review of a New Perspective on CSR and its Implications for the Firm, Governance, and Democracy
Authors: Scherer Andreas Georg , Palazzo Guido
Published: May 2010

abstract

Scholars in management and economics widely share the assumption that business firms focus on profits only, while it is the task of the state system to provide public goods. In this view business firms are conceived of as economic actors, and governments and their state agencies are considered the only political actors. We suggest that, under the conditions of globalization, the strict division of labour between private business and nation‐state governance does not hold any more. Many business firms have started to assume social and political responsibilities that go beyond legal requirements and fill the regulatory vacuum in global governance. Our review of the literature shows that there are a growing number of publications from various disciplines that propose a politicized concept of corporate social responsibility. We consider the implications of this new perspective for theorizing about the business firm, governance, and democracy.
Resampling Strategies for Deforming MLS Surfaces
Authors: Gois João Paulo , Buscaglia Gustavo C.
Published: May 2010

Moving‐least‐squares (MLS) surfaces undergoing large deformations need periodic regeneration of the point set (point‐set resampling) so as to keep the point‐set density quasi‐uniform. Previous work by the authors dealt with algebraic MLS surfaces, and proposed a resampling strategy based on defining the new points at the intersections of the MLS surface with a suitable set of rays. That strategy has very low memory requirements and is easy to parallelize. In this article new resampling strategies with reduced CPU‐time cost are explored. The basic idea is to choose as set of rays the lines of a regular, Cartesian grid, and to fully exploit this grid: as data structure for search queries, as spatial structure for traversing the surface in a continuation‐like algorithm, and also as approximation grid for an interpolated version of the MLS surface. It is shown that in this way a very simple and compact resampling technique is obtained, which cuts the resampling cost by half with affordable memory requirements.
Gross muscle morphology and structure in spastic cerebral palsy: a systematic review
Authors: BARRETT ROD S , LICHTWARK GLEN A
Published: May 2010

Aim  This systematic review and critical evaluation of the literature was conducted to determine how gross muscle morphology and structure are altered in individuals with spastic cerebral palsy (CP).

Method  Electronic databases were searched for articles describing studies of muscle morphological and structural properties in individuals with spastic CP. Data describing muscle fascicle length, belly length, fascicle angle, cross‐sectional area, volume, and thickness were extracted and effect sizes were computed for comparisons between individuals with spastic CP and typically developed individuals, between the paretic and non‐paretic side in individuals with hemiplegia for all muscles examined, and across the full spectrum of gross motor function in individuals with spastic CP.

Results  The final yield consisted of 15 articles that met the inclusion criteria. The main finding of the review was the consistent evidence for reduced muscle belly length, muscle volume, cross‐sectional area, and muscle thickness in the comparisons between paretic and typically developed muscle and the paretic and non‐paretic muscle across a range of muscles.

Interpretation  Given the importance of muscle morphology and structure for generating muscle force, it is likely that the observed alterations that occur secondary to the neural lesion in individuals with spastic CP contribute to muscle weakness and the attendant loss of motor function in spastic CP.
PKC links Gq‐coupled receptors to DAT‐mediated dopamine release
Authors: Opazo Felipe , Schulz Jörg B. , Falkenburger Björn H.
Published: May 2010

J. Neurochem.(2010)114, 587–596.

The dopamine transporter (DAT) mediates dopamine uptake in many brain areas and has been suggested to underlie dopamine release in the substantia nigra pars reticulata. This release modulates basal ganglia output and motor performance. It is triggered by glutamatergic subthalamic afferents. We show here that activation of (Gq‐coupled) group I metabotropic glutamate receptors are sufficient to induce dopamine release in rat substantia nigra pars reticulata slices. Release was measured by amperometry and inhibited by a DAT antagonist. In a DAT‐expressing cell line, dopamine release could be induced by activation of Gq‐coupled muscarinic receptors. Release was measured by HPLC and inhibited by a DAT antagonist. In both paradigms, activation of protein kinase C (PKC) was necessary and sufficient for dopamine release, suggesting that Gq‐coupled receptors can induce DAT‐mediated dopamine release through PKC, and providing a physiological role for the known regulation of DAT‐mediated release by PKC. Activation of muscarinic receptors and PKC also induced release from a cell line expressing the norepinephrine transporter, suggesting that transport‐mediated release might be relevant in further brain areas.
Mechanisms underlying striatal vulnerability to 3‐nitropropionic acid
Authors: Herrera‐Mundo Nieves , Sitges María
Published: May 2010

J. Neurochem.(2010)114, 597–605.

The striatum is a cerebral structure particularly susceptible to the metabolic challenge exerted by 3‐nitropropionic acid (3‐NPA), a toxin that inhibits the respiratory chain at complex II. The striatum, which receives the nerve endings of the nigro‐striatal pathway, concentrates the largest amount of 3,4‐dihydroxyphenylethylamine or dopamine (DA) in the brain. DA is metabolized to 3,4‐dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO), an enzyme that contains a redox‐active disulfide in the active site. In striatum isolated nerve endings exposed to 3‐NPAin vitro, DA increased and DOPAC decreased already after 10 min, and after 2 h also an increase in reactive oxygen species and DA‐quinone products formation was detected. These 3‐NPA‐induced effects resulted in an increase in DA release after 2 h. In striatum homogenates from animals presenting motor disturbances in response to 3‐NPAin vivo,the DA metabolites homovanillic acid and DOPAC were increased. It is concluded that in the striatum nerve endings where DA is particularly concentrated, the increase in reactive oxygen species induced by 3‐NPA, oxidizes DA generating DA‐quinones. These DA‐quinones may form adducts with the active site of MAO type A reducing its activity. The DA not metabolized to DOPAC is both, used to unchain generation of more of the harmful DA‐oxidation products and released to the external medium, where is metabolized by the non‐neuronal enzymes MAO type B and catechol‐O‐methyltransferase.
GABA modulates development of cerebellar Purkinje cell dendrites under control of endocannabinoid signaling
Authors: Kawaguchi Koji , Habara Tomomi , Terashima Toshio , Kikkawa Satoshi
Published: May 2010

J. Neurochem. (2010) 114, 627–638.

Purkinje cells (PCs) are the sole projection neurons in the cerebellar cortex with highly arborized dendrites, on which they receive glutamatergic and GABAergic inputs. Whereas influences of glutamatergic inputs on dendritic development of PCs have been well studied, those of GABA remain elusive. Here we examined effects of GABAergic signaling on dendritogenesis of PCs in dissociated cerebellar cultures. Treatment with GABAA agonists such as muscimol altered Purkinje dendrites to longer and less branched morphology, while GABAA antagonists resulted in shorter dendrites. In contrast, neither a GABAB agonist nor antagonist had major effects on dendritic morphology. Simultaneous addition of a glutamatergic antagonist cocktail or the Trk receptor antagonist K252a did not block muscimol. Furthermore, blockade of endocannabinoid signaling by either AM251 or tetrahydrolipstatin resulted in longer and less branched dendrites similar to those treated with GABAA agonists suggesting upstream regulation by endocannabinoids. Notably, whereas Purkinje dendrites extended in random directions in the presence of muscimol, they oriented to coexisting GABAergic interneurons when treated with AM251. Taken together, our results postulate the hypothesis that GABA released from the cerebellar interneurons modulates dendritogenesis of PCs in an endocannabinoid‐dependent manner in the developing cerebellar cortex.
The major determinant of exendin‐4/glucagon‐like peptide 1 differential affinity at the rat glucagon‐like peptide 1 receptor N‐terminal domain is a hydrogen bond from SER‐32 of exendin‐4
Authors: Mann RJ , Nasr NE , Sinfield JK , Paci E , Donnelly D
Published: May 2010

BACKGROUND AND PURPOSE

Exendin‐4 (exenatide, Ex4) is a high‐affinity peptide agonist at the glucagon‐like peptide‐1 receptor (GLP‐1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP‐1 and Ex4 bound to the isolated N‐terminal domain (NTD) of GLP‐1R. However, these structures do not account for the large difference in affinity between GLP‐1 and Ex4 at this isolated domain, or for the published role of the C‐terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP‐1R in the context of these new structural data.

EXPERIMENTAL APPROACH

The affinities of GLP‐1, Ex4 and various analogues were measured at human and rat GLP‐1R (hGLP‐1R and rGLP‐1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data.

KEY RESULTS

The membrane‐tethered NTD of hGLP‐1R displayed similar affinity for GLP‐1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP‐1R for Ex4(9–39) over Ex4(9–30) was due to Ser‐32 in the ligand. While this selectivity was not observed at hGLP‐1R, it was regained when Glu‐68 of hGLP‐1R was mutated to Asp.

CONCLUSIONS AND IMPLICATIONS

GLP‐1 and Ex4 bind to the NTD of hGLP‐1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp‐68 of rGLP‐1R, which is not formed with Glu‐68 of hGLP‐1R, is responsible for the improved affinity of Ex4 at the rat receptor.
Long‐term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome
Authors: Liukkonen Elina , Kantola‐Sorsa Elisa , Paetau Ritva , Gaily Eija , Peltola Maria , Granström Marja‐Liisa
Published: May 2010

Purpose:  To prospectively evaluate the efficacy of drug treatment and long‐term cognitive outcome in children with encephalopathy with status epilepticus during sleep (ESESS).

Methods:  Thirty‐two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty‐seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients.

Results:  Six children had atypical rolandic (AR) epilepsy, nine Landau‐Kleffner syndrome (LKS), and 17 symptomatic epilepsy. Before ESESS, 20 children were cognitively normal. Prospective treatment with VPA and ESM was effective in 3 of the 17 children (18%) treated. Abolition of SES with drug treatment was observed in 16 patients. In all, 10 children (31%), 4 with AR (67%), 3 with LKS (33%), and 3 with symptomatic etiology (19%), including 9 with treatment response regained the pre‐ESESS cognitive level. Unfavorable cognitive outcome was predicted by younger age at ESESS diagnosis, lower IQ at the time of the diagnosis, and no response to drug treatment when compared with those with favorable cognitive outcome. Eight of the 16 nonresponders underwent epilepsy surgery.

Discussion:  Treatment response with VPA combined with ESM was observed more often than with other drug combinations. Most children with ESESS experienced permanent cognitive impairment. Cognitive outcome depends on treatment response on electroencephalography (EEG) and seizures, and on underlying etiology.
Successful epilepsy surgery in a patient with neurosarcoidosis
Authors: Malmgren Kristina , Lycke Jan , Engman Elisabeth , Hedström Anders , Jönsson Lars , Rydenhag Bertil , Nordborg Claes
Published: May 2010

This case concerns a patient with generalized neurosarcoidosis and pharmacoresistant focal epilepsy. Although immunosuppressive therapy resulted in remission of the neurosarcoidosis, seizures continued and were shown to originate from the right temporal lobe (TL). The patient underwent a right anterior temporal lobe resection (TLR) and obtained >90% reduction of seizure frequency.
Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: A common mechanism?
Authors: Bisulli Francesca , Vignatelli Luca , Naldi Ilaria , Licchetta Laura , Provini Federica , Plazzi Giuseppe , Di Vito Lidia , Ferioli Simona , Montagna Pasquale , Tinuper Paolo
Published: May 2010

Purpose:  Retrospective observations disclosed an overlap between parasomnias and nocturnal frontal lobe epilepsy (NFLE) not only in patients but also in their relatives, suggesting a possible common pathogenetic mechanism. This study aimed to verify whether relatives of patients with NFLE have a higher frequency of parasomnias, namely arousal disorders, and thereby shed light on the still unknown pathophysiologic mechanisms underlying NFLE.

Methods:  We undertook a case–control family study in which we recruited NFLE probands and healthy controls, matched for age, sex, education, and geographic origin. At least four relatives were included for each proband and control. Each subject underwent a standardized interview, with application of the International Classification of Sleep Disorders–Revised (ICSD‐R 2001) minimal criteria to diagnose the lifetime prevalence of the main parasomnias.

Results:  Four hundred fifty‐eight individuals were recruited: 33 NFLE probands, 200 relatives of probands, 31 controls, and 194 control relatives. All NFLE probands but one have sporadic NFLE. The lifetime prevalence of the following parasomnias differed in proband relatives versus control relatives: arousal disorders [odds ratio (OR) 4.7, 95% confidence interval (CI) 2.0–11.6; p < 0.001] and nightmares (OR 2.6, 95% CI 1.6–4.2; p < 0.001) were more frequent among NFLE proband relatives. In the secondary analysis comparing NFLE probands to controls, arousal disorders (OR 6.3, 95% CI 1.3–31.7; p = 0.023) and bruxism (OR 5.4, 95% CI 1.3–21.7; p = 0.017) were more frequent among NFLE probands.

Discussion:  The higher frequency of arousal disorders in NFLE families suggests an intrinsic link between parasomnias and NFLE and an abnormal (possibly cholinergic) arousal system as a common pathophysiologic mechanism.
Anxiety disorders, subsyndromic depressive episodes, and major depressive episodes: Do they differ on their impact on the quality of life of patients with epilepsy?
Authors: Kanner Andres M. , Barry John J. , Gilliam Frank , Hermann Bruce , Meador Kimford J.
Published: May 2010

Aims of the study:  To compare the impact of anxiety disorders, major depressive episodes (MDEs), and subsyndromic depressive episodes (SSDEs) on the quality of life of patients with epilepsy (PWEs), and to identify the variables predictive of poor quality of life.

Methods:  A psychiatric diagnosis according to DSM‐IV‐TR criteria was established in 188 consecutive PWEs with the MINI International Neuropsychiatric Interview. Patients also completed the Beck Depression Inventory‐II (BDI‐II), the Centers for Epidemiologic Studies‐Depression (CES‐D), and the Quality of Life in Epilepsy‐89 (QOLIE‐89). A diagnosis of SSDE was made in any patient with total scores of the BDI‐II >12 or CES‐D >16 in the absence of any DSM‐IV diagnosis of mood disorder according to the MINI.

Results:  Patients with SSDEs (n = 26) had a worse quality of life than asymptomatic patients (n = 103). This finding was also observed among patients with MDEs only (n = 10), anxiety disorders only (n = 21), or mixed MDEs/anxiety disorders (n = 28). Furthermore, having mixed SSDEs/anxiety disorders yielded a worse quality of life than having only SSDEs. Independent predictors of poor quality of life included having a psychiatric disorder and persistent epileptic seizures in the last 6 months.

Conclusions:  Although isolated mood and anxiety disorders, including SSDE, have a comparable negative impact on the quality of life of PWEs; the comorbid occurrence of mood and anxiety disorders yields a worse impact. In addition, seizure freedom in the previous 6 months predicts a better quality of life.
Densities of glutamatergic and GABAergic presynaptic terminals are altered in experimental cortical dysplasia
Authors: Zhou Fu‐Wen , Roper Steven N.
Published: May 2010

Purpose:  Cortical dysplasia (CD) is a major cause of epilepsy in children and adults, but underlying mechanisms of epileptogenesis in this disorder are poorly understood. We have utilized the irradiated rat model to study an injury‐based form of diffuse CD in rats. Prior studies in this model have shown reduced numbers of γ‐aminobutyric acid (GABA)ergic interneurons and reduced inhibitory synaptic currents in pyramidal cells in CD. We analyzed the number of excitatory and inhibitory presynaptic terminals in the neocortex of irradiated rats to better characterize altered connectivity in experimental CD.

Methods:  Antibodies to vesicular glutamate transporter 1 (VGLUT1), vesicular glutamate transporter 2 (VGLUT2), vesicular GABA transporter (VGAT), and parvalbumin (PV) were used to quantify glutamatergic and GABAergic presynaptic terminals in control and dysplastic cortex.

Results:  We found that the density of VGLUT1 terminals was increased in CD in comparison to layers IV, V, and VI in control cortex. VGLUT2 terminals were increased in CD compared to layers IV and VI. VGAT terminals were reduced in CD compared to layers II/III, IV, and V in controls as were PV‐immunoreactive somata and terminals.

Discussion:  These findings suggest an overall increase in excitatory synaptic connectivity and decrease in inhibitory synaptic connectivity in CD in irradiated rat. We propose that these changes contribute to hyperexcitability in these animals and may contribute to epileptogenicity in some forms of human CD.
Modulating P‐glycoprotein regulation: Future perspectives for pharmacoresistant epilepsies?
Authors: Potschka Heidrun
Published: May 2010

Enhanced brain efflux of antiepileptic drugs by the blood–brain barrier transporter P‐glycoprotein is discussed as one mechanism contributing to pharmacoresistance of epilepsies. P‐glycoprotein overexpression has been proven to occur as a consequence of seizure activity. Therefore, blocking respective signaling events should help to improve brain penetration and efficacy of P‐glycoprotein substrates. A series of recent studies revealed key signaling factors involved in seizure‐associated transcriptional activation of P‐glycoprotein. These data suggested several interesting targets, including theN‐methyl‐d‐aspartate (NMDA) receptor, the inflammatory enzyme cyclooxygenase‐2, and the prostaglandin E2 EP1 receptor. These targets have been further evaluated in rodent models, demonstrating that targeting these factors can control P‐glycoprotein expression, improve antiepileptic drug brain penetration, and help to overcome pharmacoresistance. In general, the approach offers particular advantages over transporter inhibition as it preserves basal transporter function. In this review the different strategies for blocking P‐glycoprotein upregulation, including their therapeutic promise and drawbacks are discussed. Moreover, pros and cons of the approach are compared to those of alternative strategies to overcome transporter‐associated resistance. Regarding future perspectives of the novel approach, there is an obvious need to more clearly define the clinical relevance of transporter overexpression. In this context current efforts are discussed, including the development of imaging tools that allow an evaluation of P‐glycoprotein function in individual patients.
Infantile spasms treated with the ketogenic diet: Prospective single‐center experience in 104 consecutive infants
Authors: Hong Amanda M. , Turner Zahava , Hamdy Rana F. , Kossoff Eric H.
Published: May 2010

Purpose:  In 2002, we reported our preliminary experience using the ketogenic diet (KD) for predominantly intractable infantile spasms (IS) in 23 infants. Since that time, we have increased our use of the KD for this condition including those with new‐onset IS.

Methods:  Infants were referred and prospectively started on the traditional KD from 1996 to 2009 at our institution. Included subjects had documented clinical IS, hypsarrhythmia on electroencephalography (EEG), and parental consent to start the KD. Efficacy was assessed through phone communication, clinic visits, and EEG every 3 months.

Results:  One hundred four infants, mean age 1.2 years, were started on the KD for IS, of which 74 (71%) had a symptomatic etiology. Previous therapy for this patients included a mean of 3.6 anticonvulsants; 71% including corticosteroids or vigabatrin. Using an intent‐to‐treat analysis, >50% spasm improvement occurred in 64% at 6 months and 77% after 1–2 years. Thirty‐eight (37%) became spasm‐free for at least a 6‐month period within a median 2.4 months of starting the KD. In addition, 62% reported improvement in development, 35% had EEG improvement, and 29% were able to reduce concurrent anticonvulsants. Adverse effects were noted in 33%, of which 6% had diminished linear growth. Older age at onset of IS and fewer prior anticonvulsants were more likely to be associated with >90% spasm improvement at 6 months.

Discussion:  The KD is an efficacious therapy for IS in approximately two‐thirds of patients treated, and it should be considered strongly after failure of corticosteroids and vigabatrin.
Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy
Authors: Zhang Chunbo , Wong Virgina , Ng Ping Wing , Lui Colin Hiu Tung , Sin Ngai Chuen , Wong Ka Sing , Baum Larry , Kwan Patrick
Published: May 2010

A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese.
CHARACTERIZATION AND EXPRESSION OF NUCLEAR‐ENCODED POLYKETIDE SYNTHASES IN THE BREVETOXIN‐PRODUCING DINOFLAGELLATE KARENIA BREVIS1
Authors: Monroe Emily A. , Johnson Jillian G. , Wang Zhihong , Pierce Richard K. , Van Dolah Frances M.
Published: May 2010

The dinoflagellate Karenia brevis (C. C. Davis) Gert Hansen et Moestrup produces a suite of brevetoxins, potent neurotoxins that have adverse effects on marine animal and human health. Brevetoxins are polyketides proposed to be synthesized by polyketide synthases (PKSs), and genes for type I PKSs have been predicted by PCR and transcript analysis. However, the full‐length transcripts in K. brevis predict an unusual protein structure for type I PKS in that individual transcripts encode for single catalytic domains. In this study, we developed peptide antibodies to in silico translated transcripts for two PKS proteins to characterize their expression and localization. Immunoreactive proteins identified by Western blotting at 40 kDa (KR domain) and 100 kDa (KS domain) are consistent with the sizes predicted by the full‐length transcripts. Immunolocalization and Western blot analysis indicate that these PKSs are associated with the chloroplasts. In order to establish evidence for a role in brevetoxin biosynthesis, PKS transcript and protein levels were examined in a “nontoxic”K. brevis substrain and its parental toxic isolate, K. brevis Wilson. DNA microarray analysis of the global transcript profiles in the “nontoxic” isolate showed that ∼7% of transcripts were differentially expressed, including photosystem genes; however, no difference was observed in PKS transcript abundance. By contrast, KS domain proteins were 55%–70% less abundant in “nontoxic”K. brevis cultures compared to toxic cultures. This finding suggests that K. brevis PKS expression is regulated posttranscriptionally, like many other processes in dinoflagellates. Further, the decrease in PKS protein abundance in the “nontoxic” cultures provides correlative evidence for their involvement in brevetoxin biosynthesis.
Effective reduction of transfusion‐related acute lung injury risk with male‐predominant plasma strategy in the American Red Cross (2006‐2008)
Authors: Eder Anne F. , Herron Jr Ross M. , Strupp Annie , Dy Beth , White Jenni , Notari Edward P. , Dodd Roger Y. , Benjamin Richard J.
Published: May 2010

BACKGROUND:Plasma components from female donors were responsible for most cases of transfusion‐related acute lung injury (TRALI) reported to the American Red Cross (ARC) between 2003 and 2005. Consequently, we began preferentially distributing plasma from male donors for transfusion in 2006 and evaluated the effect on reported TRALI cases in the ensuing 2 years.

STUDY DESIGN AND METHODS:Suspected TRALI cases reported to the ARC Hemovigilance Program in calendar years (CY) 2006, 2007, and 2008 are described. Any case involving a fatality was also independently reviewed by three ARC physicians and classified as probable TRALI or not TRALI.

RESULTS:The percentage of plasma collected from male donors and distributed for transfusion increased each year from 55% in CY2006 to 79% in CY2007 and 95% in CY2008. Independent medical review of the 77 reported TRALI cases involving a fatality identified 38 cases as probable TRALI. Plasma was the only component transfused in six of these cases in 2006, five in 2007, and zero in 2008. Overall, the analysis of reported fatalities and nonfatal cases demonstrates that TRALI involving only plasma transfusion was significantly reduced in 2008 compared to 2006 (32 vs. 7 cases; odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08‐0.45), to a level that was no longer different from the rate of TRALI observed for RBC transfusion (4.0 vs. 2.3 per 106distributed components; OR = 1.78; 95% CI = 0.67‐4.36).

CONCLUSIONS:Reported TRALI cases from plasma transfusion decreased in 2008 compared to the prior 2 years simultaneously with the conversion to male‐predominant plasma for transfusion.
Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients
Authors: Gauvin France , Spinella Philip C. , Lacroix Jacques , Choker Ghassan , Ducruet Thierry , Karam Oliver , Hébert Paul C. , Hutchison James S. , Hume Heather A. , Tucci Marisa ,   on behalf of the Canadian Critical Care Trials Group and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: May 2010

BACKGROUND: The objective was to determine if there is an association between red blood cell (RBC) storage time and development of new or progressive multiple organ dysfunction syndrome (MODS) in critically ill children.

STUDY DESIGN AND METHODS: This was an analytic cohort analysis of patients enrolled in a randomized controlled trial, TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units; ISRCTN37246456), in which stable critically ill children were randomly assigned to a restrictive or liberal strategy. Transfused patients were analyzed using three different sliding time cutoffs (7, 14, and 21 days). Storage time for multiply transfused patients was defined according to the oldest unit transfused.

RESULTS: A total of 455 patients were retained (liberal, 310; restrictive, 145). Multivariate logistic regression was performed to determine independent associations. In the restrictive group, a maximum RBC storage time of more than 21 days was independently associated with new or progressive MODS (adjusted odds ratio [OR], 3.29; 95% confidence interval [CI], 1.21‐9.04). The same association was found in the liberal group for a storage time of more than 14 days (adjusted OR, 2.50; 95% CI, 1.12‐5.58). When the two groups were combined in a meta‐analysis, a storage time of more than 14 days was independently associated with increased MODS (adjusted OR, 2.23; 95% CI, 1.20‐4.15) and more than 21 days was associated with increased Pediatric Logistic Organ Dysfunction (PELOD) scores (adjusted mean difference, 4.26; 95% CI, 1.99‐6.53) and higher mortality (9.2% vs. 3.8%).

CONCLUSION: Stable critically ill children who receive RBC units with storage times longer than 2 to 3 weeks may be at greater risk of developing new or progressive MODS.
Successful desensitization to immunoglobulin A in a case of transfusion‐related anaphylaxis
Authors: Kiani‐Alikhan Sorena , Yong Patrick F.K. , Grosse‐Kreul Dorothea , Height Susan E. , Mijovic Aleksandar , Suddle Abid R. , Ibrahim Mohammad A.A.
Published: May 2010

BACKGROUND: A history of anaphylaxis after transfusion of immunoglobulin A (IgA)‐containing blood products in selective IgA‐deficient (sIgAD) patients can be a major problem, particularly in emergencies, when large quantities of blood products are required.

CASE REPORT: A 19‐year‐old woman with end‐stage Type 2 autoimmune hepatitis required liver transplantation as her only remaining treatment option. However, she also had sIgAD, anti‐IgA antibodies, and episodes of anaphylaxis after receiving IgA‐containing blood products. Liver transplantation would have been extremely challenging due to the difficulty of obtaining sufficient blood products from suitable IgA‐deficient donors. Hence, it became imperative to devise a protocol to desensitize her to IgA‐containing blood products.

RESULTS: Using a continuous infusion of an IgA‐enriched (6 mg/mL IgA) immunoglobulin preparation with gradual increases in concentration, she was successfully desensitized to IgA. Consequently, she was able to receive standard platelets, fresh‐frozen plasma, and red blood cells with no complications.

CONCLUSION: This approach could prove very useful in similar cases that may require administration of large quantities of blood products particularly in emergency lifesaving circumstances.
Complement C1q enhances homing‐related responses of hematopoietic stem/progenitor cells
Authors: Jalili Ali , Marquez‐Curtis Leah , Shirvaikar Neeta , Wysoczynski Marcin , Ratajczak Mariusz , Janowska‐Wieczorek Anna
Published: May 2010

BACKGROUND: Previously, we reported that the complement cleavage fragments C3a and C5a are important modulators of trafficking of hematopoietic stem/progenitor cells (HSPCs). The aim of this study was to examine a possible role for complement component 1, subcomponent q (C1q) in HSPC migration.

STUDY DESIGN AND METHODS: CD34+ HSPCs isolated from cord blood (CB), bone marrow (BM), and granulocyte–colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood (mPB) were evaluated for the expression of C1q and its receptor for phagocytosis (C1qRp) using reverse transcription–polymerase chain reaction, Western blotting, and fluorescence‐activated cell sorting. Chemotactic responses and chemoinvasiveness toward stromal cell–derived factor (SDF)‐1 and expression of matrix metalloproteinase (MMP)‐9 were also examined after C1q stimulation. Moreover, G‐CSF– and zymosan‐induced mobilization was evaluated in C1q‐deficient mice.

RESULTS: C1q was expressed in CD34+ cells from mPB, but not from CB or steady‐state BM; however, stimulation of the latter with G‐CSF induced C1q expression. C1qRp receptor was found on BM, CB, and mPB CD34+ cells and more mature ex vivo expanded myeloid and megakaryocytic precursors. Although C1q itself was not a chemoattractant for HSPCs, it primed/enhanced the chemotactic response of CD34+ cells to a low SDF‐1 gradient and their chemoinvasion across the reconstituted basement membrane Matrigel and increased secretion of MMP‐9 by these cells. Moreover, in in vivo studies C1q‐deficient mice were found to be easy G‐CSF mobilizers compared to wild‐type mice and normal zymosan mobilizers.

CONCLUSION: We demonstrated that C1q primes the responses of CD34+ HSPCs to an SDF‐1 gradient, which may enhance their ability to stay within BM niches, suggesting that the C1q/C1qRp axis contributes to HSPC homing/retention in BM.