bluuebunny/crossref_metadata_2025 huggingface dataset:
Release of Glutamate and CGRP from Trigeminal Ganglion Neurons: Role of Calcium Channels and 5-HT1Receptor Signaling
Authors: Xiao Yan , Richter Judith A , Hurley Joyce H
Published: April 2008

Background:

The aberrant release of the neurotransmitters, glutamate and calcitonin-gene related peptide (CGRP), from trigeminal neurons has been implicated in migraine. The voltage-gated P/Q-type calcium channel has a critical role in controlling neurotransmitter release and has been linked to Familial Hemiplegic Migraine. Therefore, we examined the importance of voltage-dependent calcium channels in controlling release of glutamate and CGRP from trigeminal ganglion neurons isolated from male and female rats and grown in culture. Serotonergic pathways are likely involved in migraine, as triptans, a class of 5-HT1receptor agonists, are effective in the treatment of migraine and their effectiveness may be due to inhibiting neurotransmitter release from trigeminal neurons. We also studied the effect of serotonin receptor activation on release of glutamate and CGRP from trigeminal neurons grown in culture.

Results:

P/Q-, N- and L-type channels each mediate a significant fraction of potassium-stimulated release of glutamate and CGRP. We determined that 5-HT significantly inhibits potassium-stimulated release of both glutamate and CGRP. Serotonergic inhibition of both CGRP and glutamate release can be blocked by pertussis toxin and NAS-181, a 5-HT1B/1Dantagonist. Stimulated release of CGRP is unaffected by Y-25130, a 5-HT3antagonist and SB 200646, a 5-HT2B/2Cantagonist.

Conclusion:

These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT1receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture.
Similarity of DMD gene deletion and duplication in the Chinese patients compared to global populations
Authors: Wang Xiaozhu , Wang Zheng , Yan Ming , Huang Shangzhi , Chen Tian-Jian , Zhong Nanbert
Published: April 2008

Background

DNA deletion and duplication were determined as the major mutation underlying Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Method

Applying multiplex ligation-dependent probe amplification (MLPA), we have analyzed 179 unrelated DMD/BMD subjects from northern China.

Results

Seventy-three percent of the subjects were found having a deletion (66.25%) or duplication (6.25%). Exons 51–52 were detected as the most common fragment deleted in single-exon deletion, and the region of exons 45–50 was the most common exons deleted in multi-exon deletions. About 90% of DMD/BMD cases carry a small size deletion that involves 10 exons or less, 26.67% of which carry a single-exon deletion. Most of the smaller deletions resulted in an out-of-frame mutation. The most common exons deleted were determined to be between exon 48 and exon 52, with exon 50 was the model allele. Verifying single-exon deletion, one sample with a deletion of exon 53 that was initially observed from MLPA showed that there was a single base deletion that abolished the ligation site in MLPA. Confirmation of single-exon deletion is recommended to exclude single base deletion or mutation at the MLPA ligation site.

Conclusion

The frequency of deletion and duplication in northern China is similar to global ethnic populations.
14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr
Authors: Bolton Diane L , Barnitz Robert A , Sakai Keiko , Lenardo Michael J
Published: April 2008

Background

Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G2,M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade.

Results

We found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 θ during Vprv-induced G2,M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3 θ association with Cdk1 and CyclinB1. Moreover, G2,M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3 θ binding to centrosomal proteins, Plk1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, Plk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin β.

Conclusion

Thus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins.

Reviewers

This article was reviewed by David Kaplan, Nathaniel R. Landau and Yan Zhou.
Effectiveness of computer-tailored Smoking Cessation Advice in Primary Care (ESCAPE): a Randomised Trial
Authors: Gilbert Hazel , Nazareth Irwin , Sutton Stephen , Morris Richard , Godfrey Christine
Published: April 2008

Background

Smoking remains a major public health problem; developing effective interventions to encourage more quit attempts, and to improve the success rate of self-quit attempts, is essential to reduce the numbers of people who smoke. Interventions for smoking cessation can be characterised in two extremes: the intensive face-to face therapy of the clinical approach, and large-scale, public health interventions and policy initiatives. Computer-based systems offer a method for generating highly tailored behavioural feedback letters, and can bridge the gap between these two extremes. Proactive mailing and recruitment can also serve as a prompt to motivate smokers to make quit attempts or to seek more intensive help. The aim of this study is to evaluate the effect of personally tailored feedback reports, sent to smokers identified from general practitioners lists on quit rates and quitting activity. The trial uses a modified version of a computer-based system developed by two of the authors to generate individually tailored feedback reports.

Method

A random sample of cigarette smokers, aged between 18 and 65, identified from GP records at a representative selection of practices registered with the GPRF are sent a questionnaire. Smokers returning the questionnaire are randomly allocated to a control group to receive usual care and standard information, or to an intervention group to receive usual care and standard information plus tailored feedback reports. Smoking status and cognitive change will be assessed by postal questionnaire at 6-months.

Discussion

Computer tailored personal feedback, adapted to reading levels and motivation to quit, is a simple and inexpensive intervention which could be widely replicated and delivered cost effectively to a large proportion of the smoking population. Given its recruitment potential, a modest success rate could have a large effect on public health. The intervention also fits into the broader scope of tobacco control, by prompting more quit attempts, and increasing referrals to specialised services. The provision of this option to smokers in primary care can complement existing services, and work synergistically with other measures to produce more quitters and reduce the prevalence of smoking in the UK.

Trial registration

Current Controlled Trials ISRCTN05385712
Large asymptomatic Left Atrial Myxoma with ossification: case report
Authors: Panagiotou Mattheos , Panagopoulos Nikolaos D , Ravazoula Panagiota , Kaklamanis Loukas , Koletsis Efstratios N
Published: April 2008

Background

Atrial myxomas are the most common primary cardiac tumors. They are usually small or moderate in size by the time of the diagnosis, exhibiting non specific cardiac or systemic symptoms, and are most frequently soft and friable without microscopic signs of ossification. We describe herein an extremely rare case of an asymptomatic giant left atrial myxoma with angiographic neovascularization and ossification.

Case presentation

An asymptomatic 58-year-old male with a giant left atrial tumor, was transferred to our Unit for surgical treatment. The tumor was an incidental finding during a work-up for hemoptysis due to bronchectasis. The coronary angiogram showed tumor vessels originating from the RCA. The tumor macroscopically did not resemble a myxoma, considering its dimensions (12 × 10 cm) and its solid substance. The mass was excised together with the interatrial septum and the right lateral LA wall close to the right pulmonary veins orifices. The defect was closed with Dacron patches in order to prevent malformation of both atria. The pathology study revealed a benign myxoma with excessive osteoid (mature bone) content.

Conclusion

We consider our case as extremely rare because of the asymptomatic course despite the large size of the tumor, the blood supply from the right coronary artery and the bone formation.
Characterisation of human papillomavirus (HPV) genotypes in the Azorean population, Terceira island
Authors: Dutra Isa , Santos Margarida R , Soares Marta , Couto Ana R , Bruges-Armas Maria , Teixeira Fernando , Monjardino Luísa , Hodgson Shirley , Bruges-Armas Jácome
Published: April 2008

Background

Human papillomavirus detection is very important for the evaluation of prevention strategies in cervical cancer. In the Azorean population, the virus prevalence has never been studied, and there is no data available to preview a successful outcome with HPV vaccination. In this article, our objective is to characterise the HPV genotypes in Terceira Island, contributing for the epidemiological knowledge on the virus infection.

Results

Cervical samples were collected from 289 women aged 16–81 in the Gynaecological Outpatient Clinic of the Hospital de Santo Espírito de Angra do Heroísmo (HSEAH). HPV DNA was amplified by Polymerase Chain Reaction using the general consensus primers PGMYO9/PGMY11. Commercially available Papillomavirus Clinical Arrays® kits (Genomica) were used to perform HPV genotyping. 30 women were HPV positive, with a median age of 41 years old. Our results show that the overall HPV prevalence was 10.49%. Seventeen genotypes were identified, including 58.82% high risk, 17.65% low risk and 23.53% undetermined risk.

Conclusion

Unlike other epidemiological studies, HPV31 was the most frequent type (26.67%) in Terceira Island, followed by HPV16 (10.00%), HPV51, HPV53, HPV70 and HPV82 (6.67%). Further studies are needed to investigate if the HPV types found in our population are associated with the risk of progression to high-grade squamous intraepithelial lesions or cervical cancer.
Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication
Authors: Ballif Blake C , Theisen Aaron , Coppinger Justine , Gowans Gordon C , Hersh Joseph H , Madan-Khetarpal Suneeta , Schmidt Karen R , Tervo Raymond , Escobar Luis F , Friedrich Christopher A , McDonald Marie , Campbell Lindsey , Ming Jeffrey E , Zackai Elaine H , Bejjani Bassem A , Shaffer Lisa G
Published: April 2008

Background

Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported.

Results

In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities.

Conclusion

Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.
Position of chromosomes 18, 19, 21 and 22 in 3D-preserved interphase nuclei of human and gorilla and white hand gibbon
Authors: Manvelyan Marina , Hunstig Friederike , Mrasek Kristin , Bhatt Samarth , Pellestor Franck , Weise Anja , Liehr Thomas
Published: April 2008

Background

Even though comparative nuclear architecture studies in hominoids are sparse, nuclear chromosome architecture was shown to be conserved during hominoid evolution. Thus, it is suspected that yet unknown biological mechanisms must underlie this observation.

Results

Here for the first time a combination of multicolor banding (MCB) and three-dimensional analysis of interphase cells was used to characterize the position and orientation of human chromosomes #18, #19, #21 and #22 and their homologues in primate B-lymphocytic cells. In general, our data is in concordance with previous studies. The position of the four studied human chromosomes and their homologues were conserved during primate evolution. However, comparison of interphase architecture in human B-lymphocytic cells and sperm revealed differences of localization of acrocentric chromosomes. The latter might be related to the fact that the nucleolus organizing region is not active in sperm.

Conclusion

Studies in different tissue types may characterize more – potentially biologically relevant differences in nuclear architecture.
An eosinophil immune response characterizes the inflammatory skin disease observed in Tie-2 transgenic mice
Authors: Voskas Daniel , Babichev Yael , Ling Ling S , Alami Jennifer , Shaked Yuval , Kerbel Robert S , Ciruna Brian , Dumont Daniel J
Published: April 2008

Although mouse models of inflammatory skin diseases such as psoriasis and atopic dermatitis fail to completely phenocopy disease in humans, they provide invaluable tools to examine the molecular and cellular mechanisms responsible for the epidermal hyperplasia, inflammation, and excess angiogenesis observed in human disease. We have previously characterized a tyrosine kinase with immunoglobin-like and epidermal growth factor-like domain-2 (Tie-2) transgenic mouse model of an inflammatory skin disease exhibiting these features. More specifically, we demonstrated that the inflammatory component consisted of increased infiltration of CD3-positive T lymphocytes and mast cells in the skin. Here, we further characterize the inflammatory component in the blood and skin of Tie-2 transgenic mice at cellular and molecular levels. We observed increased numbers of CD3-positive T lymphocytes in the blood and increased infiltration of eosinophils in the skin. Furthermore, we characterized cytokine protein and gene expression in the blood and skin, respectively, and observed the deregulated expression of cytokines associated with Th1 and eosinophil immune responses. Interestingly, treatment of Tie-2 transgenic mice with anti-CD4 antibody appeared to resolve aspects of inflammation but did not resolve epidermal hyperplasia, suggesting an important role for eosinophils in mediating the inflammatory skin disease observed in Tie-2 transgenic mice.
An antibody against the surfactant protein A (SP-A)-binding domain of the SP-A receptor inhibits T cell-mediated immune responses toMycobacterium tuberculosis
Authors: Samten Buka , Townsend James C , Sever-Chroneos Zvjezdana , Pasquinelli Virginia , Barnes Peter F , Chroneos Zissis C
Published: April 2008

Surfactant protein A (SP-A) suppresses lymphocyte proliferation and IL-2 secretion, in part, by binding to its receptor, SP-R210. However, the mechanisms underlying this effect are not well understood. Here, we studied the effect of antibodies against the SP-A-binding (neck) domain (α-SP-R210n) or nonbinding C-terminal domain (α-SP-R210ct) of SP-R210 on human peripheral blood T cell immune responses against Mycobacterium tuberculosis. We demonstrated that both antibodies bind to more than 90% of monocytes and 5–10% of CD3+ T cells in freshly isolated PBMC. Stimulation of PBMC from healthy tuberculin reactors [purified protein derivative-positive (PPD+)] with heat-killed M. tuberculosis induced increased antibody binding to CD3+ cells. Increased antibody binding suggested enhanced expression of SP-R210, and this was confirmed by Western blotting. The antibodies (α-SP-R210n) cross-linking the SP-R210 through the SP-A-binding domain markedly inhibited cell proliferation and IFN-γ secretion by PBMC from PPD+ donors in response to heat-killed M. tuberculosis, whereas preimmune IgG and antibodies (α-SP-R210ct) cross-linking SP-R210 through the non-SP-A-binding, C-terminal domain had no effect. Anti-SP-R210n also decreased M. tuberculosis-induced production of TNF-α but increased production of IL-10. Inhibition of IFN-γ production by α-SP-R210n was abrogated by the combination of neutralizing antibodies to IL-10 and TGF-β1. Together, these findings support the hypothesis that SP-A, via SP-R210, suppresses cell-mediated immunity against M. tuberculosis via a mechanism that up-regulates secretion of IL-10 and TGF-β1.
Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer
Authors: Gamelin Erick , Delva Remy , Jacob Jacques , Merrouche Yacine , Raoul Jean Luc , Pezet Denis , Dorval Etienne , Piot Gilles , Morel Alain , Boisdron-Celle Michele
Published: April 2008

Purpose

A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival.

Patients and Methods

Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m2 FU plus 200 mg/m2 folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg·h·L−1) previously established in other studies was reached.

Results

An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m2/wk in arm A and 1,790 ± 386 mg/m2/wk (range, 900 to 3,300 mg/m2/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003).

Conclusion

Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.
Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Rubnitz Jeffrey E. , Wichlan David , Devidas Meenakshi , Shuster Jonathan , Linda Stephen B. , Kurtzberg Joanne , Bell Beverly , Hunger Stephen P. , Chauvenet Allen , Pui Ching-Hon , Camitta Bruce , Pullen Jeanette
Published: April 2008

Purpose

To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL).

Patients and Methods

TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years.

Results

Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (± SE) for patients with TEL rearrangements was 86% ± 2%, compared with 72% ± 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002).

Conclusion

We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.
MGMT Promoter Methylation Status Can Predict the Incidence and Outcome of Pseudoprogression After Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma Patients
Authors: Brandes Alba A. , Franceschi Enrico , Tosoni Alicia , Blatt Valeria , Pession Annalisa , Tallini Giovanni , Bertorelle Roberta , Bartolini Stefania , Calbucci Fabio , Andreoli Alvaro , Frezza Giampiero , Leonardi Marco , Spagnolli Federica , Ermani Mario
Published: April 2008

Purpose

Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression.

Methods

Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m2/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m2 for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy.

Results

In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival.

Conclusion

PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.
Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines
Authors: Haller Daniel G. , Cassidy Jim , Clarke Stephen J. , Cunningham David , Van Cutsem Eric , Hoff Paulo M. , Rothenberg Mace L. , Saltz Leonard B. , Schmoll Hans-Joachim , Allegra Carmen , Bertino Joseph R. , Douillard Jean-Yves , Gustavsson Bengt G. , Milano Gerard , O'Connell Michael , Rustum Youcef , Tabernero Josep , Gilberg Frank , Sirzén Florin , Twelves Chris
Published: April 2008

Purpose

We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability.

Methods

Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study).

Results

In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR.

Conclusion

Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
Treatment With the Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate: Toxicity, Efficacy, and Survival
Authors: Kwekkeboom Dik J. , de Herder Wouter W. , Kam Boen L. , van Eijck Casper H. , van Essen Martijn , Kooij Peter P. , Feelders Richard A. , van Aken Maarten O. , Krenning Eric P.
Published: April 2008

Purpose

Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients.

Patients and Methods

Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients.

Results

Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis.

Conclusion

Treatment with [177Lu-DOTA0,Tyr3]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.
Leukocytosis and Risk Stratification Assessment in Essential Thrombocythemia
Authors: Carobbio Alessandra , Antonioli Elisabetta , Guglielmelli Paola , Vannucchi Alessandro M. , Delaini Federica , Guerini Vittoria , Finazzi Guido , Rambaldi Alessandro , Barbui Tiziano
Published: April 2008

Purpose

Established risk factors for thrombosis in essential thrombocythemia (ET) include age and previous vascular events. We aimed to refine this risk stratification by adding baseline leukocytosis.

Patients and Methods

We enrolled 657 patients with ET followed for a median of 4.5 years who developed 72 major thrombosis. Cox proportional hazard model was performed to analyze the thrombotic risk and to discriminate ET patients with or without thrombosis, multivariable C statistic index was used. We searched for leukocytes cutoff with the best sensitivity and specificity by a receiver operating characteristic curve.

Results

Results confirmed that age and prior events are independent risk factors for thrombosis and showed a gradient between baseline leukocytosis and thrombosis. On the contrary, no significant association was found either for JAK2V617F allele burden and for other laboratory parameters, including platelet number. In the model with conventional risk factors alone, C statistic ratio for total thrombosis was 0.63 and when leukocytosis was added, the change was small (C = 0.67). In contrast, in younger and asymptomatic patients (low-risk category), C statistic value indicated an high risk for thrombosis in patients with leukocytosis, similar to that calculated in conventionally defined high-risk group (C = 0.65). The best leukocyte cutoff values for predicting the events was found to be 9.4 (× 109/L).

Conclusion

We suggest to include baseline leukocytosis in the risk stratification of ET patients enrolled in clinical trials.
Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy
Authors: Mateo Gema , Montalbán M. Angeles , Vidriales Maria-Belén , Lahuerta Juan J. , Mateos Maria V. , Gutiérrez Norma , Rosiñol Laura , Montejano Laura , Bladé Joan , Martínez Rafael , de la Rubia Javier , Diaz-Mediavilla Joaquín , Sureda Anna , Ribera José M. , Ojanguren José M. , de Arriba Felipe , Palomera Luis , Terol Maria J. , Orfao Alberto , San Miguel Jesús F.
Published: April 2008

Purpose

To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM).

Patients and Methods

We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol.

Results

Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001).

Conclusion

To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.
The impact of numeracy on reactions to different graphic risk presentation formats: An experimental analogue study
Authors: Wright Alison J. , Whitwell Sophia C. L. , Takeichi Chika , Hankins Matthew , Marteau Theresa M.
Published: April 2008

Objectives. Numeracy, the ability to process basic mathematical concepts, may affect responses to graphical displays of health risk information. Displays of probabilistic risk information using grouped dots are easier to understand than displays using dispersed dots. However, dispersed dots may better convey the randomness with which health threats occur, so increasing perceived susceptibility. We hypothesized that low numeracy participants would better understand risks presented using grouped dot displays, while high numeracy participants would have good understanding, regardless of display type. Moreover, we predicted that dispersed dot displays, in contrast to grouped dot displays, would increase risk perceptions and worry only for highly numerate individuals.

Design and method. One hundred and forty smokers read vignettes asking them to imagine being at risk of Crohn's disease, in a 2(display type: dispersed/grouped dots)×3(risk magnitude: 3%/6%/50%)×2(numeracy: high/low) design. They completed measures of risk comprehension, perceived susceptibility and worry.

Results. More numerate participants had better objective risk comprehension, but this effect was not moderated by display type. There was marginally significant support for the predicted numeracy × display type interaction for worry about Crohn's disease, but not for perceived susceptibility to the condition.

Conclusions. Dispersed dot displays somewhat increase worry in highly numerate individuals, but only numeracy influenced objective risk comprehension. The most effective display type for communicating risk information will depend on the numeracy of the population and the goal(s) of the communication.
A qualitative investigation of women's experiences of the self and others in relation to their menstrual cycle
Authors: Slade Pauline , Haywood Annette , King Helen
Published: April 2008

Objectives. This study aimed to compare and contrast detailed accounts of a community sample of women, with prospectively defined low or high premenstrual symptoms, highlighting differences/similarities.

Methods. Semi‐structured interviews were conducted with 16 women (9 with ‘low’ and 7 with ‘high’ symptom levels) and analysed using template analysis.

Results. ‘Low symptom’ women perceived themselves as generally laid back but demonstrated a need for organization and control in the family environment. They accepted less than perfect relationships, compared themselves favourably to others and perceived themselves as having strong support networks. There was a negative perception of the introduction to menarche but this was coupled with strong maternal support. ‘High symptom’ women showed patterns of perfectionism, an emphasis on self‐sacrifice and unfavourable comparison of self with others. They reported feeling alone, overwhelmed by tasks and experienced relationships as characterized by unresolved tensions. Menarche was viewed as a positive experience but accompanied by low maternal support. Both groups viewed their symptoms as irrational and controllable outside the home, but vented on partner, close family and children. There was acknowledgement of difference from ‘normal’ (‘low’) with an emphasis on the all‐encompassing nature of symptoms (‘high’).

Conclusions. Women with high and low menstrual cycle symptoms viewed aspects of themselves and their relationships with others in both similar and different ways. A major issue for high symptom women was that they struggled to tolerate imperfections, both in their own performance or in their relationships with others, potentially emphasizing the role of cognitive appraisals in interventions.
Face inversion disrupts the perception of vertical relations between features in the right human occipito‐temporal cortex
Authors: Goffaux Valerie , Rossion Bruno , Sorger Bettina , Schiltz Christine , Goebel Rainer
Published: April 2008

The impact of inversion on the extraction of relational and featural face information was investigated in two fMRI experiments. Unlike previous studies, the contribution of horizontal and vertical spatial relations were considered separately since they have been shown to be differentially vulnerable to face inversion (Goffaux & Rossion, 2007). Hence, inversion largely affects the perception of vertical relations (e.g. eye or mouth height) while the processing of features (e.g. eye shape and surface) and of horizontal relations (e.g. inter‐ocular distance) is affected to a far lesser extent. Participants viewed pairs of faces that differed either at the level of one local feature (i.e. the eyes) or of the spatial relations of this feature with adjacent features. Changes of spatial relations were divided into two conditions, depending on the vertical or horizontal axis of the modifications. These stimulus conditions were presented in separate blocks in the first (block) experiment while they were presented in a random order in the second event‐related (ER) experiment. Face‐preferring voxels located in the right‐lateralized middle fusiform gyrus (rMFG) largely decreased their activity with inversion. Inversion‐related decreases were more moderate in left‐lateralized middle fusiform gyrus (lMFG). ER experiment revealed that inversion affected rMFG and lMFG activity in distinct stimulus conditions. Whereas inversion affected lMFG processing only in featural condition, inversion selectively affected the processing of vertical relations in rMFG. Correlation analyses further indicated that the inversion effect (IE) observed in rMFG and right inferior occipital gyrus (rIOG) reliably predicted the large behavioural IE observed for the processing of vertical relations. In contrast, lMFG IE correlated with the weak behavioural IE observed for the processing of horizontal relations. Our findings suggest that face configuration is mostly encoded in rMFG, whereas more local aspects of face information, such as features and horizontal spatial relations drive lMFG processing. These findings corroborate the view that the vulnerability of face perception to inversion stems mainly from the disrupted processing of vertical face relations in the right‐lateralized network of face‐preferring regions (rMFG, rIOG).
Expression of Calcyclin-binding Protein/Siah-1 Interacting Protein in Normal and Malignant Human Tissues: An Immunohistochemical Survey
Authors: Zhai Huihong , Shi Yongquan , Jin Haifeng , Li Yuanfei , Lu Yuanyuan , Chen Xiong , Wang Jinbo , Ding Liping , Wang Xin , Fan Daiming
Published: April 2008

Calcyclin-binding protein (CacyBP)/Siah-1 interacting protein (SIP), a component of ubiquitin-mediated proteolysis, could bind the Skp1-Cul1-F box protein complex. Although CacyBP/SIP was implicated in p53-induced β-catenin degradation, its exact function was still unknown. Our previous studies showed that CacyBP/SIP could modulate the multidrug-resistant phenotype of gastric cancer cells and was highly expressed in gastric cancer tissues compared with that in non-cancerous tissues. In this study, CacyBP/SIP protein expression profile in a broad range of human normal tissues and carcinomas was analyzed by immunohistochemistry staining with anti-CacyBP/SIP monoclonal antibody first produced in our laboratory. CacyBP/SIP was generally localized in the cytoplasm/nucleus. Positive staining of CacyBP/SIP was found in brain, heart, lymph node, and esophagus. Weak staining was shown in the rectum and kidney. No CacyBP/SIP was detected in other normal tissues. However, CacyBP/SIP was ubiquitously detected in all kinds of tumor tissues and was highly expressed in nasopharyngeal carcinoma, osteogenic sarcoma, and pancreatic cancer. To our knowledge, this is the first study on the CacyBP/SIP expression pattern in a broad range of human normal and tumor tissues. The data presented should serve as a useful reference for other investigators in future studies of CacyBP/SIP functions. Hopefully, this knowledge will lead to discovery of more roles of CacyBP/SIP in tumorigenesis.
Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-deficient Mice: Simvastatin Exacerbates the Reduction
Authors: Hou Charles Jia-Yin , Tsai Cheng-Ho , Su Cheng-Huang , Wu Yih-Jer , Chen Su-Jen , Chiu Jing-Jing , Shiao Ming-Shi , Yeh Hung-I
Published: April 2008

We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male apolipoprotein E (apoE)-deficient mice were made diabetic by streptozotocin. Three weeks later, the animals were treated with simvastatin for 2 weeks. The expression of aortic gap junctions in the non-diabetic ( n=10), untreated diabetic ( n=10), and simvastatin-treated diabetic animals ( n=6) was analyzed. There was a >4-fold increase in serum cholesterol level and >50% increase in plaque areas in the diabetic mice, regardless of simvastatin treatment. Western blotting of aortae showed reduced expression of connexin37 (Cx37) and Cx40 in the diabetic mice, which were further decreased in the simvastatin-treated diabetic mice. Immunoconfocal microscopy showed that endothelial gap junctions made of Cx37 and Cx40 were both reduced in the untreated diabetic mice compared with the non-diabetic mice (decrease: Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrease in treated diabetic vs non-diabetic: Cx37, 61%; Cx40, 79%; both p<0.01; decrease in treated diabetic vs untreated diabetic: Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were decreased in the endothelium of plaque surface. Cx43 appeared in the medial layer and inner layer of the intima. All three connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice, streptozotocin-induced diabetes is associated with downregulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the downregulation.
An Apparatus for Direct Shear, Pullout, and Uniaxial Testing of Geogrids
Authors: Abdelrahman Ahmed H. , Ashmawy Alaa K. , Abdelmoniem Mohamed
Published: April 2008

In this paper, design and calibration procedures for a new large-scale testing apparatus for testing geosynthetic-soil systems are described. The multiple functionalities of the apparatus are implemented through the use of a single loading frame, driving mechanism, instrumentation, and data acquisition system for three distinct modes of loading: pullout, direct shear, and uniaxial loading. The design is similar to a conventional pullout device, but also includes key modifications and additional modules to adapt it for additional types of experiments. For example, in the uniaxial tension configuration, extension rods are used to transfer the load from the driving mechanism to the mounted specimen. In the direct shear configuration, the bottom half of the shear box is allowed to slide horizontally on low friction roller bearings while connected to the driving mechanism, whereas the top half of the box is fixed. Hydraulic jacks and a steel plate are used to apply the normal pressure in the pullout and direct shear configuration. A series of pullout experiments were performed to validate the functionality of the apparatus and to examine the relationship between the geometry of the geogrid opening and its pullout resistance.
Mortality of Geriatric and Younger Patients with Schizophrenia in the Community
Authors: Ran Mao‐Sheng , Lai‐Wan Cecilia , Chen Eric Yu‐Hai , Tang Cui‐Ping , Lin Fu‐Rong , Li Li , Li Si‐Gan , MAO Wen‐Jun , Hu Shi‐Hui , Schwab Gerhard , Conwell Yeates
Published: April 2008

Little is known about the differences in mortality among non‐institutionalized geriatric and younger patients with schizophrenia. In this study long‐term mortality and suicidal behavior of all the geriatric (age ≥ 65 years), middle‐age (age 41–64 years), and young (age 15–40 years) subjects with schizophrenia living in a Chinese rural community were compared. A 10 year follow‐up investigation among a 1994 cohort (n = 510) of patients with schizophrenia was conducted in Xinjin County, Chengdu, China. Compared with young subjects, geriatric subjects with schizophrenia were more likely to be female, have more previous physical illness, never accepted treatment, and practice religious (p ≤ 0.01). There were no significant differences of suicide attempts among the three groups. Young subjects had a higher rate of suicide (1,033.8 per 100,000 person‐years), and geriatric subjects had a higher rate of deaths due to other causes (accident and natural causes) (4,314.2 per 100,000 person‐years). Standardized mortality ratios for both suicide and deaths due to other causes were highest in young subjects and the lowest in geriatric subjects. Patients with schizophrenia in all age groups had a marked increase in mortality and suicide. Specific intervention strategies for decreasing mortality and suicide should be developed for patients with schizophrenia in different age groups.
Prevalence, Course, Incidence, and 1‐Year Prediction of Deliberate Self‐Harm and Suicide Attempts in Early Norwegian School Adolescents
Authors: Larsson Bo , Sund Anne Mari
Published: April 2008

In this survey of early Norwegian school adolescents, the prevalence, course, and incidence of self‐harm behavior with or without suicide intent were examined, in addition to predictors of self‐harm for a 1‐year follow‐up period. Lifetime prevalence rates of self‐harm without suicide intent and suicide attempts were 2.9% and 3.0%, respectively, while 1‐year incidence rates were 3.6% and 1.7%, respectively. In multivariate analysis, five predictors significantly differentiated self‐harmers from non‐self‐harming adolescents. Early school adolescents having frequent or intense suicidal ideation over an extended time period and attempting self‐harm repeatedly with or without suicide intent should be identified and offered treatment.
Changes in Suicide Methods in Quebec between 1987 and 2000: The Possible Impact of Bill C‐17 Requiring Safe Storage of Firearms
Authors: Caron Jean , Julien Marie , Huang Jean Hua
Published: April 2008

This study presents the changes in the overall and firearm suicide rates for Québec (Canada) before and after Bill C‐17, which was implemented to secure safe storage of firearms. It covers 20,009 suicide cases reported to the coroner's office. Interrupted time series analysis is used to compare suicide rates in the two periods. Firearm suicide rates have dropped among males and females, but the downward trends were not significant when compared to those prior to the law. Hanging suicide rates have risen considerably among men and women, but those upward trends did not increase significantly when compared with those preceding the law. The decline in suicide rates involving firearms has not resulted in a parallel decline in overall suicide rates. The analyses suggest that Bill C‐17 neither improved the downward trend in firearm suicide, which had already begun before the enactment of the law, nor reduced the upward trend of the overall suicide rate. Correlation analyses between firearm suicide, hanging suicide, and the overall suicide rate suggest that firearm suicide is replaced by hanging suicide among males.
Pattern Analysis of Suicide Mortality Surveillance Data in Urban South Africa
Authors: Burrows Stephanie , Laflamme Lucie
Published: April 2008

The typical circumstances of suicide occurrence in post‐apartheid urban South Africa are described. Data comprise suicide cases from all geographical locations (urban municipalities) where an injury surveillance system has full coverage. Typical patterns were identified by means of a classification technique applied to eight variables descriptive of the events, their victims, and the suicide level of the cities. Six suicide mortality patterns were identified, most being race‐specific and each associated with particular suicide methods. Preventive strategies should target local communities and specific population subgroups, and be appropriate and responsive to their sociocultural needs.