bluuebunny/crossref_metadata_2025 huggingface dataset:
Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor, Inhibits HIF-1α Expression in an AhR-Independent Fashion
Authors: Terzuoli Erika , Puppo Maura , Rapisarda Annamaria , Uranchimeg Badarch , Cao Liang , Burger Angelika M. , Ziche Marina , Melillo Giovanni
Published: August 2010

Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/AhR, which is shared with HIF-1α, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1α expression in AhR100 cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1α mRNA expression by ∼50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1α mRNA, indicating that active transcription was required for the inhibition of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of HIF-1 target genes in MCF-7 xenografts. These results show that AF inhibits HIF-1α in an AhR-independent fashion, and they unveil additional activities of AF that may be relevant for its further clinical development. Cancer Res; 70(17); 6837–48. ©2010 AACR.
HER-2 Signaling, Acquisition of Growth Factor Independence, and Regulation of Biological Networks Associated with Cell Transformation
Authors: Bollig-Fischer Aliccia , Dziubinski Michele , Boyer Alaina , Haddad Ramsi , Giroux Craig N. , Ethier Stephen P.
Published: August 2010

Activated oncogenes are the dominant drivers of malignant progression in human cancer, yet little is known about how the transformation from proto-oncogene to activated oncogene drives the expression of transformed phenotypes. An isogenic model of HER-2–mediated transformation of human mammary epithelial cells was used along with HER-2–amplified human breast cancers to investigate how HER-2 activation alters its properties as a signaling molecule and changes the networks of HER-2–regulated genes. Our results show that full oncogenic activation of HER-2 is the result of a transition in which activated HER-2 acquires dominant signaling properties that qualitatively alter the network of genes regulated by the activated oncogene compared with the proto-oncogene. Consequently, gene expression programs related to invasion, cell stress, and stemness become regulated by HER-2 in a manner not observed in nontransformed cells, even when HER-2 is overexpressed. Our results offer novel insights into biological processes that come under the control of HER-2 after it acquires full oncogenic potential. Cancer Res; 70(20); 7862–73. ©2010 AACR.
Interaction with Vascular Endothelium Enhances Survival in Primary Chronic Lymphocytic Leukemia Cells via NF-κB Activation andDe novoGene Transcription
Authors: Buggins Andrea G.S. , Pepper Chris , Patten Piers E.M. , Hewamana Saman , Gohil Satyen , Moorhead Jane , Folarin Najeem'deen , Yallop Deborah , Thomas N. Shaun B. , Mufti Ghulam J. , Fegan Chris , Devereux Stephen
Published: August 2010

Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found in peripheral blood samples, coupled with its short half-life, led us to hypothesize that it must be actively maintained in the peripheral circulation. Coculture of CLL cells with human vascular endothelial cells significantly enhanced tumor cell survival, an effect that was not observed with normal B cells. This was associated with elevated levels of the antiapoptotic proteins Bcl-2, Mcl-1, and Bcl-XL and marked increased expression of CD38 and CD49d, both of which are associated with clinically aggressive disease. Because CD38, CD49d, and some Bcl-2 family genes are transcriptional targets for NF-κB, we assessed NF-κB activation following coculture with endothelial cells. DNA binding of the NF-κB subunit Rel A was significantly increased and strongly correlated with changes in transcription of CD38, CD49d, BCL2, MCL1, and BCLXL, effects that were reversed by a peptide inhibitor of Rel A. These effects were not observed following coculture with nonendothelial cell lines. Therefore, CLL cells receive specific survival signals following interaction with endothelial cells mediated through the activation of NF-κB and the induction of downstream target genes. This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease. Cancer Res; 70(19); 7523–33. ©2010 AACR.
Prediction of Stage, Grade, and Survival in Bladder Cancer Using Genome-wide Expression Data: A Validation Study
Authors: Lauss Martin , Ringnér Markus , Höglund Mattias
Published: August 2010

Purpose: To evaluate performances of published gene signatures for the assessment of urothelial carcinoma.

Experimental Design: We evaluated 28 published gene signatures designed for diagnostic and prognostic purposes of urothelial cancer. The investigated signatures include eight signatures for stage, five for grade, four for progression, and six for survival. We used two algorithms for classification, nearest centroid classification and support vector machine, and Cox regression to evaluate signature performance in four independent data sets.

Results: The overlap of genes among the signatures was low, ranging from 11% among stage signatures to 0.6% among survival signatures. The published signatures predicted muscle-invasive and high-grade tumors with accuracies in the range of 70% to 90%. The performance for a given signature varied considerably with the validation data set used, and interestingly, some of the best performing signatures were not designed for the tested classification problem. In addition, several nonbladder-derived gene signatures performed equally well. Large randomly selected gene signatures performed better than the published signatures, and by systematically increasing signature size, we show that signatures with >150 genes are needed to obtain robust performance in independent validation data sets. None of the published survival signatures performed better than random assignments when applied to independent validation data.

Conclusion: We conclude that gene expression signatures with >150 genes predict muscle-invasive growth and high-grade tumors with robust accuracies. Special considerations have to be taken when designing gene signatures for outcome in bladder cancer. Clin Cancer Res; 16(17); 4421–33. ©2010 AACR.
Food and Oral Antineoplastics: More Than Meets the Eye
Authors: Jain Rajul K. , Brar Satjit S. , Lesko Lawrence J.
Published: August 2010

Food can alter the bioavailability of orally administered drugs. Description of food effects in product labels and information about administration in relation to food are influenced by a variety of factors. Because food effects can change drug efficacy and toxicity, it is important that physicians and patients be aware of them. Clin Cancer Res; 16(17); 4305–7. ©2010 AACR.
Activating Stress-Activated Protein Kinase–Mediated Cell Death and Inhibiting Epidermal Growth Factor Receptor Signaling: A Promising Therapeutic Strategy for Prostate Cancer
Authors: Kumar Raj , Srinivasan Sowmyalakshmi , Pahari Pallab , Rohr Jürgen , Damodaran Chendil
Published: August 2010

Epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal–regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH2-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC. Mol Cancer Ther; 9(9); 2488–96. ©2010 AACR.
Substitution of Adenovirus Serotype 3 Hexon onto a Serotype 5 Oncolytic Adenovirus Reduces Factor X Binding, Decreases Liver Tropism, and Improves Antitumor Efficacy
Authors: Short Joshua J. , Rivera Angel A. , Wu Hongju , Walter Mark R. , Yamamoto Masato , Mathis J. Michael , Curiel David T.
Published: August 2010

Following intravascular delivery, an important route of administration for many clinical applications, the liver is the predominant site of adenovirus serotype 5 (Ad5) sequestration, thereby posing a risk of toxicity. In this regard, it has recently been shown that the Ad5 capsid binds to the blood coagulation factor X (FX) via the Ad5 hexon protein. This interaction mediates the majority of Ad5 liver transduction. Patient FX levels can be diminished by the administration of warfarin, a vitamin K inhibitor in the liver that decreases FX production; however, warfarin is a potent anticoagulant and can have a number of undesired side effects. Therefore, genetic modification of the virus to ablate FX binding is the preferred approach. Modifications of the hexon protein, specifically within the hypervariable 5 (HVR5) and 7 (HVR7) regions, have produced Ad5 vectors that show minimal liver sequestration. Our laboratory has pioneered adenovirus hexon modifications, including insertion of peptide ligands into the hypervariable regions and substitution of the adenovirus hexon with hexon proteins from alternate serotypes. Substitution of the adenovirus serotype 3 (Ad3) hexon protein onto the Ad5 capsid has been further characterized with regard to its interaction with FX and incorporated into an infectivity-enhanced conditionally replicative adenovirus (CRAd). In vitro evaluation of these hexon-modified vectors showed decreased binding to FX and decreased cell transduction via FX-mediated pathways. Furthermore, in vivo biodistribution studies in mice exhibited a decrease in liver sequestration. With the use of xenograft tumor models, the antitumor efficacy of the hexon-modified CRAds was enhanced over nonmodified controls. Mol Cancer Ther; 9(9); 2536–44. ©2010 AACR.
The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias
Authors: Kojima Kensuke , Burks Jared K. , Arts Janine , Andreeff Michael
Published: August 2010

The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in apoptosis preferentially of S-phase cells. E2F1 knockdown blocked apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maintained in leukemia/stroma cocultures, unlike doxorubicin, which has reduced cytrotoxicity in coculture systems. JNJ-26854165 synergizes with 1-β-arabinofuranosylcytosine or doxorubicin to induce p53-mediated apoptosis. Our data suggest that JNJ-26854165 may provide a novel therapeutic approach for the treatment of acute leukemias. The presence of p53-independent apoptotic activity in addition to p53-mediated apoptosis induction, if operational in vivo, may prevent the selection of p53 mutant subclones during therapy. Mol Cancer Ther; 9(9); 2545–57. ©2010 AACR.
Ipsilateral Double Parathyroid Adenoma and Thyroid Hemiagenesis
Authors: Mydlarz W.K. , Zhang K. , Micchelli S.T. , Kim M. , Tufano R.P.
Published: August 2010

Background/Aims: To describe a case of left thyroid dysgenesis, accompanied by ipsilateral double parathyroid adenomas in a setting of primary hyperparathyroidism, and to review the pertinent literature on the diagnosis of these rare clinical scenarios. Methods: Review of the English literature with addition of a case report. Results: Preoperative evaluation included both sestamibi and ultrasound evaluation of the neck. Fine-needle aspiration biopsies of what was thought to be two concerning thyroid nodules revealed potential double intrathyroidal parathyroid adenomas. Video-assisted exploration verified double parathyroid adenomas and revealed concomitant left thyroid lobe dysgenesis. Intact parathyroid hormone level returned to normal and a greater than 50% drop from baseline was achieved intraoperatively with subsequent long-term cure. Conclusions: Thyroid dysgenesis is a rare, poorly understood and potentially confusing variety of developmental anomalies, which can be associated with thyroid as well as parathyroid disease. Clinical diagnosis is highly dependent upon the clinician maintaining an index of suspicion for these anomalies, thorough physical examination and careful review of available imaging modalities, especially while investigating thyroid and parathyroid disorders.
Contribution of Magnetic Resonance Imaging to Prenatal Differential Diagnosis of Renal Tumors: Report of Two Cases and Review of the Literature
Authors: Linam L.E. , Yu X. , Calvo-Garcia M.A. , Rubio E.I. , Crombleholme T.M. , Bove K. , Kline-Fath B.M.
Published: August 2010

Enlargement of a kidney on prenatal imaging is usually due to hydronephrosis or cystic renal disease, and much less often results from solid tumors such as mesoblastic nephroma, Wilms’ tumor, nephroblastomatosis, renal sarcoma, and angiomyolipoma. All can be diagnosed by ultrasound. Magnetic resonance imaging is useful not only in confirming the presence of a renal mass, but also in the evaluation of the contralateral kidney for subtle abnormalities. We present one case each of Wilms’ tumor and mesoblastic nephroma, both detected on antenatal ultrasound and further studied with fetal magnetic resonance imaging.
Feticide Followed by Mifepristone-Misoprostol Regimen for Midtrimester Termination of Pregnancy in Two Cases of Complete Placenta Previa
Authors: Borrás A. , Gómez O. , Sanz M. , Martínez J.M. , Puerto B.
Published: August 2010

Placenta previa (PP), with a frequency of 5–7% in the second trimester, is considered one of the most important causes of obstetric hemorrhage. Surgical curettage is the classically recommended method to perform a midtrimester termination of pregnancy (TOP) in the presence of PP. Recent clinical reports suggest that induction of delivery is possible in these cases, but no information on mifepristone-misoprostol regimen is available. We present 2 cases of mifepristone-misoprostol midtrimester TOP with a diagnosis of complete PP. In both cases, a preinduction feticide was performed. Neither of the 2 cases presented a significant maternal bleeding. This report is relevant considering that this regimen is the most widely used and generally reported as the safest and most effective medical midtrimester TOP method.
The Diagnostic and Therapeutic Challenge of Early Psoriatic Arthritis
Authors: Gisondi Paolo , Tinazzi Ilaria , Del Giglio Micol , Girolomoni Giampiero
Published: August 2010

Psoriasis is a complex disease involving the skin, nails and musculoskeletal structures. Psoriatic arthritis (PsA) affects peripheral joints, entheses, the synovial sheaths of tendons and the axial skeleton. PsA is now recognised as a potentially debilitating disease, with bone erosions and deformities affecting about half of patients and arising early after disease onset. Because PsA usually coincides with or follows the development of psoriasis, dermatologists are in a strategic position to diagnose and manage early PsA. In general, patients with severe psoriasis appear to have a higher risk of arthritis than patients with mild psoriasis. In addition, scalp lesions, nail dystrophy and intergluteal/perianal lesions have been found to be associated with a higher risk of PsA development. The diagnosis of PsA is based primarily on clinical features, and several classification criteria have been developed. Ultrasonography, magnetic resonance imaging and bone scintigraphy, rather than standard radiography, are the most accurate and effective diagnostic imaging approaches for documenting early PsA. The therapeutic strategy for early PsA should be aimed at inducing lasting remission, preventing permanent damage and possibly modifying the natural disease course.
Nailing down the Genetic and Immunological Basis for Psoriatic Disease
Authors: McGonagle Dennis , Palmou Fontana Natalia , Tan Ai Lyn , Benjamin Michael
Published: August 2010

Psoriatic disease encompassing skin, joint and nail involvement is largely viewed as autoimmune – a finding supported by data from animal models, the human leucocyte antigen (HLA)-Cw6 disease association in man, T-lymphocyte infiltration in lesional skin and the favourable skin response to T-cell-directed therapies. However, this immunopathogenetic model only applies to the skin, as recent studies failed to demonstrate a HLA-Cw6 association with the nails or joints. Furthermore, the nails and joints are intimately associated with inflammation at points of ligament or tendon insertion (i.e., enthesitis), so it is now appreciated that both of these sites also share a common microanatomical basis. Moreover, inflammation at insertion sites and nails does not appear to be associated with a particular antigenic territory but is quite diffuse in nature. This suggests that an aberrant response to tissue stressing of the integrated nail-joint apparatus, rather than autoimmunity, is driving the inflammatory process. Therefore, HLA-Cw6-associated type 1 psoriasis is more closely linked to autoimmunity, whereas nail and joint disease may be linked to tissue-specific factors, including tissue biomechanical stressing and microtrauma, that lead to activation of aberrant innate immune responses. These observations that stem from nail disease point toward a relative differential involvement of adaptive and innate immunity in the psoriatic disease spectrum and offer a fresh perspective on the pathophysiology of psoriatic disease and how it can be classified along the immunological disease continuum of self-directed inflammation.
Methods of Outcomes Measurement in Nail Psoriasis
Authors: Augustin M. , Ogilvie A.
Published: August 2010

Background: Nail involvement is a common feature of psoriasis, predicting higher disease severity and greater impairment in quality of life. Valid assessment of nail psoriasis is relevant for research and routine clinical use. However, no measurement standards have currently been developed. Objective: To identify state-of-the-art outcomes measurements in nail psoriasis by literature analysis. Methods: Systematic Web-based literature search, followed by structured critical appraisal and consecutive descriptive report. The search focused on methodological and epidemiological publications and papers describing outcomes of clinical trials on nail psoriasis. Results: Initially, 646 publications met the primary criteria. After non-relevant or replicate publications were excluded, 66 papers were analysed, including clinical trials or case reports (n = 41), reviews (n = 11) and methodological or epidemiological studies (n = 14). In total, 23 clinical outcomes measures and 15 patient-reported outcomes (PRO) tools were used. None had been validated according to recent standards. In the studies with clinical interventions (n = 41), NAPSI (Nail Psoriasis Severity Index; n = 4) or target NAPSI (n = 2) were the most often used single tools, followed by Physician’s Global Assessment (n = 3). However, in 16 studies, no specifically described outcomes measures were used. Conclusion: Valid clinical outcomes measures in nail psoriasis are rare. Existing tools lack validation and standardisation. A need exists for accurate and scientifically sound evaluation of nail psoriasis severity in trials and clinical practice. To cover all elements of nail psoriasis, the optimal nail psoriasis assessment tool would include both PRO and physician-assessed outcomes measures.
Treatment and Management of Psoriasis with Nail Involvement: A Focus on Biologic Therapy
Authors: Langley Richard G. , Daudén Esteban
Published: August 2010

Nail involvement in psoriasis is typically overlooked, although it can affect up to 50% of patients with psoriasis and cause functional impact as well as psychological stress that can significantly affect quality of life. In addition, psoriatic patients with nail disease tend to have a more severe skin condition, a higher rate of unremitting and progressive arthritis and more associated anxiety and depression. Historically, the treatment of nail psoriasis has proven difficult, with most patients feeling that the treatment for their nail disease was unsatisfactory. The current management of nail psoriasis includes topical, intralesional and systemic therapies, although little clinical evidence is available on the effectiveness of conventional treatments and, consequently, no specific treatment approach has been fully supported. Biologic agents are beginning to emerge as a viable option to treat patients with both cutaneous and nail clinical manifestations of psoriasis and psoriatic arthritis. The extra disease burden that nail symptoms place on the patient can be considered indicative of a more severe form of the disease and should be taken into consideration when assessing treatment options.
The Impact of Methodological Approaches for Presenting Long-Term Clinical Data on Estimates of Efficacy in Psoriasis Illustrated by Three-Year Treatment Data on Infliximab
Authors: Papoutsaki M. , Talamonti M. , Giunta A. , Costanzo A. , Ruzzetti M. , Teoli M. , Chimenti S.
Published: August 2010

Background: Psoriasis affects about 2–3% of the Caucasian population. Biologics such as infliximab, etanercept, adalimumab and ustekinumab are efficacious treatments of plaque-type psoriasis. Critical to monitoring drug efficacy and safety is availability of long-term data. Despite the chronic nature of psoriasis, to date limited long-term clinical data have been available, as challenges are inherent in conducting a long-term analysis. With increasing time, it is more likely that the number of patients discontinuing treatment will also increase, due to loss of efficacy, adverse events or loss to follow-up. Interpretation of these data becomes confounded when one must consider missing data. Several approaches to analysing long-term data exist, and each accounts for missing data differently. Objective: To demonstrate that the choice of a particular analysis method to account for missing data has great impact on the assessed response rate. Methods: We used data from an open-label study over 3 years of continuous treatment with infliximab in patients with plaque-type psoriasis. These data were analysed by three methods – last observation carried forward, observed values and non-responder imputation – to account for missing data. Results: The 3-year PASI 75 responses varied from 41 to 75%, depending on the method of analysis; this shows that the response rate can almost double when a more liberal analytical approach is used. Conclusions: While it is clear that the need for long-term data on biologics in psoriasis is great, considering the analysis undertaken is important when designing long-term studies and interpreting the resulting data. When analysis methods such as observed values only or last observation carried forward are used, the results of the more conservative non-responder imputation should also be presented to give a fair overview of the long-term efficacy of a treatment for plaque-type psoriasis.
Functional Capillary Density Decreases after the First Week of Life in Term Neonates
Authors: Top A.P.C. , van Dijk M. , van Velzen J.E. , Ince C. , Tibboel D.
Published: August 2010

Background: Changes in the microcirculation have been recognized to play a crucial role in many disease processes. In premature neonates, functional capillary density (FCD) decreases during the first months of life. Objectives: The aims of this study were to obtain microcirculatory parameters in term neonates and older children who did not present with compromised respiration or circulation and to determine developmental changes in the microcirculation in young children. Methods: This single-center prospective observational study was performed at a level III university children’s hospital. Subjects eligible for inclusion were children up to the age of 3 years who did not have any respiratory compromise, circulatory compromise or signs of dehydration. The buccal mucosa of 45 children was assessed, using orthogonal polarization spectral imaging. Results: We found a significantly higher FCD in neonates younger than 1 week compared with older children. The median FCD was 8.1 cm/cm2 (range 7.3–9.4) for 0- to 7-day-old neonates (n = 12), 6.9 cm/cm2 (range 4.7–8.7) for 8- to 28-day-olds (n = 10), 7.3 cm/cm2 (range 6.1–8.8) for 1- to 6-month-olds (n = 19) and 6.7 cm/cm2 (range 6.5–9.2) for 3-year-olds (n = 4). After the first week, there was no significant correlation between age and FCD. Conclusion: FCD of the buccal mucosa decreases after the first week of life.
Effect of Hypothyroidism on Postnatal Conjunctival Development in Rats
Authors: Micali A. , Pisani A. , Puzzolo D. , Spinella R. , Roszkowska A. , Aragona P.
Published: August 2010

Aim: To study the conjunctival development in hypothyroid genetically epilepsy-prone rats (GEPRs) with serum T3 and T4 significantly lower than in normal rats. Methods: A structural, ultrastructural and histochemical study on the conjunctival epithelium of GEPRs and of control Sprague-Dawley (SD) rats before and after eyelid opening, with particular regard to goblet cell differentiation. Results: From birth to day 12, no goblet cells were demonstrated on the conjunctival surface of both strains, so that the epithelium was formed only by a cuboidal basal layer and by a superficial layer of roundish or flattened cells. On day 16, after the eyelid opening, Alcian blue (AB)-positive goblet cells filled with homogeneous granules were demonstrated isolated, in GEPRs, or clustered, in SD rats, in both the fornices and palpebral conjunctiva. The epithelium showed a basal layer and many layers of flattened cells and was taller in SD rats (8–10 layers) than in GEPRs (6–7 layers). At 3 months, the epithelium in SD rats was higher with generally clustered goblet cells, whilst in GEPRs goblet cells were both isolated or clustered. In both strains, the goblet cells showed a marked AB/periodic acid-Schiff positivity all over the conjunctival surface and were filled with granules of different density. In both strains, goblet cells were absent at birth and their appearance, as AB-positive cells, was concomitant with eyelid opening. Conclusions: Hypothyroid rats showed a conjunctival development different than that of normothyroid rats for both epithelial and goblet cells. It appears that thyroid hormone imbalance may influence conjunctival development.
Short- and Long-Term Efficacy of Combined Cabergoline and Octreotide Treatment in Controlling IGF-I Levels in Acromegaly
Authors: Mattar Priscilla , Alves Martins Manoel Ricardo , Abucham Julio
Published: August 2010

Objective: Nearly 40% of acromegalic patients fail to control GH/IGF-I levels with somatostatin analogues (SA). Dopaminergic agonists (DA) are even less effective, but combination therapy with SA and DA normalizes IGF-I levels in 33–56% of patients not controlled by octreotide alone in short-term studies. This study was designed to evaluate short- and long-term efficacy of cabergoline in controlling IGF-I levels in acromegalic patients receiving octreotide. Design: Open-label, single arm, prospective trial. Nineteen patients (14 females, 29–78 years of age) with high IGF-I on octreotide-LAR (30 mg/month IM) for ≧6 months were enrolled. Study I: Cabergoline (PO) was started at 1.0, increased to 2.0 and 3.5 mg/week, and withdrawn at 6-week intervals. IGF-I, GH, and PRL were measured at baseline and at 6-week intervals. Study II: Responder patients (IGF-I ≤1 ULN) resumed cabergoline at individual lowest effective doses and were evaluated at 6-month intervals for ≧12 months. Study III: Responders were withdrawn from octreotide and hormonally evaluated at 3-month intervals. Methods: Serum IGF-I (IRMA), GH (ICMA) and PRL (ICMA) levels were determined by commercially available kits. Results: Addition of cabergoline to octreotide-LAR normalized IGF-I levels in 7 of 19 patients (37%) during both short- and long-term follow-up (12–27 months, mean: 18 months). Octreotide withdrawal increased IGF-I levels in only 2 of 6 responder patients. Normalization of IGF-I levels by cabergoline was strongly associated with IGF-I ≤2.2 ULNR and/or GH ≤4.0 ng/ml under octreotide treatment. Conclusion: Addition of cabergoline to octreotide was effective in both short- and long-term control of IGF-I in acromegaly, especially in patients with mild/moderately elevated GH/IGF-I levels during octreotide.
Awareness of Memory Failures and Motivation for Cognitive Training in Mild Cognitive Impairment
Authors: Werheid Katja , Ziegler Matthias , Klapper Annina , Kühl Klaus-Peter
Published: August 2010

Background: Awareness of cognitive deficits is considered to be decisive for the effectiveness of cognitive training in mild cognitive impairment (MCI). However, it is unclear in what way awareness influences motivation to participate in cognitive training. Methods: Thirty-two elderly adults with MCI and 72 controls completed the 5-scale Memory Functioning Questionnaire (MFQ) and a motivation questionnaire. The predictive value of the MFQ scales on motivation was analyzed using regression analysis. Results: In the MCI group, but not in controls, higher perceived frequency of memory failures was associated with a lower motivation score. Conclusion: Our findings indicate that, in MCI, greater awareness of cognitive deficits does not necessarily increase motivation to participate in cognitive trainings, and suggest that success expectancy may be a moderating factor.
Association between Tumor Necrosis Factor-Alpha (–308G→A and –238G→A) Polymorphisms and Homocysteine Levels in Patients with Ischemic Strokes and Silent Brain Infarctions
Authors: Kim Ok Joon , Lee Jae Ho , Choi Jeong Kwon , Oh Seung Hun , Hong Seung Ho , Oh Doyeun , Kim Nam Keun
Published: August 2010

Background and Purpose: The aims of this study were to evaluate the role of tumor necrosis factor-α (TNF-α) polymorphisms in patients susceptible to ischemic stroke and silent brain infarction (SBI), and to determine the relationship between TNF-α polymorphisms and plasma total homocysteine (tHcy) levels. Methods: We studied 237 patients with ischemic stroke, 257 patients with SBIs, and 216 control subjects. For control subjects, we selected healthy individuals matched for gender and age from those individuals who came to our hospital for health examinations. The TNF-α–308G→A and –238G→A genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Results: The frequency of the TNF-α–308G→A polymorphism was significantly different between the patients with ischemic stroke and the control group (GG vs. GA+AA; adjusted odds ratio, AOR, 0.50; 95% CI 0.255–0.989). By subgroup analysis, when tHcy levels were stratified into high (>10.80 µmol/l), moderate (8.21–10.80 µmol/l), and low levels (<8.21 µmol/l), the frequency of the TNF-α–308GA+AA genotype in the highest tertile group was higher than in the lowest tertile group (AOR 2.46; 95% CI 1.063–5.699). However, the relationship between SBI susceptibility and polymorphisms of TNF-αwas not established. The tHcy levels were significantly and inversely correlated with folate levels in the TNF-α–308GG and TNF-α–238GG genotypes in the ischemic stroke, SBI, and control groups (p< 0.05). Conclusions: Our results suggest that the TNF-α–308G→A polymorphism is responsible for susceptibility to ischemic stroke and is associated with high tHcy levels in Koreans.
Cerebrospinal Fluid Pressure Measurement in the Ovine Intrathecal Space: A Preliminary Study towards the Diagnosis of Intrathecal Drug Administration Catheter Dislodgement or Occlusion
Authors: Coffey Robert J. , Miesel Keith , Billstrom Tina
Published: August 2010

Background and Objective: Intrathecal drug delivery catheter malfunctions are a principal cause of therapy interruption. We determined that normal baseline intrathecal cerebrospinal fluid (CSF) pressure recordings could be obtained in an ovine model and in a catheter dislodgement scenario. Methods: Two sheep were implanted with spinal catheters: 2 in the T6 epidural space in sheep No. 1; 1 T6 intrathecal catheter plus 1 L2 epidural catheter with a deliberate CSF leak to simulate dislodgement in sheep No. 2. Pressure waves were recorded intraoperatively and at multiple times after the implantation in the awake condition. On day 21, the animals were anesthetized for pressure recordings while on and temporarily off mechanical ventilation. They were then necropsied. Results: CSF pressure waves were obtained in this animal model under anesthesia with or without mechanical ventilation and in the awake state. Fluid accumulation at the tip of a dislodged (epidural) catheter temporarily caused apparent coupling of fluid pressures across the dura. An unintentional extraspinal fluid collection in sheep No. 2 was associated with a raised baseline epidural pressure. Conclusions: These findings support the notion that pressure sensors can play a role in determining the status of intraspinal drug delivery catheters.
Role of Genetic and Acquired Prothrombotic Risk Factors in Genesis of Sudden Sensorineural Hearing Loss
Authors: Fusconi Massimo , Chistolini Antonio , Angelosanto Noemi , Pignoloni Patrizia , Tombolini Mario , De Virgilio Armando , Pagliarella Martina , de Vincentiis Marco
Published: August 2010

The methylenetetrahydrofolate reductase C677T mutation, factor V G1691A (factor V Leiden) mutation, prothrombin G20210A mutation and 8 other laboratory values associated with increased thrombotic risk were analyzed in 40 patients with sudden sensorineural hearing loss (SSHL). The results were compared with those obtained from 120 controls not affected by SSHL. We found a statistically significant higher frequency of hyperhomocysteinemia in the SSHL group compared with controls, and that this was also associated with the presence of homozygosity for the MTHFR C677T mutation. The study results suggest that SSHL might be caused, among other factors, by a combination of these 2 variables. We suggest that this analysis of the MTHFR C677T mutation should be further investigated to establish the etiology of SSHL, and that the same analysis should be taken into account in those patients with high levels of homocysteine.
Incidence of Epilepsy in a Defined Area of Central Anatolia, Turkey, after 15 Years of Age
Authors: Çelikkaş Emine , Erdinç Oğuz Osman , Metintas Selma , Fidan Hüseyin Seyhan , Arıkan İnci , Kalyoncu Cemalettin , Özdemir Gazi
Published: August 2010

Background: The aim of this study was to establish the incidence rate, incidence-related characteristics, and epidemiological profile of epilepsy in Eskisehir, Turkey. Methods: Cases were prospectively recorded by utilizing multiple data sources, including case records obtained through the Hospital Information System, files kept by family physicians, and files kept by private neurologists. Patients diagnosed with epilepsy between July 1, 2007, and June 30, 2008, and above the age of 15 years were included in the study. Results: 219 new cases were diagnosed with epilepsy. The adjusted incidence rate was 33.51/100,000 cases in males and 42.22/ 100,000 cases in females, for a total of 37.59/100,000 persons. The incidence rates according to age were found to be highest in the 15–19-year age group and in the ≧70-year age group. Partial seizures were observed more than generalized seizures after the age of 40. Unknown etiology accounted for 77.2% of the epilepsies. Stroke was the most common etiological cause of epilepsy among the symptomatic group. Conclusions: The incidence rate of epilepsy in Eskisehir was comparable with the rates reported for developed countries.
An MRI-Based Semiquantitative Index for the Evaluation of Brain Atrophy and Lesions in Alzheimer’s Disease, Mild Cognitive Impairment and Normal Aging
Authors: Chen Wei , Song Xiaowei , Zhang Yunting , Darvesh Sultan , Zhang Ningnannan , D’Arcy Ryan C.N. , Black Sandra , Rockwood Kenneth
Published: August 2010

Background: This study investigates how T1-weighted MRI can be used to evaluate brain anatomical changes. We investigated these changes in Alzheimer’s disease (AD) and normal aging. Methods: A semiquantitative brain atrophy and lesion index (BALI) was constructed by adapting existing visual rating scales and validated in 3 datasets. Results: The T1- and T2-weighted-imaging-based scores were highly correlated. They were both closely associated with age and with cognitive test scores. Conclusion: The T1-based BALI helps describe brain structural variability in AD, mild cognitive impairment and normal aging.
A Nomogram to Assess Small-Intestinal Neuroendocrine Tumor (‘Carcinoid’) Survival
Authors: Modlin Irvin M. , Gustafsson Bjorn I. , Pavel Marianne , Svejda Bernhard , Lawrence Benjamin , Kidd Mark
Published: August 2010

Neuroendocrine tumors (NETs) are a heterogeneous group of cancers of which the commonest site is the small intestine (SI). Most information available to determine tumor behavior reflects univariate assessment of factors or is anecdotal or experience based. There currently exists no objective multivariate analysis of indices that defines SI NET prognosis. A key unmet need is the lack of a rigorous mathematical-based tool – a nomogram – for the assessment of parameters that define progress, determine prognosis and can guide therapy. Since prediction of NET behavior is a critical criterion in determining clinical strategy, we constructed a NET nomogram (Modlin Score) for prognosis prediction, patient group comparisons and a guide for stratification of treatment and surveillance. We used hazard ratio (HR), Cox analysis and Kaplan-Meier analysis of published data and the current Surveillance, Epidemiology and End Results (SEER) database (approx. 20,000 patients) to develop a nomogram from 15 variables demonstrated to provide significant multivariate HRs. These included age, gender, ethnicity, symptoms, urinary 5-hydroxyindoleacetic acid, plasma chromogranin A, liver function tests, tumor size, invasion, metastasis, histology, Ki-67 index, carcinoid heart disease and therapy (surgery or long-acting somatostatin analogs). Internal validation was assessed using 33 SI NET patients. A NET nomoscore (Modlin Score) was developed by HR weighting and stratification into low (<75), medium (75–95) and high risk (>95). This identified significant differences (p <0.03, Kaplan-Meier) in survival (15.5 ± 4.3, 9.7 ± 2.5 and 6.4 ± 1.1 years, respectively). The Modlin Score was significantly elevated (p <0.01) in deceased compared to alive patients. This nomogram represents an optimized construct based upon currently analyzable data, and application will facilitate accurate stratification for comparison in clinical trials. External validation and amplification by identification of additional indices, e.g. molecular biomarkers, are necessary. The development of a mathematically validated nomogram provides a platform for objective assessment of SI NET disease, a finite basis for precise prognostication and a tool to guide management strategy.
Utilization of Intraoperative Motor Mapping in Glioma Surgery with High-Field Intraoperative Magnetic Resonance Imaging
Authors: Hatiboglu Mustafa Aziz , Weinberg Jeffrey S. , Suki Dima , Tummala Sudhakar , Rao Ganesh , Sawaya Raymond , Prabhu Sujit S.
Published: August 2010

Background/Aims: The main goal of glioma surgery is to maximize tumor resection while minimizing neurologic injury. The use of high-field intraoperative magnetic resonance imaging (iMRI) and intraoperative cortical mapping (IOM) together enable the surgeon to increase the extent of tumor resection (EOR) and preserve the neurological function. However, there is insufficient evidence to validate the use of IOM with high-field iMRI. Methods: To study the safety and utility of IOM in a high-field (1.5 T) iMRI suite, we retrospectively studied 38 patients with glioma who underwent surgery with IOM in the iMRI suite. Results: We were able to use IOM in the iMRI suite without any adverse side effects or difficulty. Median EOR was 97%. A new or worsening motor deficit occurred in 14 (37%) patients immediately after the surgery, with 3 (8%) patients exhibiting persistent deficit at 6 months. Conclusion: Our findings suggest that IOM can be successfully used in a high-field MRI environment and can help minimize postoperative motor deficit with a higher EOR.
Antigen-Specific IgG and IgA, but Not IgE, Activate the Effector Functions of Eosinophils in the Presence of Antigen
Authors: Muraki Masato , Gleich Gerald J. , Kita Hirohito
Published: August 2010

Background: Activated eosinophils are thought to play an important role in allergic inflammation. Prior reports suggest that eosinophils have receptors recognizing IgA, IgG and IgE; however, little is known regarding the direct effects of antigens and antigen-specific immunoglobulins on the functions of eosinophils. Methods: To investigate eosinophil activation by antigens mediated by the various antigen-specific immunoglobulins, we used dansyl-conjugated bovine serum albumin (DNS-BSA) and recombinant dansyl-specific antibodies (human IgG 1–4, IgA and IgE). Eosinophils from healthy donors were incubated in the wells coated with dansyl-specific immunoglobulins with or without DNS-BSA. Eosinophil activation was monitored by superoxide production and eosinophil-derived neurotoxin (EDN) release. Results: Superoxide production and EDN release by eosinophils were induced by the dansyl-specific reaction via all IgG subclasses (IgG 1–4) and IgA in the presence of DNS-BSA; the responses were not observed in the absence of antigen, DNS-BSA. The immune complexes (ICs) of DNS-BSA and dansyl-specific IgE did not induce these responses. Furthermore, IgE ICs did not enhance eosinophil activation stimulated with various immunoglobulins, IL-5 or platelet-activating factor. Conclusion: These data suggest that ICs of antigens and antigen-specific IgGs and IgA, but not IgE, in inflamed tissues may activate eosinophils and play an important role in allergic inflammation.
Annexin 1-Derived Peptide Ac2-26 Inhibits Eosinophil Recruitment in vivo via Decreasing Prostaglandin D2
Authors: Wang Lian-ming , Li Wen-hui , Xu Yong-chen , Wei Qiang , Zhao Hong , Jiang Xiao-feng
Published: August 2010

Background: Asthma is a chronic inflammatory disease of the mucosa and is associated with excess TH2 cytokines, eotaxin, prostaglandin D2 (PGD2) and eosinophilia in the lungs. Previous studies have emphasized that the N-terminal peptide of annexin 1 (peptide Ac2-26) can inhibit mast cell degranulation, antigen-induced eotaxin release as well as the accumulation of both neutrophils and eosinophils in a model of rat pleurisy. The purpose of this study was to demonstrate anti-asthmatic effects of Ac2-26 in an asthma model and to explore possible mechanisms involved. Methods: The effect of Ac2-26 on TH2 cytokine release, eotaxin production, PGD2 levels and the development of pulmonary eosinophilic inflammation was compared with glucocorticoids in an asthmatic rat model. The study was conducted on rats sensitized and challenged with ovalbumin and plethysmography measured airway responsiveness. Bronchoalveolar lavage (BAL) histopathology and the levels of cytokines, chemokines as well as PGD2 were examined. Results: Our results showed that Ac2-26 suppressed the accumulation of eosinophils in airways, reduced IL-4, IL-5, IL-13, PGD2 and eotaxin levels in the BAL fluid, and lowered the expression of CRTH2. Exogenous PGD2 significantly attenuated the biological effects of Ac2-26. Conclusion: These results indicated that Ac2-26 exerted broad inhibitory effects on airway inflammation and hyperresponsiveness in a rat model of asthma. Exogenous PGD2 reversed the inhibitory effects of AC2-26 on eosinophil recruitment. Ac2-26 exhibited anti-asthmatic, immunomodulatory activity that was substantially mediated by decreasing PGD2 production and its CRTH2 receptor expression in vivo.
Mugwort-Sensitized Individuals from North Europe, South Europe and North America Show Different IgE Reactivity Patterns
Authors: Movérare Robert , Larsson Håkan , Carlsson Raimo , Holmquist Ingrid
Published: August 2010

Background: Sensitization to weed pollen allergens at the molecular level is not fully understood. We studied IgE reactivity to the major mugwort allergen Art v 1 in relation to allergens from other weed pollen and cross-reactive components in mugwort-sensitized subjects. Methods: Art v 1 and Amb a 1 were affinity purified and coupled to experimental ImmunoCAP® tests. Samples from North Europe (n = 50), South Europe (n = 19) and North America (n = 41) were analyzed for IgE against mugwort pollen, weed allergen components, pan-allergens and cross-reactive carbohydrate determinants (CCDs). Results: The prevalence of IgE reactivity (>0.35 kUA/l) to Art v 1 was significantly higher in samples from North Europe than in those from North America. IgE to Amb a 1 was more common in North America than in North and South Europe, while IgE to Par j 2 was common in South Europe, less common in North America, and absent in North Europe. IgE to Art v 3 in mugwort-allergic patients was more common in North Europe than in South Europe and North America, while IgE to Sal k 1 was similar between the areas. Subjects with an Art v 1/mugwort-specific IgE ratio <0.5 had more often IgE to Amb a 1, profilin, polcalcin and CCDs than subjects with a ratio >0.5. Conclusions: Mugwort-sensitized subjects have different IgE reactivity profiles to weed allergens, reflecting their exposure to various pollens. Subjects with a low ratio between the IgE levels to Art v 1 and mugwort have a diverse IgE reactivity profile, indicating a role for cross-reactive allergens in their mugwort sensitization.