bluuebunny/crossref_metadata_2025 huggingface dataset:
Headache‐type adverse effects of NO donors: vasodilation and beyond
Authors: Bagdy G , Riba P , Kecskeméti V , Chase D , Juhász G
Published: March 2010

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side‐effects, mainly headaches, the summaries of product characteristics of nitrate‐containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate‐induced migraine. Two different types of nitrate‐induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine‐type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3–6 h after the intake of nitrates, with debilitating, long‐lasting symptoms including nausea, vomiting, photo‐ and/or phono‐phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene‐related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S‐nitrosylation. Migraines usually need anti‐attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti‐migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.
GSK3β: role in therapeutic landscape and development of modulators
Authors: Phukan S , Babu VS , Kannoji A , Hariharan R , Balaji VN
Published: March 2010

Glycogen synthase kinase‐3 beta (GSK3β) is a multifunctional serine/threonine kinase which was originally identified as a regulator of glycogen metabolism. It plays a key role in the regulation of numerous signalling pathways including cellular process such as cell cycle, inflammation and cell proliferation. Over the last few years there is a considerable rise in the number of journals and patents publication by different workers worldwide. Many pharmaceutical companies are focusing on GSK3β as a therapeutic target for the treatment of disease conditions. The present review is focused on signalling pathways of different disease conditions where GSK3β is implicated. In this review, we present a comprehensive map of GSK3β signalling pathways in disease physiologies. Structural analysis of GSK3β along with molecular modelling reports from numerous workers are reviewed in context of design and development of GSK3β inhibitors. Patent landscape of the small molecule modulators is profiled. The chemo space for small molecule modulators extracted from public and proprietary Kinase Chembiobase for GSK3β are discussed. Compounds in different clinical phases of discovery are analysed. The review ends with the overall status of this important therapeutic target and challenges in development of its modulators.
Expression and functional role of adenosine receptors in regulating inflammatory responses in human synoviocytes
Authors: Varani K , Vincenzi F , Tosi A , Targa M , Masieri FF , Ongaro A , De Mattei M , Massari L , Borea PA
Published: March 2010

Background and purpose: Adenosine is an endogenous modulator, interacting with four G‐protein coupled receptors (A1, A2A, A2Band A3) and acts as a potent inhibitor of inflammatory processes in several tissues. So far, the functional effects modulated by adenosine receptors on human synoviocytes have not been investigated in detail. We evaluated mRNA, the protein levels, the functional role of adenosine receptors and their pharmacological modulation in human synoviocytes.

Experimental approach: mRNA, Western blotting, saturation and competition binding experiments, cyclic AMP, p38 mitogen‐activated protein kinases (MAPKs) and nuclear factor (NF)‐κB activation, tumour necrosis factor α (TNF‐α) and interleukin‐8 (IL‐8) release were assessed in human synoviocytes isolated from patients with osteoarthritis.

Key results: mRNA and protein for A1, A2A, A2Band A3adenosine receptors are expressed in human synoviocytes. Standard adenosine agonists and antagonists showed affinity values in the nanomolar range and were coupled to stimulation or inhibition of adenylyl cyclase. Activation of A2Aand A3adenosine receptors inhibited p38 MAPK and NF‐κB pathways, an effect abolished by selective adenosine antagonists. A2Aand A3receptor agonists decreased TNF‐α and IL‐8 production. The phosphoinositide 3‐kinase or Gspathways were involved in the functional responses of A3or A2Aadenosine receptors. Synoviocyte A1and A2Badenosine receptors were not implicated in the inflammatory process whereas stimulation of A2Aand A3adenosine receptors was closely associated with a down‐regulation of the inflammatory status.

Conclusions and implications: These results indicate that A2Aand A3adenosine receptors may represent a potential target in therapeutic modulation of joint inflammation.
Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase‐2 activity and expression in a model of renovascular hypertension
Authors: Ceron CS , Castro MM , Rizzi E , Montenegro MF , Fontana V , Salgado MCO , Gerlach RF , Tanus‐Santos JE
Published: March 2010

Background and purpose: Increased oxidative stress and up‐regulation of matrix metalloproteinases (MMPs) may cause structural and functional vascular changes in renovascular hypertension. We examined whether treatment with spironolactone (SPRL), hydrochlorothiazide (HCTZ) or both drugs together modified hypertension‐induced changes in arterial blood pressure, aortic remodelling, vascular reactivity, oxidative stress and MMP levels and activity, in a model of renovascular hypertension.

Experimental approach: We used the two‐kidney,one‐clip (2K1C) model of hypertension in Wistar rats. Sham‐operated or hypertensive rats were treated with vehicle, SPRL (25 mg·kg−1·day−1), HCTZ (20 mg·kg−1·day−1) or a combination for 8 weeks. Systolic blood pressure was monitored weekly. Aortic rings were isolated to assess endothelium‐dependent and ‐independent relaxations. Morphometry of the vascular wall was carried out in sections of aorta. Aortic NADPH oxidase activity and superoxide production were evaluated. Formation of reactive oxygen species was measured in plasma as thiobarbituric acid‐reactive substances. Aortic MMP‐2 levels and activity were determined by gelatin andin situzymography, fluorimetry and immunohistochemistry.

Key results: Treatment with SPRL, HCTZ or the combination attenuated 2K1C‐induced hypertension, and reversed the endothelial dysfunction in 2K1C rats. Both drugs or the combination reversed vascular aortic remodelling induced by hypertension, attenuated hypertension‐induced increases in oxidative stress and reduced MMP‐2 levels and activity.

Conclusions and implications: SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension‐induced MMP‐2 up‐regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension.
Caspase‐3 knock‐down reverses contractile dysfunction induced by sepsis in adult rat ventricular myocytes
Authors: Chopra Mani , Das Padmalaya , Sharma Avadhesh C
Published: March 2010

Background and purpose:  The present study tested the hypothesis that selective caspase‐3 (C‐3) knock‐out would regulate the contractile actions of noradrenaline (NA) in the dysfunction of adult rat ventricular myocytes (ARVMs) induced by sepsis. Here, we have studied the contractile response of ARVMs, transfected with C‐3 small interfering RNA (C‐3 siRNA), to NA.

Experimental approach:  Single ARVMs were isolated from the hearts of male Sprague‐Dawley rats 3 days after induction of sepsis, and from sham‐treated rats. The sham and septic ARVMs were treated with NA (10 µM) alone or after transfection with C‐3 siRNA or non‐silencing RNA (2 µM). Mechanical properties were measured digitally, and immunoblotting and immunocytochemical analyses were carried out.

Key results:  The NA‐induced increase in peak shortening (PS) was less in septic ARVMs and transfection with C‐3 siRNA produced a significant increase in this PS. Immunocytochemical and immunoblot analyses revealed that NA exacerbated sepsis‐induced up‐regulation of C‐3. Transfection of septic ARVMs with C‐3 siRNA exhibited a decreased expression of C‐3 fluorescence after NA. In septic ARVMs, we also observed a down‐regulation of contractile proteins (α‐actin, myosin light chain‐1 and tropomyosin) along with DNA damage. Transfection of septic ARVMs with C‐3 siRNA produced an increase in the expression of contractile proteins, and a decrease in DNA damage.

Conclusions and implications:  These data suggest that C‐3 knock‐down improved the loss of contractile response to NA in septic ARVMs, suggesting that C‐3 regulated contractile dysfunction induced by sepsis in ARVMs.
Bisphenol A activates Maxi‐K (KCa1.1) channels in coronary smooth muscle
Authors: Asano Shinichi , Tune Johnathan D , Dick Gregory M
Published: March 2010

Background and purpose:  Bisphenol A (BPA) is used to manufacture plastics, including containers for food into which it may leach. High levels of exposure to this oestrogenic endocrine disruptor are associated with diabetes and heart disease. Oestrogen and oestrogen receptor modulators increase the activity of large conductance Ca2+/voltage‐sensitive K+ (Maxi‐K; KCa1.1) channels, but the effects of BPA on Maxi‐K channels are unknown. We tested the hypothesis that BPA activates Maxi‐K channels through a mechanism that depends upon the regulatory β1 subunit.

Experimental approach:  Patch‐clamp recordings of Maxi‐K channels were made in human and canine coronary smooth muscle cells as well as in AD‐293 cells expressing pore‐forming α or α plus β1 subunits.

Key results:  BPA (10 µM) activated an outward current in smooth muscle cells that was inhibited by penitrem A (1 µM), a Maxi‐K blocker. BPA increased Maxi‐K activity in inside‐out patches from coronary smooth muscle, but had no effect on single channel conductance. In AD‐293 cells with Maxi‐K channels composed of α subunits alone, 10 µM BPA did not affect channel activity. When channels in AD‐293 cells contained β1 subunits, 10 µM BPA increased channel activity. Effects of BPA were rapid (<1 min) and reversible. A higher concentration of BPA (100 µM) increased Maxi‐K current independent of the β1 subunit.

Conclusions and implications:  Our data indicate that BPA increased the activity of Maxi‐K channels and may represent a basis for some potential toxicological effects.
The melanocortin MC1 receptor agonist BMS‐470539 inhibits leucocyte trafficking in the inflamed vasculature
Authors: Leoni G , Voisin M‐B , Carlson K , Getting SJ , Nourshargh S , Perretti M
Published: March 2010

Background and purpose:  Over three decades of research evaluating the biology of melanocortin (MC) hormones and synthetic peptides, activation of the MC type 1 (MC1) receptor has been identified as a viable target for the development of novel anti‐inflammatory therapeutic agents. Here, we have tested a recently described selective agonist of MC1 receptors, BMS‐470539, on leucocyte/post‐capillary venule interactions in murine microvascular beds.

Experimental approach:  Intravital microscopy of two murine microcirculations were utilized, applying two distinct modes of promoting inflammation. The specificity of the effects of BMS‐470539 was assessed using mice bearing mutant inactive MC1 receptors (the recessive yellow e/e colony).

Key results:  BMS‐470539, given before an ischaemia–reperfusion protocol, inhibited cell adhesion and emigration with no effect on cell rolling, as assessed 90 min into the reperfusion phase. These properties were paralleled by inhibition of tissue expression of both CXCL1 and CCL2. Confocal investigations of inflamed post‐capillary venules revealed immunostaining for MC1 receptors on adherent and emigrated leucocytes. Congruently, the anti‐inflammatory properties of BMS‐470539 were lost in mesenteries of mice bearing the inactive mutant MC1 receptors. Therapeutic administration of BMS‐470539 stopped cell emigration, but did not affect cell adhesion in the cremasteric microcirculation inflamed by superfusion with platelet‐activating factor.

Conclusions and implications:  Activation of MC1 receptors inhibited leucocyte adhesion and emigration. Development of new chemical entities directed at MC1 receptors could be a viable approach in the development of novel anti‐inflammatory therapeutic agents with potential application to post‐ischaemic conditions.
AE9C90CB: a novel, bladder‐selective muscarinic receptor antagonist for the treatment of overactive bladder
Authors: Sinha S , Gupta S , Malhotra S , Krishna NS , Meru AV , Babu V , Bansal V , Garg M , Kumar N , Chugh A , Ray A
Published: March 2010

Background and purpose: AE9C90CB (N‐ [(1R, 5S, 6R)‐3‐azabicyclo [3.1.0] hex‐6‐ylmethyl]‐2‐hydroxy‐N‐methyl‐2, 2‐diphenylacetamide), a novel muscarinic receptor antagonist, was synthesized for the treatment of overactive bladder. Here we describe thein vitroandin vivoprofiles of AE9C90CB for action in bladder over salivary gland and compare it with four agents already in clinical use (tolterodine, oxybutynin, solifenacin and darifenacin).

Experimental approach: Radioligand binding assay and isolated tissue‐based functional assay were used to evaluate affinity, potency, and receptor subtype selectivity of compounds. Inhibition of carbachol‐induced increase in intravesicular pressure and salivary secretion were measured in anaesthetized rabbits to assess the functional selectivity.

Key results: In vitroradioligand binding study using human recombinant muscarinic receptors showed that AE9C90CB had greater affinity for M3muscarinic receptors with pKi of 9.90 ± 0.11 and was 20‐fold more selective for M3than for M2muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pKB, 9.13 ± 0.12). In anaesthetized rabbits after intravenous administration, AE9C90CB dose dependently inhibited carbachol‐induced increase in intravesicular pressure and salivary secretion, and exhibited functional selectivity for urinary bladder over salivary gland which was ninefold better than that of oxybutynin.

Conclusions and implications: We have identified AE9C90CB, a compound exhibiting moderate selectivity for M3over M2receptors but greater selectivity for urinary bladder over salivary gland than oxybutynin, tolterodine, solifenacin and darifenacin. Therefore, AE9C90CB may be a promising compound for the treatment of overactive bladder with reduced potential to cause dry mouth than currently available antimuscarinic drugs.
Making a Model Meaningful to Coral Reef Managers in a Developing Nation: a Case Study of Overfishing and Rock Anchoring in Indonesia
Authors: MAYNARD JEFFREY A. , ANTHONY KENNETH R. N. , AFATTA SIHAM , DAHL‐TACCONI NANCY , HOEGH‐GULDBERG OVE
Published: March 2010

Abstract:  Most of the world's coral reefs line the coasts of developing nations, where impacts from intense and destructive fishing practices form critical conservation issues for managers. Overfishing of herbivorous fishes can cause phase shifts to macroalgal dominance, and fishers’ use of rocks as anchors lowers coral cover, giving further competitive advantage to macroalgae. Overfishing and anchoring have been studied extensively, but the role of their interaction in lowering coral reef resilience has not been quantified formally. We analyzed the combined effects of overfishing and rock anchoring on a range of reef habitat types—varying from high coral and low macroalgae cover to low coral and high macroalgae cover—in a marine park in Indonesia. We parameterized a model of coral and algal dynamics with three intensities of anchoring and fishing pressure. Results of the model indicated that damage caused by rock anchoring was equal to or possibly more devastating to coral reefs in the area than the impact of overfishing. This is an important outcome for local managers, who usually have the funds to distribute less‐damaging anchors, but normally are unable to patrol regularly and effectively enough to reduce the impact of overfishing. We translated model results into an interactive visual tool that allows managers to explore the benefits of reducing anchoring frequency and fishing pressure. The potential consequences of inaction were made clear: the likelihood that any of the reef habitats will be dominated in the future by macroalgae rather than corals depends on reducing anchoring frequency, fishing pressure, or both. The tool provides a platform for strengthened relationships between managers and conservationists and can facilitate the uptake of recommendations regarding resource allocation and management actions. Conservation efforts for coral reefs in developing nations are likely to benefit from transforming model projections of habitat condition into tools local managers can understand and interact with.
Quantitative Determination of Rarity of Freshwater Fishes and Implications for Imperiled‐Species Designations
Authors: PRITT JEREMY J. , FRIMPONG EMMANUEL A.
Published: March 2010

Abstract:  Conserving rare species and protecting biodiversity and ecosystem functioning depends on sound information on the nature of rarity. Rarity is multidimensional and has a variety of definitions, which presents the need for a quantitative classification scheme with which to categorize species as rare or common. We constructed such a classification for North American freshwater fishes to better describe rarity in fishes and provide researchers and managers with a tool to streamline conservation efforts. We used data on range extents, habitat specificities, and local population sizes of North American freshwater fishes and a variety of quantitative methods and statistical decision criteria, including quantile regression and a cost‐function algorithm to determine thresholds for categorizing a species as rare or common. Species fell into eight groups that conform to an established framework for rarity. Fishes listed by the American Fisheries Society (AFS) as endangered, threatened, or vulnerable were most often rare because their local population sizes were low, ranges were small, and they had specific habitat needs, in that order, whereas unlisted species were most often considered common on the basis of these three factors. Species with large ranges generally had few specific habitat needs, whereas those with small ranges tended to have narrow habitat specificities. We identified 30 species not designated as imperiled by AFS that were rare along all dimensions of rarity and may warrant further study or protection, and we found three designated species that were common along all dimensions and may require a review of their imperilment status. Our approach could be applied to other taxa to aid conservation decisions and serve as a useful tool for future revisions of listings of fish species.
Anti‐adhesive Membrane for Pleural Cavity
Authors: Noishiki Yasuharu , Shintani Noriyuki
Published: March 2010

An anti‐adhesive membrane containing a large amount of glycerin was developed for lung surgery and was tested in the pleural cavity of six dogs. The test membranes were put between the lung and the chest wound of the pleural cavity wall to separate them. In five of the animals, no adhesion was observed after 3 weeks in the area where the membrane had been inserted, but the area without the membrane showed firm adhesion between the lung and the pleural cavity wall. A sixth animal observed for 3 months also showed no adhesion. Seprafilm, which is the product of choice for peritoneal surgeries, was used as a control in six dogs. Seprafilm could not prevent adhesion in the pleural cavity of all six animals after 3 weeks observation. The new test membrane contained glycerin, which gathered and dispersed abundant water. Together with this, growth factors are also dispersed, resulting in dilution of excessive growth factors at the wound sites. In general, fibroblasts do not migrate in an extremely hydrous gel matrix. Migration of fibroblasts into the membrane is minimized, resulting in the prevention of formation of adhesion tissue composed of fibroblasts and collagen fibers. From the results, we assume that water can prevent adhesion after surgery.
Beating‐Heart Coronary Artery Bypass Grafting With Miniaturized Cardiopulmonary Bypass Results in a More Complete Revascularization When Compared to Off‐Pump Grafting
Authors: Reber Delawer , Brouwer René , Buchwald Dirk , Fritz Markus , Germing Alfried , Lindstaedt Michael , Klak Krzysztof , Laczkovics Axel
Published: March 2010

The technique of miniaturized cardiopulmonary bypass (M‐CPB) for beating‐heart coronary artery bypass grafting (CABG) is relatively new and has potential advantages when compared to conventional cardiopulmonary bypass (CPB). M‐CPB consists of less tubing length and requires less priming volume. The system is phosphorylcholine coated and results in minimal pump‐related inflammatory response and organ injury. Finally, this technique combines the advantages of the off‐pump CABG (OPCAB) with the better exposure provided by CPB to facilitate complete revascularization. The hypothesis is that CABG with M‐CPB has a better outcome in terms of complete coronary revascularization and perioperative results as that compared to off‐pump CABG (OPCAB). In a retrospective study, 302 patients underwent beating‐heart CABG, 117 (39%) of them with the use of M‐CPB and 185 (61%) with OPCAB. After propensity score matching 62 patients in both groups were demographically similar. The most important intra‐ and early‐postoperative parameters were analyzed. Endpoints were hospital mortality and complete revascularization. Hospital mortality was comparable between the groups. The revascularization was significantly more complete in M‐CPB patients than in patients in the OPCAB group. Beating‐heart CABG with M‐CPB is a safe procedure and it provides an optimal operative exposure with significantly more complete coronary revascularization when compared to OPCAB. Beating‐heart CABG with the support of a M‐CPB is the operation of choice when total coronary revascularization is needed.
Is It Possible to Create a “Mechanical” Arteriovenous Fistula in Hemodialysis Patients?
Authors: Lo Monte Attilio Ignazio , Buscemi Giuseppe
Published: March 2010

Manual suturing still remains the best technique for the creation of vascular anastomoses on uremic patients with excellent results, despite being time consuming, difficult to perform with small vessels, and associated with a significant learning curve. We created a full mechanical arteriovenous fistula on a 65‐year‐old uremic patient with a new device already used in cardiac bypass surgery. The fistula was created automatically and rapidly, without the need for temporary occlusion of the artery, reducing the risk of blood clotting. We believe that mechanical devices may be useful to produce precise and fast anastomoses requiring minimal training for the surgeon.
Recombinant Human Erythropoietin Treatment of Chronic Renal Failure Patients Normalizes Altered Phenotype and Proliferation of CD4‐positive T Lymphocytes
Authors: Lisowska Katarzyna A. , Debska‐Slizien Alicja , Radzka Monika , Witkowski Jacek M. , Rutkowski Boleslaw , Bryl Ewa
Published: March 2010

Patients with chronic renal failure (CRF) receive recombinant human erythropoietin (rhEPO) for the correction of anemia. However, rhEPO also has an immunomodulatory effect. Detailed changes of phenotype and function of CD4+ T lymphocytes in CRF patients receiving rhEPO have not been reported yet; their study may bring insight into understanding of this immunomodulatory action of rhEPO. Two groups of CRF patients were included into the study: those treated; and those not receiving rhEPO. The expression of activation markers on CD4+ lymphocytes was measured with flow cytometry, both ex vivo and in vitro. The kinetics of CD4+ T lymphocytes proliferation was calculated using a dividing cells tracing method and numerical approach. Significantly higher percentages of CD4+CD95+, CD4+HLA‐DR+ cells, and lower percentages of CD4+CD69+ and CD4+CD28+ cells were observed in both rhEPO‐treated and untreated patients when compared with healthy controls. Changes in the proportions of CD4+CD28+ and CD4+HLA‐DR+ subpopulations were dependent on the type of rhEPO, being more pronounced for rhEPOβ. CD4+ lymphocytes from untreated patients exhibited decreased expression of CD28 and CD69 after stimulation in vitro, whereas the expression of these antigens on lymphocytes of rhEPO‐treated patients was similar to that observed in healthy controls. Fewer CD4+CD28+ T lymphocytes of untreated patients proliferated in vitro; these cells had longer G0→G1 time, which negatively correlated with surface expression of CD28. Our study confirms that rhEPO treatment normalizes activation parameters of CD4+ T lymphocytes and their proliferative capacity, which could explain earlier described immunomodulatory effects of rhEPO in patients suffering from CRF.
Propagation of Tears in Pericardium From Young Bulls: Influence of the Suture
Authors: García Páez José María , Jorge‐Herrero Eduardo , Claramunt Rafael , Millán Isabel , Rocha Aurora , Martínez Belén , Cordón Ángeles , Ros Antonio
Published: March 2010

The tearing of the collagen fibers of biological materials utilized in implants or bioprostheses is an important, and sometimes early cause of the failure of these devices. We studied the force necessary to propagate a tear in a biomaterial, pericardium from young bulls, and the influence of the suture. An Elmendorf pendulum capable of measuring the force necessary to tear a given length of tissue was employed. We analyzed 112 trials (70%) that proved valid after achieving the homogeneity of the samples according to their thickness, thus making the results comparable. Mean forces ranging between 19.87 and 150 N were required to propagate tears measuring from 0.25 to 2.0 cm. In the samples with a 1‐cm‐long suture, sewn using an edge‐to‐edge technique, the propagation of the tear required a mean force of 15.75 N when the suture was made of nylon and 28.73 N when Prolene was utilized. When these results were compared with the mean recorded in an unsutured control series (56.76 N), the loss of resistance was significant in both sutured series (P = 0.000 and P = 0.011, respectively). Finally, the equation that relates the force (y) with the length of the tear made in unsutured tissue (x) was also obtained: y = 58.14 + 9.62x2 (R2 = 0.924). The force necessary to produce a microtear, thus estimated, can be utilized as a parameter for comparison.
Aortic Valve Surgery in Congenital Heart Disease: A Single‐Center Experience
Authors: Coskun Kasim Oguz , Popov Aron Frederik , Tirilomis Theodor , Schmitto Jan Dieter , Coskun Sinan Tolga , Hinz Jose , Schoendube Friedrich Albert , Ruschewski Wolfgang
Published: March 2010

The optimal treatment of congenital aortic valve lesions is a controversial issue. This study was performed to evaluate the outcome after surgical treatment of aortic valve lesions in congenital aortic valve disease. Between the years of 2000 and 2008, 61 patients (mean age: 12.6 ± 9.6 years, range: 1 day to 40 years) underwent aortic valve surgery for congenital aortic valve disease. Twenty‐four patients had undergone previous cardiovascular operations. Indications for surgery were aortic regurgitation in 14.7% (n = 9), aortic stenoses in 26.2% (n = 16), and mixed disease in 59.1% (n = 36). The Ross procedure was performed in 37.7% (n = 23), aortic valve replacement with biological or mechanical prostheses in 29.5% (n = 18). Concomitant procedures were performed in 91.8% (n = 56) due to associated congenital cardiac defects. The overall mortality rate was 5%. Six patients needed reoperation. Implantation of permanent pacemakers occurred in six patients for permanent atrioventricular block. At the latest clinical evaluation, all survivors are in New York Heart Association class I–II and are living normal lives. Aortic valve surgeries in patients with congenital heart disease have had low mortality and morbidity rates in our series. Surgical technique as well as timing should be tailored for each patient. Aortic valve replacement should be delayed until the implantation of an adult‐sized prosthesis is possible.
Long‐term add‐on pregabalin treatment in patients with partial‐onset epilepsy: Pooled analysis of open‐label clinical trials
Authors: Uthman Basim M. , Bazil Carl W. , Beydoun Ahmad , Schulze‐Bonhage Andreas , Benabou Reina , Whalen Ed , Emir Birol , Griesing Teresa , Leon Teresa
Published: March 2010

Purpose:  To evaluate the safety, tolerability, and efficacy of long‐term pregabalin as add‐on therapy for patients with poorly controlled partial seizures.

Methods:  Analysis of data from six long‐term clinical trials involving 2,061 patients receiving open‐label pregabalin 75–600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs.

Results:  Total pregabalin exposure was 3,877 person‐years. The mean duration of pregabalin treatment was 534 days (range 0.3–8 years) and 59% completed 1 year. One‐third of patients discontinued for lack of efficacy. The most common dose was ≥300 mg/day; over half took ≥450 mg/day. There was a mean reduction in the 28‐day seizure rate of 25–40%, and more than 40% of all patients had a ≥50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6‐month period continuously free of seizures. In the last year, 6% were seizure‐free for the entire year. Pregabalin was generally well‐tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short‐term placebo‐controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population.

Conclusions:  Adjunctive pregabalin was effective, generally well tolerated, and safe in the long‐term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow‐up.
Infantile epileptic encephalopathy with late‐onset spasms: Report of 19 patients
Authors: Auvin Stéphane , Lamblin Marie‐Dominique , Pandit Florence , Vallée Louis , Bouvet‐Mourcia Agnès
Published: March 2010

Purpose:  Late‐onset spasms (LOS) are epileptic spasms starting after the first year of life. Our aim was to assess the electroclinical features and the follow‐up of the patients with this particular type of epileptic seizure.

Methods:  We retrospectively included all patients with LOS confirmed by electroencephalography between 1989 and 2008. Clinical and electroencephalographic findings at diagnosis and during follow‐up were collected. The Vineland scale was used to evaluate the neuropsychological outcome.

Results:  We report 19 patients with LOS of 240 patients with recorded epileptic spasms. Eighteen patients had an epileptic encephalopathy with late‐onset spasms. The ictal electroencephalography (EEG) showed a focal or generalized discharge of triphasic slow‐waves, slow‐spikes, or slow spikes‐waves with fast activities. The interictal EEG usually showed focal or generalized slow‐waves or slow spikes‐waves without hypsarhythmia. LOS were controlled in only six patients. Three developed typical Lennox‐Gastaut syndrome and 10 had a severe epileptic encephalopathy. Neuropsychological outcome was evaluated in 15 patients with the Vineland scale. Cognitive functions were normal in only one patient, whereas severe cognitive delay was observed in 12 of 15.

Conclusion:  Epileptic spasms may appear after the age of one. They are more frequently observed in patients with epileptic encephalopathy. In few patients this type of seizure was observed before the patients fulfill Lennox‐Gastaut syndrome criteria. In one patient, we diagnosed a focal epilepsy with seizures occurring in cluster. When LOS are related to an epileptic encephalopathy, this epileptic syndrome seems to be linked to refractory epilepsy and severe cognitive outcome unrelated to the etiology.
Febrile infection–related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood
Authors: Van Baalen Andreas , Häusler Martin , Boor Rainer , Rohr Axel , Sperner Jürgen , Kurlemann Gerhard , Panzer Axel , Stephani Ulrich , Kluger Gerhard
Published: March 2010

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3–15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2–14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2–42 cells/μl (median 5 cells/μl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy‐refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection‐related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term “febrile infection–related epilepsy syndrome” (FIRES).
Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy
Authors: Fisher Robert , Salanova Vicenta , Witt Thomas , Worth Robert , Henry Thomas , Gross Robert , Oommen Kalarickal , Osorio Ivan , Nazzaro Jules , Labar Douglas , Kaplitt Michael , Sperling Michael , Sandok Evan , Neal John , Handforth Adrian , Stern John , DeSalles Antonio , Chung Steve , Shetter Andrew , Bergen Donna , Bakay Roy , Henderson Jaimie , French Jacqueline , Baltuch Gordon , Rosenfeld William , Youkilis Andrew , Marks William , Garcia Paul , Barbaro Nicolas , Fountain Nathan , Bazil Carl , Goodman Robert , McKhann Guy , Babu Krishnamurthy K. , Papavassiliou Steven , Epstein Charles , Pollard John , Tonder Lisa , Grebin Joan , Coffey Robert , Graves Nina ,   the SANTE Study Group
Published: March 2010

Purpose:  We report a multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy.

Methods:  Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3‐month blinded phase; then all received unblinded stimulation.

Results:  One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and “most severe” seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure‐free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation‐associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.

Discussion:  Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.
Clinical features of seizures associated with parahippocampal/inferior temporal lesions compared to those with hippocampal sclerosis
Authors: Mirandola Laura , Badawy Radwa A. , Saunders Ann M. , McIntosh Anne , Berkovic Samuel F. , Jackson Graeme D.
Published: March 2010

Temporal lobe epilepsy (TLE) is not a unitary electroclinical imaging syndrome. We asked if seizures arising from the parahippocampal‐inferior temporal (PIT) region differ from those associated with hippocampal sclerosis (HS). The electroclinical features of 22 patients with HS and 14 patients with lesions in the PIT region who underwent epilepsy surgery and were seizure free for at least 2 years postoperatively were analyzed retrospectively. Patients with PIT lesions had a higher frequency of hypermotor and bilateral features and a lower frequency of behavioral arrest at the onset of seizure compared to cases with HS, suggesting that TLE originating in the PIT area can mimic frontal lobe epilepsy or contralateral mesial TLE.
Surgery for medically intractable epilepsy due to postinfectious etiologies
Authors: Chandra P. S. , Bal Chandrashekar , Garg Ajay , Gaikwad Shailesh , Prasad Kameshwar , Sharma Bhawani S. , Sarkar Chitra , Singh M. B. , Padma Vasantha M. , Tripathi Manjari
Published: March 2010

Medically intractable epilepsy (MIE) resulting from postinfectious etiologies requiring surgery have been uncommonly reported. A series of 28 cases are presented (hospital prevalence 5.7%). The mean duration of epilepsy prior to surgery was 8.2 ± 2.1 years. The mean time of onset of epilepsy after central nervous system infection was 1.4 ± 0.9 years (range 0–19 years). The pathologies included postpyogenic meningitic/encephalitic sequel (8), neurocysticercosis (6), tuberculomas/posttuberculous etiology (4), postpyogenic abscess of otogenic etiology (4), posttraumatic abscess–related gliosis (2), and gliosis of unknown infectious etiology (4) cases. Surgery included mesial temporal (11), lateral temporal (4), frontal (9), parietal (2) resections and hemispherotomy (1). Hippocampal sclerosis was seen in nine cases (4 neurocysticercosis) and this occurred in younger persons as compared to neocortical epilepsies. Good outcome (Engel class I and II) was seen in 23 of 28 cases (Engel class I in 17).
Type 1 diabetes and epilepsy: Efficacy and safety of the ketogenic diet
Authors: Dressler Anastasia , Reithofer Eva , Trimmel‐Schwahofer Petra , Klebermasz Katrin , Prayer Daniela , Kasprian Gregor , Rami Birgit , Schober Edith , Feucht Martha
Published: March 2010

Diabetes type 1 seems to be more prevalent in epilepsy, and low‐carbohydrate diets improve glycemic control in diabetes type 2, but data on the use of the classic ketogenic diet (KD) in epilepsy and diabetes are scarce. We present 15 months of follow‐up of a 3 years and 6 months old girl with diabetes type 1 (on the KD), right‐sided hemiparesis, and focal epilepsy due to a malformation of cortical development. Although epileptiform activity on electroencephalography (EEG) persisted (especially during sleep), clinically overt seizures have not been reported since the KD. An improved activity level and significant developmental achievements were noticed. Glycosylated hemoglobin (HbA1c) levels improved, and glycemic control was excellent, without severe side effects. Our experience indicates that diabetes does not preclude the use of the KD.
Alterations of intracerebral γ‐aminobutyric acid (GABA) levels by titration with levetiracetam in patients with focal epilepsies
Authors: Doelken Marc T. , Hammen Thilo , Bogner Wolfgang , Mennecke Angelika , Stadlbauer Andreas , Boettcher Uwe , Doerfler Arnd , Stefan Hermann
Published: March 2010

Purpose:  The objective of this study was to determine if levetiracetam (LEV) modulates brain γ‐aminobutyric acid (GABA) in patients with epilepsy.

Methods:  Occipital GABA was assessed by protein magnetic resonance spectroscopy (1H‐MRS) in 16 patients with focal epilepsy at baseline and following the initiation of oral administration of LEV as monotherapy. Responder profiles were calculated as percentage of baseline seizure frequency. Alterations of GABA/Cr (creatine) of baseline measurements compared to GABA/Cr under LEV therapy were analyzed by Student’s t‐test for paired samples.

Results:  After administration of LEV, partial seizure reduction (>50%) was noticed in 5 of 16 patients (31%; 7 of 16 (44%) patients turned out to be free of seizures. Patients with 50–100% seizure reduction under LEV titration were referred to as LEV responders. Of the 32 GABA spectra, only 22 (approximately 70%) yielded a result that met the criteria for spectral quality; therefore, GABA/Cr data from only seven patients were paired. A significant increase of GABA/Cr during titration with LEV was noted in patients responding to LEV (n = 5; p = 0.007). No differences in baseline GABA/Cr levels were detected between patients with and without previous antiepileptic treatment (p = 0.74).

Discussion:  The increasing GABA/Cr levels under drug titration only in LEV‐responding epilepsy patients suggest a more complex and indirect influence of LEV on the GABAergic system.
Clinical Comparison of a Novel Extracapsular Stabilization Procedure and Tibial Plateau Leveling Osteotomy for Treatment of Cranial Cruciate Ligament Deficiency in Dogs
Authors: Cook James L. , Luther Jill K. , Beetem Jodi , Karnes Josh , Cook Cristi R.
Published: March 2010

Objective: To develop and test a novel extracapsular technique, TightRope CCL technique (TR), and compare its 6‐month clinical outcomes to tibial plateau leveling osteotomy (TPLO) in dogs with cranial cruciate ligament (CCL) deficiency.

Study Design: Prospective clinical cohort study.

Animals: Medium, large, and giant breed dogs (n=47) with CCL deficiency.

Methods: Before clinical use, TR was evaluated by mechanical testing and the surgical technique was developed and evaluated in canine cadavers. For the clinical study, dogs were assigned to either TR (n=24) or TPLO (n=23) groups and the assigned technique performed after arthroscopic assessment and treatment of joint pathology. Postoperative management was standardized for both groups. Outcome measures were performed immediately postoperatively and up to 6 months after surgery and included complication types and rate, subjective measurement of cranial drawer and tibial thrust, subjective assessment of radiographic progression of osteoarthritis (OA), and function using a validated client questionnaire (6 months only).

Results: TR with a fiber tape suture had superior mechanical properties for creep, stiffness, yield load, and load at failure. Duration of anesthesia, total surgical time, and stabilization procedure (TR versus TPLO) were all significantly (P<.001) shorter for TR compared with TPLO. Complications requiring further treatment occurred in 12.5% of TR cases and 17.4% of TPLO cases. No significant differences were noted between groups for cranial tibial thrust, but cranial drawer was significantly (P<.05) lower in TR stifles at all postoperative time points. No significant differences were noted between groups for radiographic OA scores. No statistically or clinically significant differences were noted between TR and TPLO for scores for each of the client questionnaire categories.

Conclusions: TR resulted in 6‐month outcomes that were not different than TPLO in terms of radiographic progression of OA and client‐evaluated level of function. TR was associated with shorter anesthesia and surgery times as well as a lower complication rate.

Clinical Relevance: The TR technique is safe and effective and can be considered an appropriate surgical option as part of the overall treatment plan for CCL deficiency in dogs.
Transfusion medicine knowledge in Postgraduate Year 1 residents
Authors: O'Brien Kerry L. , Champeaux Anne L. , Sundell Zoe E. , Short Matthew W. , Roth Bernard J.
Published: March 2010

BACKGROUND: Transfusion medicine is a complex important subspecialty of pathology. A transfusion carries measurable risks and benefits. Although fellowship training exists in transfusion medicine, the majority of transfusion decisions are made by clinicians without formal training.

STUDY DESIGN AND METHODS: A total of 116 recently graduated medical students entering 10 residency programs at a single medical center over 2 years were evaluated using a standardized patient encounter to determine baseline knowledge. Transfusion medicine knowledge was assessed during the encounter by obtaining verbal consent for red blood cell transfusion, answering patient questions, and completing a written quiz. Final performance was scored using a peer‐reviewed data collection sheet.

RESULTS: Scores ranged from 24.0% to 67.1%. Postgraduate Year 1 (PGY‐1) residents graduating from allopathic medical schools had higher scores than those from osteopathic schools (mean, 41.3% vs. 37.5%; p = 0.036). There was no significant difference between PGY‐1 residents entering primary care versus surgical specialties (38.2% and 41.6%; p = 0.10). Although not significant, PGY‐1 residents with previous transfusion medicine education demonstrated a trend toward better performance than those without prior education (47.0% vs. 43.0%; p = 0.057). A total of 17.2% of PGY‐1's could define transfusion‐related acute lung injury, 6.0% knew the transfusion transmission rate of human immunodeficiency virus, 5.2% knew the transfusion transmission rate of hepatitis C virus, and 0% knew the indication for blood product irradiation.

CONCLUSIONS: Marked knowledge deficits in transfusion medicine were noted. If the results of this study could be reproduced at other training institutions, medical schools may be willing to donate more resources into transfusion medicine education.