bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Nodal Involvement in Breast Cancer Based on Multiparametric Protein Analyses from Preoperative Core Needle Biopsies of the Primary Lesion
Authors: Sauer Georg , Schneiderhan-Marra Nicole , Kazmaier Cornelia , Hutzel Kathrin , Koretz Karin , Muche Rainer , Kreienberg Rolf , Joos Thomas , Deissler Helmut
Published: June 2008

Purpose: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors.

Experimental Design: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins.

Results: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values <0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87.

Conclusion: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.
A Fiber-Modified Mesothelin Promoter–Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer
Authors: Tsuruta Yuko , Pereboeva Larisa , Breidenbach Martina , Rein Daniel T. , Wang Minghui , Alvarez Ronald D. , Siegal Gene P. , Dent Paul , Fisher Paul B. , Curiel David T.
Published: June 2008

Purpose: Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenoviruses (CRAd) may contain tumor-specific promoters that restrict virus replication to cancer cells. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter–based CRAd in a murine model of ovarian cancer, using noninvasive in vivo imaging.

Experimental Design: We constructed a mesothelin promoter–based CRAd with a chimeric Ad5/3 fiber (AdMSLNCRAd5/3) that contains an Ad5 tail, Ad5 shaft, and an Ad3 knob. Previously, a chimeric Ad5/3 fiber has shown improved infectivity in many ovarian cancer cells. Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of AdMSLNCRAd5/3 in a murine model, bioluminescence imaging of tumor luciferase activity and survival analysis were done.

Results: AdMSLNCRAd5/3 achieved up to a 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all human ovarian cancer cells, compared with wild-type Ad5. AdMSLNCRAd5/3 significantly inhibited tumor growth as confirmed by in vivo imaging (P < 0.05). Survival with AdMSLNCRAd5/3 was significantly enhanced when compared with no virus or with a wild-type Ad5-treated group (P < 0.05).

Conclusions: The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLNCRAd5/3 showed that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have applied in vivo imaging that has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment.
A Phase I Study of 17-Allylamino-17-Demethoxygeldanamycin Combined with Paclitaxel in Patients with Advanced Solid Malignancies
Authors: Ramalingam Suresh S. , Egorin Merrill J. , Ramanathan Ramesh K. , Remick Scot C. , Sikorski Rachel P. , Lagattuta Theodore F. , Chatta Gurkamal S. , Friedland David M. , Stoller Ronald G. , Potter Douglas M. , Ivy S. Percy , Belani Chandra P.
Published: June 2008

Background: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel.

Methods: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1.

Results: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 ± 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 ± 0.51.

Conclusions: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.
Neuregulins and Cancer
Authors: Montero Juan Carlos , Rodríguez-Barrueco Ruth , Ocaña Alberto , Díaz-Rodríguez Elena , Esparís-Ogando Azucena , Pandiella Atanasio
Published: June 2008

The neuregulins represent the largest subclass of polypeptide factors of the epidermal growth factor family of ligands. These molecules are synthesized as membrane-bound, biologically active growth factors that act by binding to the HER/ErbB receptor tyrosine kinases. Preclinical data have indicated that increased expression and function of neuregulins may provoke cancer. Furthermore, neuregulin expression has been detected in several neoplasias, and their presence may correlate with response to treatments that target the HER receptors such as trastuzumab. In addition, the neuregulins have also been implicated in resistance to anti-HER therapies. Therefore, targeting of the neuregulins may be helpful in neoplastic diseases in which these polypeptide factors contribute to tumor generation and/or maintenance.
A Novel Functional Polymorphism C1797G in the MDM2 Promoter Is Associated with Risk of Bladder Cancer in a Chinese Population
Authors: Wang Meilin , Zhang Zhizhong , Zhu Haixia , Fu Guangbo , Wang Shouyu , Wu Dongmei , Zhou Jianwei , Wei Qingyi , Zhang Zhengdong
Published: June 2008

Purpose: MDM2 is believed to regulate the p53 level in modulating DNA repair, cell cycle control, cell growth, and apoptosis. We hypothesize that genetic variants in the MDM2 gene are associated with risk of bladder cancer.

Experimental Design: We first conducted a case-control study of 234 bladder cancer cases and 253 cancer-free controls, using the haplotype-based tagging single nucleotide polymorphism (SNP) approach involving 13 common SNPs initially identified in 100 control subjects. We then examined the functionality of the important SNP.

Results: We found that the C1797G polymorphism in the MDM2 promoter region is an important SNP because its homozygous variant genotype, but none of the haplotypes, was associated with risk of bladder cancer. Electrophoretic mobility shift assay indicated that the 1797C to 1797G transition within the CAAT/enhancer binding protein α (C/EBP α) core sequence greatly enhanced the C/EBPα binding affinity to the promoter region. The in vitro luciferase assays in various cell lines further showed an increased transcriptional activity of the 1797G allele compared with the 1797C allele. Additional experiments with tumor tissues revealed that the transcriptional activator C/EBPα containing the 1797G allele increased levels of the MDM2 mRNA and protein in bladder tumor tissues.

Conclusions: These data suggested that the novel MDM2 promoter C1797G polymorphism may affect the MDM2 activity by altering the C/EBPα binding affinity to the promoter and, thus, may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Further validation of the functionality of the MDM2 C1797G polymorphism and its association with risk of bladder and other cancers in other ethnic populations is warranted.
Lymphocyte Activation Gene-3 Fusion Protein Increases the Potency of a Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy
Authors: Li Betty , VanRoey Melinda , Triebel Frederic , Jooss Karin
Published: June 2008

Purpose: The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy, which is known to stimulate a potent and long-lasting antigen-specific immune response in combination with lymphocyte activation gene-3 fusion protein (LAG-3Ig), which has been shown to act as an adjuvant for priming T helper type 1 and cytotoxic T-cell responses.

Experimental Design: Survival and immune monitoring studies were done in the B16 melanoma model. GM-CSF–secreting tumor cell immunotherapy was administered as a single s.c. injection and LAG-3Ig was administered s.c. at the immunotherapy site.

Results: The studies reported here show that combining LAG-3Ig with GM-CSF–secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with increased numbers of systemic IFNγ-secreting CD8+ T cells and a significantly increased infiltration of activated effector CD8+ T cells into the tumor. Moreover, an increase in antigen-specific IgG1 humoral responses was detected in serum of animals injected with the combination therapy compared with animals injected with either therapy alone.

Conclusion: LAG-3Ig combined with a GM-CSF–secreting tumor cell immunotherapy stimulated both cellular and humoral antitumor immune responses that correlated with prolonged survival in tumor-bearing animals.
Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer
Authors: Woloszynska-Read Anna , Mhawech-Fauceglia Paulette , Yu Jihnhee , Odunsi Kunle , Karpf Adam R.
Published: June 2008

Purpose: The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.

Experimental Design: We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated in vitro with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC.

Results: Compared with normal ovary, bulk EOC tissues display increased NY-ESO-1 expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, NY-ESO-1 expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines.

Conclusion: DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.
Causes of Variation in the Cystic Fibrosis Phenotype
Authors: Cutting Garry R.
Published: June 2008

Cystic fibrosis (CF) is caused by abnormal function of the CF transmembrane conductance regulator (CFTR) gene. CF is highly variable with some individuals succumbing to the disease in their first decade while others live into their fourth and fifth decades. Patients also differ in the involvement of organ systems and in complications. Some of the variation in CF phenotype can be attributed to the nature of the defect in the CFTR gene. The CFTR genotype primarily determines the degree of pancreatic exocrine dysfunction and correlates with a degree of abnormality in the sweat chloride concentration and malformation of the male reproductive tract. However, factors independent of CFTR are responsible for variation in lung disease, the primary cause of morbidity and mortality in CF. Over the past few years, modifier genes have been identified that influence lung disease severity in CF patients. Non-genetic factors such as socioeconomic status and exposure to passive smoking also affect pulmonary outcome. A more complete understanding of the causes of variation among CF patients is emerging, facilitating the development of new prognostic measures as well as novel therapies.
Care of Patients with Cystic Fibrosis
Authors: Strandvik Birgitta
Published: June 2008

Cystic fibrosis (CF), the most common autosomal hereditary pediatric disease, is no longer restricted to childhood as modern therapy has given patients both increased longevity and better quality of life. When the gene was identified more than 16 years ago and the most common mutation, ΔF508, found, general hope of a rapid cure for the disease was expressed. The discovery entailed a marked increase in research on pathophysiology, but to date the improvements in clinical therapy are entirely due to developments in traditional treatment. Improvements in the patient’s condition are related to better pancreatic enzyme supplements and more intense nutritional treatment, including the attention paid to abnormal lipid metabolism. Pulmonary treatment has resulted in better preserved lung function into adulthood with access to a battery of efficient antibiotics and the development of new strategies; mucus-dissolving agents in combination with encouragement of physical activity from an early age together with modifications in physiotherapy, and improved results in lung transplantations as the ultimate treatment. Liver disease is recognized more, and often treated long-term with ursodeoxycholic acid, although its effect in preventing progression of liver disease has not been fully explored. Neonatal screening is increasing, challenging short-term problems such as those of a psychological nature when carriers or very mild diseases are discovered, and exploring long-term results to prove that clinical status improves and survival further increases. The limitations in survival still present seem mainly to be due to the mystery behind the chronic colonization of the airways by microorganisms.
The Intonation of Gapping and Coordination in Japanese: Evidence for Intonational Phrase and Utterance
Authors: Kawahara Shigeto , Shinya Takahito
Published: June 2008

In previous studies of Japanese intonational phonology, levels of prosodic constituents above the Major Phrase have not received much attention. This paper argues that at least two prosodic levels exist above the Major Phrase in Japanese. Through a detailed investigation of the intonation of gapping and coordination in Japanese, we argue that each syntactic clause projects its own Intonational Phrase, while an entire sentence constitutes one Utterance. We show that the Intonational Phrase is characterized by tonal lowering, creakiness and a pause in final position, as well as a distinctive large initial rise and pitch reset at its beginning. The Utterance defines a domain of declination, and it is signaled by an even larger initial rise, as well as a phrasal H tone at its right edge. Building on our empirical findings, we discuss several implications for the theory of intonational phonology.
Skin Irritation and Sensitization: Mechanisms and New Approaches for Risk Assessment
Authors: Fluhr J.W. , Darlenski R. , Angelova-Fischer I. , Tsankov N. , Basketter D.
Published: June 2008

Cutaneous irritation presents a major health problem with serious social and occupational impact. The interaction between an irritant and the human skin depends on multiple factors: the intrinsic properties and the nature of the irritant itself, and specific individual- and environment-related variables. The main pathological mechanisms of irritancy include skin barrier disruption, induction of a cytokine cascade and involvement of the oxidative stress network; all of them resulting in a visible or subclinical inflammatory reaction. In vivo, different non-invasive parameters for the evaluation of skin irritation and irritant potential of compounds and their specific formulations have been introduced, such as epidermal barrier function, skin hydration, surface pH, lipid composition, skin colour and skin blood flow. The diverse physiological changes caused by irritating agents require implementation of a multiparametric approach in the evaluation of cutaneous irritancy.
Nanotechnology, Cosmetics and the Skin: Is There a Health Risk?
Authors: Nohynek G.J. , Dufour E.K. , Roberts M.S.
Published: June 2008

Cosmetic formulations may contain nano-emulsions and microscopic vesicles consisting of traditional cosmetic materials, although it is uncertain whether they should be qualified as actual nanomaterials. Vesicle materials do not penetrate into living human skin. Vesicle formulations may enhance or reduce skin absorption of ingredients, albeit at a limited scale. Sunscreens contain TiO2 or ZnO nanoparticles (NP), which are efficient UV filters. A number of studies suggest that insoluble NP do not penetrate into or through human skin. The results of in vivo toxicity tests showed that TiO2 and ZnO NP are non-toxic. In vitro and in vivo cytotoxicity, genotoxicity, photogenotoxicity, acute toxicity, sensitisation and ecotoxicology studies on TiO2 NP found no difference in the safety profile of micro- or nano-sized materials, all of which were non-toxic. Although some in vitro investigations on TiO2 particles reported cell uptake, oxidative cell damage or genotoxicity, these results may be secondary to phagocytosis of cells exposed to excessive particle concentrations. Studies on wear debris nano- and microparticles support the traditional view that toxicity of small particles is related to their chemistry, rather than their particle size. There is little evidence supporting a general rule that adverse effects of particles on the skin or other tissues increase with smaller particle size, or produce novel toxicities relative to those of larger particles. Overall, the current evidence suggests that nano-sized cosmetic or sunscreen ingredients pose no potential risk to human health, whereas their use in sunscreens has large benefits, such as the protection of human skin against skin cancer.
Activity of Different Desoximetasone Preparations Compared to Other Topical Corticosteroids in the Vasoconstriction Assay
Authors: Borelli C. , Gassmueller J. , Fluhr J.W. , Nietsch K.H. , Schinzel S. , Korting H.C.
Published: June 2008

Introduction: We report on a double-blind, vehicle-controlled, single-center confirmatory study with random assignment. The purpose of the study was to investigate the topical bioavailability of different topical corticosteroid formulations in healthy human beings focussing on desoximetasone (DM). Materials and Methods: Two DM 0.25% formulations [ointment (DM-o) and fatty ointment (DM-fo, water-free); class III corticosteroids], the corresponding active ingredient-free vehicles and three comparators of different strength [clobetasol propionate 0.05% (CP 0.05%), fatty ointment, class IV; hydrocortisone (HC) 1%, fatty ointment, class I, and betamethasone (BM) 0.05%, fatty ointment, class III] were tested using the vasoconstriction assay. The degree of vasoconstriction (blanching) in the treatment field was compared to the one found in untreated control fields using chromametric measurements and clinical assessment. Results/Conclusion: DM-o 0.25%, DM-fo 0.25% and BM 0.05% showed similar vasoconstrictive potential, i.e., clear blanching. In fact, both DM preparations were proven to be noninferior to BM 0.05%, while CP 0.05% was found a little less active. HC 1.0% and the DM vehicles showed no clear-cut vasoconstrictive effect. No adverse events related to the study medications were observed. Good topical bioavailability of both DM formulations was detected by chromametric measurement and clinical assessment.
Identification of Phonemes: Differences between Phoneme Classes and the Effect of Class Size
Authors: Wagner Anita , Ernestus Mirjam
Published: June 2008

This study reports general and language-specific patterns in phoneme identification. In a series of phoneme monitoring experiments, Castilian Spanish, Catalan, Dutch, English, and Polish listeners identified vowel, fricative, and stop consonant targets that are phonemic in all these languages, embedded in nonsense words. Fricatives were generally identified more slowly than vowels, while the speed of identification for stop consonants was highly dependent on the onset of the measurements. Moreover, listeners’ response latencies and accuracy in detecting a phoneme correlated with the number of categories within that phoneme’s class in the listener’s native phoneme repertoire: more native categories slowed listeners down and decreased their accuracy. We excluded the possibility that this effect stems from differences in the frequencies of occurrence of the phonemes in the different languages. Rather, the effect of the number of categories can be explained by general properties of the perception system, which cause language-specific patterns in speech processing.
Hospital Deaths of People Aged 90 and Over: End-of-Life Palliative Care Management
Authors: Formiga Francesc , López-Soto Alfons , Navarro Margarita , Riera-Mestre Antoni , Bosch Xavier , Pujol Ramón
Published: June 2008

Background: In developed countries, hospital deaths at very advanced age are increasingly common.Few studies have addressed end-of-life care in very elderly patients with non-cancer chronic diseases. Objective: To evaluate the circumstances related to end-stage death of non-cancer nonagenarians in an acute care hospital. The results were compared with those from a sample of younger patients. Methods: We conducted a prospective assessment in two teaching hospitals of the written instructions for the following actions: do not resuscitate (DNR) orders, the graduation of therapeutic decisions, information provided to relatives about prognosis, total withdrawal of normal drug therapy and provision of palliative care. Results: 80 patients over 89 years of age with end-stage congestive heart failure (57.5%) or dementia (42.5%) were included. The control group comprised 52 younger patients (65–74 years). DNR orders were specified in 56% of cases, graduation of therapeutic decisions in 35%, and knowledge of relatives regarding the prognosis in 61%. Drug therapy was withdrawn in 66% of cases and terminal palliative care was initiated in 69%. In the nonagenarians who died, we detected a predominance of females (p = 0.001), a higher percentage of DNR orders (p = 0.02) and a higher percentage of graduation of therapeutic measures (p = 0.02) in comparison with younger patients. Conclusion: Our results indicate that there are marked differences according the palliative care provided to oldest-old patients with end-stage non-cancer chronic diseases admitted to an acute care hospital. In any case, care should be improved for both age groups.
Coenzyme Q10 Administration Suppresses both Oxidative and Antioxidative Markers in Hemodialysis Patients
Authors: Sakata Tomoko , Furuya Ryuichi , Shimazu Takako , Odamaki Mari , Ohkawa Sakae , Kumagai Hiromichi
Published: June 2008

Background: Increased oxidative stress is associated with various complications in hemodialysis (HD) patients. Methods: We examined the effect of coenzyme Q10 (CoQ10) administration on the plasma oxidative products and antioxidant capacity in 36 HD patients for 6 months. Results: The advanced oxidation protein products (AOPP), malondialdehyde and the percentage of ubiquinone in total CoQ10 were significantly higher in HD patients than in healthy subjects before administration (0 month). Oxygen radical absorbing capacity (ORAC) and Trolox equivalent antioxidant capacity (TEAC), indicators of total antioxidant capacity, were also paradoxically higher in the HD patients at 0 month. AOPP and the percentage of ubiquinone significantly decreased during CoQ10 administration, but increased again after the discontinuation. ORAC and TEAC were also decreased during CoQ10 administration. Conclusion: The CoQ10 administration was partially effective for suppressing the oxidative stress in HD patients. The unexpected decrease of ORAC and TEAC by CoQ10 seemed to be associated with a decreased oxidative stress.
Imaging Epileptic Activity Using Functional MRI
Authors: Krakow Karsten
Published: June 2008

This review concentrates on functional MRI (fMRI) methods to identify the epileptic focus, i.e. ictal and interictal fMRI. First, established clinical applications of fMRI in the field of epilepsy are briefly introduced: fMRI of sensorimotor, language and memory function can already be considered as clinically relevant tools to identify the eloquent cortex and to predict postoperative functional deficits in patients considered for epilepsy surgery. fMRI offers a valid alternative to invasive methods like the Wada test for establishing language dominance, and it is likely that it will also replace the Wada test for assessing presurgical memory function in the nearer future. Ictal fMRI (fMRI studies of epileptic seizures) will remain confined to exceptional cases due to practical limitations. The generators of interictal epileptiform discharges (IED) can be studied with EEG-correlated fMRI. Despite its technical challenges, it has proved useful to provide insights into the generation of IED in patients with focal and generalized epilepsy. In selected patients with focal IED, EEG-correlated fMRI has the potential to reproducibly identify cortical areas involved in generating IED, i.e. the irritative zone. In patients with generalizes IED, suspension of functional networks due to the IED can be demonstrated. The utility of EEG-correlated fMRI in clinical epileptology cannot be definitely determined yet.
Effects of HMG-CoA Reductase Inhibition by Simvastatin on Vascular Dysfunction Induced by Lipopolysaccharide in Rats
Authors: Alvarez de Sotomayor Maria , Vega Silvia , Mingorance Carmen , Marhuenda Elisa , Herrera Maria Dolores
Published: June 2008

Aims: Statins have been identified as a potentially interesting treatment against sepsis. Here, we study the vascular reactivity of aortae from rats treated with lipopolysaccharide (LPS), 4 mg · kg–1, following chronic administration of simvastatin (SV) 10 mg · kg–1. Methods: The rats were treated with either vehicle or SV for 4 weeks before administration of LPS. After 18 h, the systolic blood pressure (SBP) was measured using a tail cuff and vascular and endothelial responses of aortic rings to several agonists were studied in an organ bath. Results: LPS injection decreased the SBP by 38 mm Hg and vascular response to phenylephrine (Phe) by 60%. Plasma nitrates and nitrites (NOx) were 3-fold higher after LPS. This attenuated response to Phe was prevented by incubation with either the inducible-nitric-oxide-synthase (iNOS)-selective inhibitor 1400W or the endothelial nitric oxide synthase (eNOS)/iNOS nonselective blocker L-NAME. The presence of endothelium did not alter these findings. Administering LPS to SV-treated rats also decreased the SBP and increased the NOx concentration. The impaired response to Phe was restored by blocking NO synthesis in endothelium-denuded but not in intact aortic rings. The response to acetylcholine demonstrated an enhanced reduction in arteries from the SV + LPS group compared with the LPS group. The inhibition of iNOS prevented acetylcholine-induced relaxation in rings from LPS-treated rats but not in those from the SV + LPS group. Conclusion: These results suggest that statins may reduce iNOS-mediated NO production in endothelial but not in vascular smooth-muscle cells.
Skin Irritation and Sensitization: Mechanisms and New Approaches for Risk Assessment
Authors: Basketter D. , Darlenski R. , Fluhr J.W.
Published: June 2008

Allergic contact dermatitis (ACD) is a common skin disease with a significant social and economic impact. In contrast to irritation, skin sensitization is a response of the adaptive immune system, in which there is a delayed T-cell-mediated allergic response to chemically modified skin proteins. The chemicals that can covalently modify the skin proteins and trigger an allergic reaction are referred to as haptens or sensitizers. Attempts have been made in many countries to reduce the problems of ACD by the implementation of legislations related to skin-sensitizing chemicals, as well as by the early detection and risk assessment of substances with sensitizing properties. For many years, the simple identification of sensitizing chemicals was performed in guinea pig tests. A murine test, the local lymph node assay (LLNA), has been validated as a replacement for the guinea pig tests. Despite the recent introduction of in vitro methods for the identification of sensitizing chemicals, the LLNA results (when coupled with good exposure data) can be used as the starting point for a quantitative risk assessment. The quantitative risk assessment is aimed to identify the safe use thresholds for any potential skin sensitizer.
Fungicidal Activity Plus Reservoir Effect Allow Short Treatment Courses with Terbinafine in Tinea pedis
Authors: Schäfer-Korting M. , Schoellmann C. , Korting H.C.
Published: June 2008

Terbinafine, a synthetic allylamine, exerts fungicidal activity against dermatophytes, the causative pathogens of tinea pedis. As proven in numerous clinical trials, tinea pedis can be effectively and safely treated by topical terbinafine. In fact, a 1-week application of terbinafine 1% cream eradicated fungal pathogens at least as effectively as 4-week treatment courses with topical azole derivative antifungals and showed lower relapse rates. A new innovative single-application formulation of terbinafine 1% in a film-forming solution produces a high concentration gradient on the skin surface and enables a prolonged (up to 13 days) exposure of the skin to terbinafine. High drug penetration into the skin results in an otherwise not obtained drug reservoir in the horny layer, the location of dermatophytes in tinea pedis. Although azole antimycotics can also effectively penetrate into the horny layer of the skin, short-term therapy might not be feasible due to its primarily fungistatic activity against dermatophytes. Thus, we conclude that the high efficacy of short-term treatment with terbinafine in patients with tinea pedis is possible due to its fungicidal activity coupled with a distinct reservoir formation in the upper layers of the epidermis.
Claudin 2 mRNA and Protein Are Present in Human Keratinocytes and May Be Regulated by All-trans-Retinoic Acid
Authors: Telgenhoff D. , Ramsay S. , Hilz S. , Slusarewicz P. , Shroot B.
Published: June 2008

Tight junctions are composed of claudins, occludins, junctional adhesion molecules and plaque proteins. Claudin 2 protein forms a cation-selective channel which confers increased permeability in renal epithelial cells and in the intestine where its expression is restricted to the leaky epithelium. Immunohistochemical staining revealed claudin 2 staining in the granular layer of adult epidermis. Analysis of Western blots revealed bands corresponding to the molecular weight of claudin 2 in Madin-Darby canine kidney II cells, human kidney, adult skin and neonatal keratinocytes. Reverse transcriptase polymerase chain reaction on mRNA and cDNA sequence analysis found a 99% sequence homology between our cDNA and human claudin 2 (NIH BLAST sequence). Further, we show that all-trans-retinoic acid increases the expression of claudin 2 in keratinocytes in a dose-dependent manner. The discovery of claudin 2 transcript and protein in the skin could be of importance in epidermal differentiation, barrier function and pathological conditions.
Antiproliferative Effect of Vitamin A and D Analogues on Adult Human Keratinocytes in vitro
Authors: Popadic S. , Ramic Z. , Medenica L. , Mostarica Stojkovic M. , Trajković V. , Popadic D.
Published: June 2008

Background: Vitamin A and D analogues play an important role in epidermal homeostasis and are used in the treatment of various skin diseases. The failure of retinoid and vitamin D treatments is sometimes difficult to explain. Methods: We analyzed the effect of all-trans retinoic acid (all-trans RA), 13-cis retinoic acid (13-cis RA), ergocalciferol and cholecalciferol in keratinocyte cultures established from adult donors, on the cell proliferation by means of [3H]thymidine incorporation and apoptosis after fluorescein diacetate/trypan blue staining. Results: All tested agents exerted a dose-dependent inhibition of keratinocyte proliferation in the concentration range of 1.25–5 µM. Based on IC50 values, the antiproliferative efficiency was as follows: cholecalciferol > ergocalciferol = all-trans RA > 13-cis RA. The observed effect of cholecalciferol and ergocalciferol, but not retinoids, involved the induction of apoptotic cell death. Combining vitamins A and D did not further increase the proliferation block and even displayed an antagonistic effect. Conclusion: The susceptibility of keratinocytes to the antiproliferative action of vitamins A and D was markedly different in cell cultures derived from different donors, indicating a possible predictive value of the in vitro testing for the efficiency of the clinical response to these agents.
Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters
Authors: Buddenberg Tim E. , Topic Bianca , Mahlberg E. Demetris , de Souza Silva Maria A. , Huston Joseph P. , Mattern Claudia
Published: June 2008

Background: Recently, we found evidence that intra-nasally administered dopamine (DA), can enter the brain, leading to an immediate increase in extracellular DA levels in striatal subregions. This offers a potential alternative approach to target the brain with exogenous DA, which otherwise cannot cross the blood-brain barrier. Here, we examined whether intra-nasally applied DA also exerts behavioral activity on mesocortical and nigrostriatal dopaminergic functions. Method: Male Wistar rats (3–4 months) were tested for potential behavioral effects of intra-nasally applied DA (0.03, 0.3 or 3.0 mg/kg) in the forced swimming test (FST) for antidepressant-like activity, elevated plus-maze for anxiety-related behavior, and on motor activity in a novel and familiar environment. Results: Intra-nasally administered dopamine in a dose of 0.3 mg/kg exerted antidepressant-like activity in the FST, but had neither anxiolytic-like nor anxiogenic-like effects in the elevated plus-maze. Furthermore, intra-nasal dopamine stimulated locomotor activity in a familiar, but not novel, open field. Conclusions: These results support the view that intra-nasally applied DA can act on the central nervous system by entering the brain via the nose-brain pathway, making this kind of application procedure a promising alternative for targeting the brain, and thus treating disorders involving mesocortical and/or nigrostriatal dopaminergic disturbances.
Association of Tumor Necrosis Factor –308G/A Promoter Polymorphism with Schizophrenia and Bipolar Affective Disorder in a Polish Population
Authors: Czerski Piotr M. , Rybakowski Filip , Kapelski Paweł , Rybakowski Janusz K. , Dmitrzak-Węglarz Monika , Leszczyńska-Rodziewicz Anna , Słopień Agnieszka , Skibińska Maria , Kaczmarkiewicz-Fass Magdalena , Hauser Joanna
Published: June 2008

Background/Aims: Schizophrenia (SCH) and bipolar affective disorder (BPAD) are complex disorders with significant participation of genetic risk factors. Several lines of evidence point to the role of shared neurobiological mechanisms and common genetic background in SCH and BPAD. Immune disturbances have been suggested as contributing factor in the pathogenesis of both SCH and BPAD. The gene coding cytokine tumor necrosis factor (TNF) has been the object of a number of association studies in SCH, with ambiguous results. Only 3 such studies were performed in BPAD. The aim of our study was to perform a case-control association analysis of the TNF –308G/A polymorphism in a Polish sample of patients with SCH, BPAD and healthy controls. Methods: We genotyped the TNF –308G/A polymorphism (rs1800629) by PCR-RFLP in 348 patients with SCH, 361 patients with BPAD and in 351 controls. Results: We observed an association of the –308G allele with both SCH (p = 0.008) and BPAD (p = 0.039), and also with a positive family history in patients with SCH (p = 0.048) and BPAD (p = 0.027). For TNF genotypes, the association was only seen in SCH (p = 0.018). Conclusions: Our results may point to an association of the TNF –308G allele and –308G/G genotype with both SCH and BPAD, and to a relationship of the –308G allele with the risk of SCH and BPAD in patients with a positive family history. TNF could be potentially a susceptibility gene, shared between SCH and BPAD. Complex TNF gene studies – based on multiple single-nucleotide polymorphisms and involving haplotype analysis – are necessary for the clarification of currently contradictory findings.
Prevalence of Stroke and Transient Ischemic Attack in Three Elderly Populations of Central Spain
Authors: Díaz-Guzmán J. , Bermejo-Pareja F. , Benito-León J. , Vega S. , Gabriel R. , Medrano M.J.
Published: June 2008

Objective: Our aim was to assess prevalence rates of cerebrovascular disease (CVD; stroke and transient ischemic attacks) according to age and gender in three populations in central Spain using data from the Neurological Disorders in Central Spain (NEDICES) study, a population-based survey of elderly participants. Methods: Individuals from one suburban municipality of Greater Madrid (Las Margaritas neighborhood, Getafe), one urban district of Madrid (Lista) and one rural site (Arévalo county, Avila) were evaluated at baseline (n = 5,278). The evaluation included a screening questionnaire and a neurological assessment when possible. We used point prevalence with a reference date of May 1, 1994. Results: Of the 5,278 subjects, there were 186 prevalent stroke cases and 71 cases of transient ischemic attacks. Prevalence rates, adjusted to the standard European populations, were 4.9% for CVD (95% confidence interval [CI] = 4.3–5.4), 3.4% for stroke (95% CI = 2.9–3.9) and 1.3% for transient ischemic attacks (95% CI = 1.0–1.6) in the total population. Age-specific prevalence rates of CVD, stroke and transient ischemic attacks increased exponentially with advancing age. The prevalence rates of CVD, stroke and transient ischemic attacks were higher for men than for women. Prevalence figures were higher in the suburban area of Margaritas compared to the rural region. Conclusions: In this study, the prevalence of stroke and transient ischemic attacks were higher in men and in urban areas. Central Spain would be a medium stroke prevalence zone.
Neurological Symptoms in Aortic Dissection: A Challenge for Neurologists
Authors: Gaul Charly , Dietrich Wenke , Erbguth Frank Joachim
Published: June 2008

Typically, aortic dissection has to be considered in patients with acute thoracic or abdominal pain and accompanying cardiovascular symptoms. Due to these clinical symptoms, neurologists have not been involved in the routine emergency management of aortic dissection. However, transient or permanent neurological symptoms at onset of aortic dissection are not only frequent (17–40% of the patients), but often dramatic and may mask the underlying condition. Especially in pain-free dissection (which occurs in 5–15%) with predominant neurological symptoms diagnosis of aortic dissection can be difficult and delayed. Affecting the outflow of supra-aortal, spinal as well as extremity arteries leads to a variety of neurological symptoms including disturbances of central or peripheral nervous system. Thrombolysis as an emergency stroke therapy without considering aortic dissection may be life-threatening for these patients. Routine chest X-ray and being alert to physical examination findings such as hypotension, asymmetrical pulses or cardiac murmur may reduce risk of delayed diagnosis or misdiagnosis. Neurological symptoms at onset or in the postoperative course of aortic dissection are not necessarily associated with increased mortality.
Quantification of the Probability of Reaching Mobility Independence at Discharge from a Rehabilitation Hospital in Nonwalking Early Ischemic Stroke Patients: A Multivariate Study
Authors: Paolucci Stefano , Bragoni Maura , Coiro Paola , De Angelis Domenico , Fusco Francesca Romana , Morelli Daniela , Venturiero Vincenzo , Pratesi Luca
Published: June 2008

Background: This study was designed to quantify the probability of recovery of mobility in admission nonwalking stroke survivors. Methods: We evaluated 437 of 500 consecutive patients admitted for sequelae of first ischemic stroke within the first month. We performed several logistic regressions using mobility status at discharge (independence in stair climbing; walking outside and inside, without aid or supervision; walking with cane or other aid, or need for wheelchair) as dependent variable, and several independent variables, including stratification of patients according to their Barthel Index (BI) score into 6 classes (≤10; 11–20; 21–30; 31–40; 41–50; 51–60). Results: At discharge, 4.58% of patients were independent in stair climbing, 8.70% were able to walk outside, 14.41% to walk inside, and 27.46% to walk with cane or other aid, while 44.85% remained in wheelchair. Very low BI scores at admission were associated with a high risk of need for wheelchair, whereas patients with BI score 51–60 showed a high probability to reach independence in stair climbing (OR = 5.60). Age, severity of neurological impairment, global aphasia, unilateral spatial neglect, male gender and vocational status also played a prognostic role. Conclusions: The probability of potential mobility recovery can be quantified at admission with better accuracy for independence in stair climbing and walking outside without any aid (percentages correctly predicted 95.4 and 91.8%, respectively). Stratification of BI score may be useful to better quantify the risk for each patient.
Vessel Wall Contrast Enhancement: A Diagnostic Sign of Cerebral Vasculitis
Authors: Küker Wilhelm , Gaertner Susanne , Nägele Thomas , Dopfer Christian , Schöning Martin , Fiehler Jens , Rothwell Peter M. , Herrlinger Ulrich
Published: June 2008

Purpose: Inflammatory stenoses of cerebral arteries cause stroke in patients with florid vasculitis. However, diagnosis is often difficult even with digital subtraction angiography (DSA) and biopsy. The purpose of this study was to establish the value of contrast-enhanced MRI, proven to be sensitive to extradural arteritis, for the identification of intracranial vessel wall inflammation. Patients and Methods: Twenty-seven patients with a diagnosis of cerebral vasculitis affecting large brain vessels were retrieved from the files: 8 children (2–10 years, 7 female, 1 male) and 19 adults (16–76 years, 10 female, 9 male). Diagnosis was based on histological or serological proof of vasculitis or on clinical and imaging criteria. All MRI examinations included diffusion-weighted imaging, time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced scans. MRI scans were assessed for the presence of ischemic brain lesions, arterial stenoses, vessel wall thickening and contrast uptake. Results: Ischemic changes of the brain tissue were seen in 24/27 patients and restricted diffusion suggestive of recent ischemia in 17/27; 25/27 patients had uni- or multifocal stenoses of intracranial arteries on TOF-MRA and 5/6 had stenoses on DSA. Vessel wall thickening was identified in 25/27, wall enhancement in 23/27 patients. Conclusion: Wall thickening and intramural contrast uptake are frequent findings in patients with active cerebral vasculitis affecting large brain arteries. Further prospective studies are required to determine the specificity of this finding.
The Complications of Cardioembolic Stroke: Lessons from the VISTA Database
Authors: Hallevi Hen , Albright Karen C. , Martin-Schild Sheryl , Barreto Andrew D. , Grotta James C. , Savitz Sean I.
Published: June 2008

Background: Cardioembolic stroke (CES) accounts for 20–30% of ischemic strokes. We attempted to describe the complications of CES. Methods: We analyzed a cohort of CES patients from the VISTA database who were not given thrombolytics. Results: 397 patients were included. Recurrent stroke occurred in 2.5% (10/397); stroke progression in 7.8% (31/397); systemic bleeding in 3% (12/397), and hemorrhagic transformation (HT) in 1.5% (6/397). A bimodal temporal distribution was observed for HT. The mortality rate was 103/397 (25.9%) and was associated with stroke progression and recurrence. Conclusions: HT is common in CES patients and presents in a bimodal distribution. Stroke progression is the most frequent serious complication. Further study is indicated to identify predictors of stroke progression.