bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Folic Acid and Vitamins B6 and B12 on Microcirculatory Vasoreactivity in Patients With Hyperhomocysteinemia
Authors: Abularrage Christopher J. , Sidawy Anton N. , White Paul W. , Aidinian Gilbert , DeZee Kent J. , Weiswasser Jonathan M. , Arora Subodh
Published: August 2007

Objective: Hyperhomocysteinemia (HHcy) has been identified as an independent risk factor for atherosclerotic vascular disease. The effect of high-dose folic acid or combination vitamin therapy for the treatment of HHcy on the microcirculation is unknown. The purpose of this study was to evaluate the effect of a combination of folic acid, vitamin B6, and vitamin B12 on endothelium-dependent and endothelium-independent vasoreactivity in patientswith HHcy.

Methods: Baseline cutaneous microvascular vasoreactivity was measured in 20 patients with HHcy and 18 patients with normohomocysteinemia (NHcy). Laser Doppler scan imaging before and after iontophoresis of 1% acetylcholine chloride (endothelium-dependent response) and 1% sodium nitroprusside (endothelium-independent response) was performed for the measurement of forearm skin vasodilatation. Patients were then treated with 10 mg folic acid, 100 mg vitamin B6, and 1 mg vitamin B12 orally once a day for 6 months. Follow-up fasting serum homocysteine and cutaneous Laser Doppler scan imaging before and after iontophoresis were performed at 1, 2, 3, and 6 months. Statistical analysis was performed using Fisher's exact test, paired t test, and Wilcoxon matched-pairs signed-ranks test, with significance set at P < .05.

Results: The HHcy group was older than the NHcy group (70.89 ± 1.95 vs 61.78 ± 2.73 years, P = .02). Otherwise the groups were similar in terms of race, tobacco use, comorbid diseases, and serum lipoproteins. Over the 6-month period, fasting serum homocysteine levels decreased significantly in both the NHcy group (10.40 ± 0.59 µmol/L vs 8.97 ± 0.84 µmol/L, P = .01) and the HHcy group (19.80 ± 1.06 µmol/L vs 13.40 ± 0.86 µmol/L, P = .0002). There were no statistically significant changes in endothelium-independent vasoreactivity (voltage change from baseline) in either group. Endothelium-independent vasore activity decreased over the 6-month period in the HHcy group (0.20 ± 0.04 V vs 0.11 ± 0.03 V, P = .03). Subanalysis of HHcy with diabetes or age greater than 65 years both showed worsening trends in endothelium-independent vasoreactivity ( P = .05 for both groups). There were no statistically significant changes in endothelium-independent vasoreactivity in the NHcy group.

Conclusions: High doses of folic acid and vitamins B6 and B12 lower fasting serum homocysteine levels in patients with HHcy. Older and diabetic patients with HHcy tend to do worse possibly because of long-term fixed microvascular insult secondary to multiple sustained comorbidities.
Platelet Activation in Bypass Surgery for Critical Limb Ischemia
Authors: Mohan Irwin V. , Mikhailidis Dimitri P. , Stansby Gerard P.
Published: August 2007

Platelet activation contributes to graft occlusion after bypass surgery. This study investigated platelet activation status before, during, and after bypass. Blood was taken preoperatively from patients undergoing femoro-popliteal bypass and at incision, after dissection, after ischemia, after reperfusion, 24 hours after surgery, and almost 2 years after bypass (and given aspirin or warfarin). Platelet aggregation was measured using a turbidimetric method and platelet activation with flow cytometry. Statistical analysis was performed using Mann-Whitney U and Wilcoxon's tests. Resting platelet activation was similar between controls and patients undergoing bypass. Platelet activation decreased at incision but remained highly reactive. Platelet aggregation increased after dissection and the ischemic phase but significantly decreased after reperfusion. Platelet aggregation and activation were increased at 24 hours and subsequently after bypass. Platelets in critical limb ischemia exist in the primed state and become activated by minimum stimuli. Increased platelet activation occurs after bypass grafting for critical limb ischemia despite adjunctive therapy.
Sustainable Play
Authors: Pearce Celia , Fullerton Tracy , Fron Janine , Morie Jacquelyn Ford
Published: August 2007

This article suggests a revisit of the New Games movement, formed by Stewart Brand and others in the early 1970s in the United States as a response to the Vietnam War, against a backdrop of dramatic social and economic change fueled by a looming energy crisis, civil rights, feminism, and unhealthy widespread drug abuse. Like-minded contemporaries R. Buckminster Fuller (World Game), Robert Smithson (Spiral Jetty), and Christo and Jean-Claude (Valley Curtain) responded in kind to these environmental and sociopolitical quandaries with their “earthworks.” As digital game designers and theorists embark on developing new methods to address the creative crisis in mainstream game production, against a similar backdrop of global climate change, a controversial war, political upheaval, and complex gender issues, the authors propose a reexamination of the New Games movement and its methods as a means of constructing shared contexts for meaningful play in virtual and real-world spaces.
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance
Authors: Kantarjian Hagop M. , Giles Francis , Gattermann Norbert , Bhalla Kapil , Alimena Giuliana , Palandri Francesca , Ossenkoppele Gert J. , Nicolini Franck-Emmanuel , O'Brien Stephen G. , Litzow Mark , Bhatia Ravi , Cervantes Francisco , Haque Ariful , Shou Yaping , Resta Debra J. , Weitzman Aaron , Hochhaus Andreas , le Coutre Philipp
Published: August 2007

Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707.
Use of a T-cell interferon-γ release assay for the diagnosis of tuberculous pleurisy
Authors: Losi M. , Bossink A. , Codecasa L. , Jafari C. , Ernst M. , Thijsen S. , Cirillo D. , Ferrarese M. , Greinert U. , Fabbri L. M. , Richeldi L. , Lange C.
Published: August 2007

The diagnosis of pleural tuberculosis (plTB) by the analysis of pleural effusions (PEs) with standard diagnostic tools is difficult. In routine clinical practice, the present authors evaluated the performance of a commercially availableMycobacterium tuberculosis(MTB)-specific enzyme-linked immunospot assay on peripheral blood mononuclear cells (PBMCs) and pleural effusion mononuclear cells (PEMCs) in patients with suspect plTB.

The T-SPOT.TBtest (Oxford Immunotec Ltd, Abingdon, UK) was performed on PBMCs and PEMCs in 20 patients with a clinical and radiological suspect of plTB and in 21 control subjects with a diagnosis of PE of nontuberculous origin at four centres participating in the European Tuberculosis Network.

In total, 18 (90%) out of 20 patients with plTB tested T-SPOT.TB-positive on PBMCs and 19 (95%) out of 20 on PEMCs. Among controls, T-SPOT.TBwas positive in seven out of 21 (33%) patients when performed on PBMCs (these patients were assumed to be latently infected with MTB) and five (23%) out of 21 when performed on PEMCs. Sensitivity and specificity of T-SPOT.TBfor the diagnosis of active plTB when performed on PEMCs were 95 and 76%, respectively.

EnumeratingMycobacterium tuberculosis-specific T-cells in pleural effusion mononuclear cells by ELISPOT is feasible in routine clinical practice and may be useful for a rapid and accurate diagnosis of pleural tuberculosis.
Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study
Authors: Bathoorn E. , Slebos D-J. , Postma D. S. , Koeter G. H. , van Oosterhout A. J. M. , van der Toorn M. , Boezen H. M. , Kerstjens H. A. M.
Published: August 2007

In vitroandin vivostudies have shown that carbon monoxide (CO) has both anti-inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100–125 ppm CO inhalation in patients with stable COPD.

In total, 20 ex-smoking COPD patients with post-bronchodilator forced expiratory volume in one second (FEV1) >1.20 L and FEV1/forced vital capacity <70% were enrolled in a randomised, placebo-controlled, crossover study. Effects on inflammation were measured in induced sputum and blood.

CO inhalation was feasible and patients' vital signs were unaffected; 2 h·day−1inhalation of low-dose CO on 4 consecutive days led to a maximal individual carboxyhaemoglobin level of 4.5%. Two exacerbations occurred in the CO period. CO inhalation led to trends in reduced sputum eosinophils (median reduction 0.25% point) and improved responsiveness to methacholine (median provocative concentration causing a 20% fall in FEV10.85versus0.63 mg·mL−1).

Inhalation of 100–125 ppm carbon monoxide by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine. Further studies need to confirm the safety and efficacy in inflammatory lung diseases.
Impact on patients’ health status following early identification of a COPD exacerbation
Authors: Bourbeau J. , Ford G. , Zackon H. , Pinsky N. , Lee J. , Ruberto G.
Published: August 2007

The current study aimed to assess the impact on patient health status during an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).

A total of 421 COPD patients were enrolled in a multicentre, single-arm study with a 6-month observational follow-up period. Patients received two inhalations of Symbicort 200 Turbuhaler® twice a day. Patients were assessed before the run-in period, at baseline and at 1, 3 and 6 months. Patients were instructed to report a change in respiratory symptoms lasting >24 h. This defined an AECOPD. In addition to the initial call, the St George’s Respiratory Questionnaire (SGRQ), COPD Control Questionnaire (CCQ), Medical Research Council (MRC) dyspnoea scale and activities of daily living (ADL) were completed at 5–7 and 12–14 days.

A group of 176 patients reported at least one AECOPD. Exacerbations were associated with statistically significant mean changes (worsening) in the SGRQ activity and impact domains at onset (mean±sd12.1±18.1 and 14.0±15.2), during the first (9.8±19.0 and 9.4±16.6) and second weeks (3.1±15.5 and 3.3±14.7). Clinically significant deterioration in SGRQ impact scores was shown in 71% of patients following early identification, with 55 and 37% during the first and second weeks of an AECOPD, respectively.

Acute exacerbation severely impacts on health status. The current study provides valuable information on the change in health status during an acute exacerbation of chronic obstructive pulmonary disease that can be utilised for future trials that evaluate therapeutic intervention.
GntR family of regulators in Mycobacterium smegmatis: a sequence and structure based characterization
Authors: Vindal Vaibhav , Suma Katta , Ranjan Akash
Published: August 2007

Background

Mycobacterium smegmatis is fast growing non-pathogenic mycobacteria. This organism has been widely used as a model organism to study the biology of other virulent and extremely slow growing species like Mycobacterium tuberculosis. Based on the homology of the N-terminal DNA binding domain, the recently sequenced genome of M. smegmatis has been shown to possess several putative GntR regulators. A striking characteristic feature of this family of regulators is that they possess a conserved N-terminal DNA binding domain and a diverse C-terminal domain involved in the effector binding and/or oligomerization. Since the physiological role of these regulators is critically dependent upon effector binding and operator sites, we have analysed and classified these regulators into their specific subfamilies and identified their potential binding sites.

Results

The sequence analysis of M. smegmatis putative GntRs has revealed that FadR, HutC, MocR and the YtrA-like regulators are encoded by 45, 8, 8 and 1 genes respectively. Further out of 45 FadR-like regulators, 19 were classified into the FadR group and 26 into the VanR group. All these proteins showed similar secondary structural elements specific to their respective subfamilies except MSMEG_3959, which showed additional secondary structural elements. Using the reciprocal BLAST searches, we further identified the orthologs of these regulators in Bacillus subtilis and other mycobacteria. Since the expression of many regulators is auto-regulatory, we have identified potential operator sites for a number of these GntR regulators by analyzing the upstream sequences.

Conclusion

This study helps in extending the annotation of M. smegmatis GntR proteins. It identifies the GntR regulators of M. smegmatis that could serve as a model for studying orthologous regulators from virulent as well as other saprophytic mycobacteria. This study also sheds some light on the nucleotide preferences in the target-motifs of GntRs thus providing important leads for initiating the experimental characterization of these proteins, construction of the gene regulatory network for these regulators and an understanding of the influence of these proteins on the physiology of the mycobacteria.
CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer
Authors: Margolin Sara , Eiberg Hans , Lindblom Annika , Bisgaard Marie Luise
Published: August 2007

Background

A truncating variant, 1100delC, in check point-kinase CHEK2, has been identified as a risk factor for familial and sporadic breast cancer. The prevalence in healthy non-breast cancer cases is low and varies between populations.

Methods

We analyzed the prevalence of CHEK2 1100delC in 763 breast cancer patients with a defined family history and 760 controls from the Stockholm region. The breast cancer patients originated from; a population-based cohort (n = 452) and from a familial cancer clinic (n = 311), the detailed family history was known in both groups.

Results

The variant was found in 2.9% of the familial cases from the population-based cohort and in 1.9% from the familial cancer clinic. In total 2.2% of the patients with a family history of breast cancer carried the variant compared to 0.7% of the controls (p = 0.03). There was no increased prevalence in sporadic patients (0.3%). The variant was most frequent in young familial patients (5.1% of cases ≤45 years, p = 0.003). The mean age at diagnosis of variant carriers was 12 years lower than in non-carriers (p = 0.001).

Conclusion

In conclusion, CHEK2 1100delC exists in the Swedish population. The prevalence is increased in familial breast cancer and the variant seems to influence age at onset.
Healthcare in schizophrenia: effectiveness and progress of a redesigned care network
Authors: Tzeng Dong-Sheng , Lian Li-Chiu , Chang Chin-Un , Yang Chun-Yuh , Lee Gian-Tin , Pan Peter , Lung For-Wey
Published: August 2007

Background

The aim of this study was designed to investigate the care-effectiveness of different healthcare models for schizophrenic patients and the impact of it on caregivers.

Methods

Sample cases were randomly selected from southern Taiwan, 257 patients in redesigned care network, including a general hospital, a chronic ward, 10 outpatient clinics, and multialternative community programs, was compared to 247 patients in other traditional healthcare provider that were utilized as the control group. The quality of life (QOL) questionnaire and the Chinese health questionnaire (CHQ) were used.

Results

The controls had longer duration of illness (p = 0.001) and were older (p = 0.004). The average resource utilization in the study group (US$ 2737/year, per case) was higher than the control group (US$ 2041) (t = 7.91, p < 0.001). For the study group, the average length of stay was shorter, but the admission rate was higher. The QOL of the patients in the study group was better than that of the controls (p = 0.01). The family burden of the study group was lower (p = 0.035) and the score of general health questionnaire higher (p = 0.019).

Conclusion

We found that patients in the redesigned care network had a better QOL, lower family burden, decreased days of hospital stay, higher medical resource utilization and less frequent admission to a hospital, and the caregivers had better mental health. Although the costs were higher, the continued care network was more helpful in providing comprehensive mental illness services.
Patient, informal caregiver and care provider acceptance of a hospital in the home program in Ontario, Canada
Authors: Lemelin Jacques , Hogg William E , Dahrouge Simone , Armstrong Catherine Deri , Martin Carmel M , Zhang Wei , Dusseault Jo-Anne , Parsons-Nicota Joy , Saginur Raphael , Viner Gary
Published: August 2007

Background

Hospital in the home programs have been implemented in several countries and have been shown to be safe substitutions (alternatives) to in-patient hospitalization. These programs may offer a solution to the increasing demands made on tertiary care facilities and to surge capacity. We investigated the acceptance of this type of care provision with nurse practitioners as the designated principal home care providers in a family medicine program in a large Canadian urban setting.

Methods

Patients requiring hospitalization to the family medicine service ward, for any diagnosis, who met selection criteria, were invited to enter the hospital in the home program as an alternative to admission. Participants in the hospital in the home program, their caregivers, and the physicians responsible for their care were surveyed about their perceptions of the program. Nurse practitioners, who provided care, were surveyed and interviewed.

Results

Ten percent (104) of admissions to the ward were screened, and 37 patients participated in 44 home hospital admissions. Twenty nine patient, 17 caregiver and 38 provider surveys were completed. Most patients (88%–100%) and caregivers (92%–100%) reported high satisfaction levels with various aspects of health service delivery. However, a significant proportion in both groups stated that they would select to be treated in-hospital should the need arise again. This was usually due to fears about the safety of the program. Physicians (98%–100%) and nurse practitioners also rated the program highly. The program had virtually no negative impact on the physician workload. However nurse practitioners felt that the program did not utilize their full expertise.

Conclusion

Provision of hospital level care in the home is well received by patients, their caregivers and health care providers. As a new program, investment in patient education about program safety may be necessary to ensure its long term success. A small proportion of hospital admissions were screened for this program. Appropriate dissemination of program information to family physicians should help buy-in and participation. Nurse practitioners' skills may not be optimally utilized in this setting.
Genomic and proteomic profiling I: Leiomyomas in African Americans and Caucasians
Authors: Pan Qun , Luo Xiaoping , Chegini Nasser
Published: August 2007

Background

Clinical observations indicate that leiomyomas occur more frequently in African Americans compared to other ethnic groups with unknown etiology. To identify the molecular basis for the difference we compared leiomyomas form A. Americans with Caucasians using genomic and proteomic strategies.

Methods

Microarray, realtime PCR, 2D-PAGE, mass spectrometry, Western blotting and immunohistochemistry.

Results

Using Affymetrix U133A array and analysis based on P ranking (P < 0.01) 1470 genes were identified as differentially expressed in leiomyomas compared to myometrium regardless of ethnicity. Of these, 268 genes were either over-expressed (177 genes) or under-expressed (91 genes) based on P < 0.01 followed by 2-fold cutoff selection in leiomyomas of A. Americans as compared to Caucasians. Among them, the expression E2F1, RUNX3, EGR3, TBPIP, ECM2, ESM1, THBS1, GAS1, ADAM17, CST6, CST7, FBLN5, ICAM2, EDN1 and COL18 was validated using realtime PCR low-density arrays. 2D PAGE coupled with image analysis identified 332 protein spots of which the density/volume of 31 varied by greater than or equal to 1.5 fold in leiomyomas as compared to myometrium. The density/volume of 34 protein-spots varied by greater than or equal to 1.5 fold (26 increased and 8 decreased) in leiomyomas of A. Americans as compared to Caucasians. Tandem mass spectrometric analysis of 15 protein spots identified several proteins whose transcripts were also identified by microarray, including 14-3-3 beta and mimecan, whose expression was confirmed using western blotting and immunohistochemistry.

Conclusion

These findings imply that the level rather than the ethnic-specific expression of a number of genes and proteins may account for the difference between leiomyomas and possibly myometrium, in A. Americans and Caucasians. Further study using larger sample size is required to confirm these findings.
FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab
Authors: Zhang Wu , Gordon Michael , Schultheis Anne M. , Yang Dong Yun , Nagashima Fumio , Azuma Mizutomo , Chang Heung-Moon , Borucka Eva , Lurje Georg , Sherrod Andy E. , Iqbal Syma , Groshen Susan , Lenz Heinz-Josef
Published: August 2007

Purpose

Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcγR) play an important role in initiating ADCC. Studies have shown that two IgG FcγR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab.

Patients and Methods

Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) –based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples.

Results

FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test).

Conclusion

Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.
Noninvasive Evaluation of Late Anthracycline Cardiac Toxicity in Childhood Cancer Survivors
Authors: Hudson Melissa M. , Rai Shesh N. , Nunez Cesar , Merchant Thomas E. , Marina Neyssa M. , Zalamea Nia , Cox Cheryl , Phipps Sean , Pompeu Ronald , Rosenthal David
Published: August 2007

Purpose

Childhood cancer survivors treated with anthracyclines and cardiac radiation are at risk for late-onset cardiotoxicity. The purpose of this study was to delineate the relationship between clinical factors and abnormalities of noninvasive cardiac testing (NICT).

Patients and Methods

Participants were recruited from a long-term follow-up clinic. Study measures comprised physical examination, laboratory evaluation, echocardiogram, and ECG. Mean fractional shortening (FS) and afterload were compared for survivors who did (at risk [AR]) and did not (no risk [NR]) receive potentially cardiotoxic modalities, and with values expected for comparable age- and sex-matched controls.

Results

The 278 study participants (mean age, 18.1 years; median age, 16.8 years; range, 7.5 to 39.7 years) included 223 survivors AR for cardiotoxicity after treatment with anthracyclines (median dose ± standard deviation [SD], 202 ± 109 mg/m2) and/or cardiac radiation. Mean FS (± SD) was lower for AR (0.33 ± 0.06) compared with NR survivors (0.36 ± 0.05; P = .004) and normative controls (0.36 ± 0.04; P < .001). Mean afterload (± SD) was higher for AR (58 ± 21 g/cm2) compared with NR survivors (46 ± 15 g/cm2; P < .001) and normative controls (48 ± 13 g/cm2; P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. After adjustment for age group at diagnosis and time since completion of therapy, anthracycline dose predicted decline in distribution of FS (P < .001) and increase in distribution of afterload (P < .001). Treatment with anthracycline doses ≥ 100 mg/m2 increased the risk of abnormal NICT; survivors who received ≥ 270 mg/m2 had a 4.5-fold excess risk of abnormal NICT (95% CI, 2.1 to 9.6) compared with controls.

Conclusion

Childhood cancer survivors treated with anthracycline doses ≥ 270 mg/m2 are at greatest risk for abnormalities of FS and afterload.
Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies
Authors: Chu Quincy S.C. , Schwartz Garry , de Bono Johann , Smith Deborah A. , Koch Kevin M. , Versola Melissa J. , Pandite Lini , Arya Nikita , Curtright Jan , Fleming Ronald A. , Ho Peter T.C. , Rowinsky Eric K.
Published: August 2007

Purpose

This phase I trial ( EGF10005 ) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies.

Patients and Methods

Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.

Results

Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m2/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and α-fluoro-β-alanine, were not meaningfully altered by coadministration.

Conclusion

Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.
Trastuzumab and Metastatic Breast Cancer: Trastuzumab Use in Australia—Monitoring the Effect of an Expensive Medicine Access Program
Authors: Pearson Sallie-Anne , Ringland Clare L. , Ward Robyn L.
Published: August 2007

Purpose

Data from clinical trials are used for drug registration; however, many cancer medicines are ultimately used off-label. This study examines the extent to which the clinical practice use of trastuzumab for the treatment of metastatic breast cancer differs from its use under trial conditions.

Methods

This study involved all women (N = 1,469) with metastatic breast cancer who received trastuzumab in Australia between December 2001 and March 2005. Given that Australia operates a universal health care system, administrative databases could be examined to determine the duration of therapy, rate of off-label use, compliance with cardiac monitoring, and the extent of drug wastage (volume and cost).

Results

A total of 433 enrollees (29.5%) received trastuzumab as monotherapy and 1,036 enrollees (70.5%) received the drug in combination with chemotherapy. A total of 321 women (22%) received off-label trastuzumab. The median duration of trastuzumab therapy was longer than that on trial: 5.6 v 3.1 months for enrollees receiving monotherapy and 12.5 v 6.9 months for concomitant chemotherapy. Only 47 (3%) of enrollees received cardiac monitoring before and during trastuzumab therapy. We estimated 24% of trastuzumab dispensed was discarded, at a cost of $21.1 million Australian. Alternative administration schedules and the addition of another vial size potentially reduce wastage to 6% of volume dispensed.

Conclusion

Debates about the use of expensive cancer medicines should consider postmarketing assessments as well as trial experience. The longer duration of trastuzumab use in clinical practice and the high rates of off-label use provide incentive for new clinical trials. Strategies to improve cardiac monitoring and to minimize drug wastage are issues that require immediate attention.
Association of Methylenetetrahydrofolate Reductase Gene Polymorphisms and Sex-Specific Survival in Patients With Metastatic Colon Cancer
Authors: Zhang Wu , Press Oliver A. , Haiman Christopher A. , Yang Dong Yun , Gordon Michael A. , Fazzone William , El-khoueiry Anthony , Iqbal Syma , Sherrod Andy E. , Lurje Georg , Lenz Heinz-Josef
Published: August 2007

Purpose

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate levels, which affects DNA synthesis and methylation. Two MTHFR gene polymorphisms, C677T and A1298C, are linked to altered enzyme activity. Several studies have shown these two polymorphisms to be associated with response to fluorouracil (FU) -based treatment in advanced colon cancer patients, but data are inconsistent and contradictory. Meanwhile, epidemiologic studies demonstrated that these MTHFR polymorphisms were associated with cancer risk in a sex-specific manner. We tested the hypothesis of whether these two polymorphisms are associated with sex-specific clinical outcome in metastatic colon cancer patients treated with FU-based chemotherapy.

Patients and Methods

This study included 318 patients (177 men and 141 women) with metastatic colon cancer treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Peripheral blood samples were collected from each patient, and genomic DNA was extracted from WBCs. Two MTHFR gene polymorphisms (C677T and A1298C) were tested by fluorogenic 5′-nuclease assay.

Results

The A1298C polymorphism showed statistically significant differences in overall survival (OS) in female, but not male, patients with metastatic colon cancer (log-rank test, P = .038). Among females, OS was greater for patients with the A/A genotype (n = 67; median OS, 18.4 months) compared with patients with the A/C genotype (n = 50; median OS, 13.9 months) or C/C genotype (n = 10; median OS, 15.6 months).

Conclusion

Although preliminary, these data support the role of the A1298C polymorphism in MTHFR as prognostic marker in female patients with metastatic colon cancer. Further studies are needed to confirm these findings.
Ceramide and Adenosine 5′-Monophosphate-Activated Protein Kinase Are Two Novel Regulators of 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity in Cultured Preadipocytes
Authors: Arai N. , Masuzaki H. , Tanaka T. , Ishii T. , Yasue S. , Kobayashi N. , Tomita T. , Noguchi M. , Kusakabe T. , Fujikura J. , Ebihara K. , Hirata M. , Hosoda K. , Hayashi T. , Sawai H. , Minokoshi Y. , Nakao K.
Published: August 2007

Increased activity of intracellular glucocorticoid reactivating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obese adipose tissue contributes to adipose dysfunction. As recent studies have highlighted a potential role of preadipocytes in adipose dysfunction, we tested the hypothesis that a variety of metabolic stress mediated by ceramide or AMP-activated protein kinase (AMPK) would regulate 11β-HSD1 in preadipocytes. The present study is the first to show that 1) expression of 11β-HSD1 in 3T3-L1 preadipocytes was robustly induced when cells were treated with cell-permeable ceramide analogue C2 ceramide, bacterial sphingomyelinase, and sphingosine 1-phosphate, 2) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced activation of AMPK augmented the expression and enzyme activity of 11β-HSD1, and 3) these results were reproduced in human preadipocytes. We demonstrate for the first time that C2 ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) β and its binding to 11β-HSD1 promoter. Transient knockdown of C/EBPβ protein by small interfering RNA markedly attenuated the expression of 11β-HSD1 induced by C2 ceramide or AICAR. The present study provides novel evidence that ceramide- and AMPK-mediated signaling pathways augment the expression and activity of 11β-HSD1 in preadipocytes by way of C/EBPβ, thereby highlighting a novel, metabolic stress-related regulation of 11β-HSD1 in a cell-specific manner.
Directional asymmetry in responses of local interneurons in the crayfish deutocerebrum to hydrodynamic stimulation of the lateral antennular flagellum
Authors: Mellon DeForest , Humphrey Joseph A. C.
Published: August 2007

We have recorded spiking responses from single, bimodally sensitive local interneurons (Type I) in the crayfish deutocerebrum to hydrodynamic and odorant stimuli flowing in two directions past the lateral antennular flagellum. Changing the direction of seamless introductions (meaning, with minimal variations of fluid velocity magnitude) of odorant flow past the flagellum, from proximal→distal to distal→proximal, did not consistently affect the dose-dependent responses of Type I neurons. By contrast, changing the direction of an abruptly initiated flow of water (or odorant) past the flagellum resulted in consistently larger numbers of spikes in response to this hydrodynamic stimulation when the flow direction was proximal→distal. This response asymmetry is discussed in relation to its possible relevance regarding antennular flicking behavior. The putative involvement of flagellar hydrodynamic receptors, the beaked hairs, and the hydrodynamic flow asymmetries they are exposed to, are examined theoretically in the accompanying paper.
Thermal preference ofCaenorhabditis elegans: a null model and empirical tests
Authors: Anderson Jennifer L. , Albergotti Lori , Proulx Stephen , Peden Colin , Huey Raymond B. , Phillips Patrick C.
Published: August 2007

The preferred body temperature of ectotherms is typically inferred from the observed distribution of body temperatures in a laboratory thermal gradient. For very small organisms, however, that observed distribution might misrepresent true thermal preferences. Tiny ectotherms have limited thermal inertia, and so their body temperature and speed of movement will vary with their position along the gradient. In order to separate the direct effects of body temperature on movement from actual preference behaviour on a thermal gradient, we generate a null model (i.e. of non-thermoregulating individuals)of the spatial distribution of ectotherms on a thermal gradient and test the model using parameter values estimated from the movement of nematodes(Caenorhabditis elegans) at fixed temperatures and on a thermal gradient. We show that the standard lab strain N2, which is widely used in thermal gradient studies, avoids high temperature but otherwise does not exhibit a clear thermal preference, whereas the Hawaiian natural isolate CB4856 shows a clear preference for cool temperatures (∼17°C). These differences are not influenced substantially by changes in the starting position of worms in the gradient, the natal temperature of individuals or the presence and physiological state of bacterial food. These results demonstrate the value of an explicit null model of thermal effects and highlight problems in the standard model of C. elegans thermotaxis, showing the value of using natural isolates for tests of complex natural behaviours.
Combustion in a high-speed rotary valve spark-ignition engine
Authors: Chow P H P , Watson H C , Wallis T
Published: August 2007

The current paper describes a study of combustion in the Bishop rotary valve engine by means of computation simulations. The combustion model was developed for this research at speeds up to 18 000 r/min and the results from the simulation were compared with experimental data. Sensitivity studies were performed in order to investigate the parametric effects on the combustion simulation of the engine. The major finding of this study was that convection of the flame kernels occurs and has a strong influence on the performance of the engine. The results indicated some insights as to how the combustion process of the engine can be improved.
A simplified method for calculating the stress of a large storage tank wall
Authors: Chen Z. P. , Duan Y. Y. , Shen J. M. , Jiang J. L.
Published: August 2007

With consideration of the influences from the constraint reaction of tank bottom plate to each shell course, a simplified long-short shell method was proposed to calculate the stress of a large storage tank wall. The first shell course was regarded as a short cylindrical shell while all the others as long cylindrical shells, and the analytic solution equations of shell stress were achieved by theory of plates and shells. With resistance stress-strain method, a field stress test was done on a 15x104 m3 floating-roof oil tank during its water filling test, and the measured stress data are in good agreement with the calculation results obtained by this simplified calculation method for shell stress. Therefore, the simplified method can be adopted to calculate the shell stress of large storage tanks accurately.
Recognition, recollection, familiarity and executive function in medicated patients with moderate Parkinson's disease
Authors: Edelstyn Nicola M. J. , Mayes Andrew R. , Condon Laura , Tunnicliffe Michelle , Ellis Simon J.
Published: August 2007

There is conflicting evidence about whether Parkinson's disease (PD) is associated with deficiencies in recognition memory (RM) and the processes which underlie it, namely recollection (a form of recall) and familiarity (a feeling of memory in the absence of recall). The aims of the current study were to examine forced‐choice verbal RM (assessed with the Warrington Recognition memory Test), yes‐no RM, recollection, familiarity and executive functioning in 17 patients with moderate PD and 17 healthy volunteers matched for age and premorbid intelligence. We predicted that patients with moderate PD would display a significant recollection deficit on the yes‐no RM test, because their strategic memory processing that depends on executive functioning and is necessary for efficient encoding and/or retrieval, was disrupted. In contrast, familiarity memory, which is not dependent on these processes, and forced‐choice RM (which is largely dependent on familiarity) should show higher levels of preservation. We also predicted that recollection should be correlated with severity of executive dysfunction. Our findings revealed that the PD patients were as likely to accurately discriminate between targets and distractors as the healthy volunteers on both RM tests. However, the PD patients were significantly less reliant on recollection‐driven recognition decisions on the yes‐no RM test when compared with the healthy control group. The patients also displayed executive function deficits, but these were not correlated with recollection. The extent to which the PD patients' reliance on familiarity at the expense of recollection is explained by impairments in strategic memory processes/executive function and/or medial temporal lobe retrieval processes needs further exploration.
Event‐related oscillations (EROs) and event‐related potentials (ERPs) comparison in facial expression recognition
Authors: Balconi Michela , Pozzoli Uberto
Published: August 2007

The study aims to explore the significance of event‐related potentials (ERPs) and event‐related brain oscillations (EROs) (delta, theta, alpha, beta, gamma power) in response to emotional (fear, happiness, sadness) when compared with neutral faces during 180–250 post‐stimulus time interval. The ERP results demonstrated that the emotional face elicited a negative peak at approximately 230 ms (N2). Moreover, EEG measures showed that motivational significance of face (emotional vs. neutral) could modulate the amplitude of EROs, but only for some frequency bands (i.e. theta and gamma bands). In a second phase, we considered the resemblance of the two EEG measures by a regression analysis. It revealed that theta and gamma oscillations mainly effect as oscillation activity at the N2 latency. Finally, a posterior increased power of theta was found for emotional faces.
Serum Proprotein Convertase Subtilisin Kexin Type 9 Is Correlated Directly with Serum LDL Cholesterol
Authors: Alborn William E , Cao Guoqing , Careskey Holly E , Qian Yue-Wei , Subramaniam Danise R , Davies Julian , Conner Elaine M , Konrad Robert J
Published: August 2007

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum.

Methods: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation.

Results: Serum concentrations of PCSK9 ranged from 11 to 115 μg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL.

Conclusions: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.
A Conversation With Virus X: Outing a Malevolent and Subversive Force in Parents' Lives
Authors: Wilkins Peter , Donovan Mark
Published: August 2007

The following conversation describes a narrative means of uncovering (or ‘deconstructing’) some of the invisible forces that undermine parents' capacities in caring for their children in preferred ways. In the authors' experience, parents can be hugely resourceful and provide a clear account of what they ‘should’ be doing, yet seem unable to act upon their own good advice — it is as though an external agent, named below as ‘Virus X’, prevents them from being the parents they would like to be. Through naming this external agent, identifying its influences and noticing parents' acts of resistance in the face of these influences, antidotes to Virus X can be developed. This paper describes the development of such an approach within a child behaviour management group. In keeping with the playful approach encouraged by narrative therapy, the authors of this paper join forces to act as investigative journalists in exposing Virus X to the readers.
The Baby as Subject: The Hospitalised Infant and the Family Therapist
Authors: Jones Sarah
Published: August 2007

This article is concerned with the experience of infants who endure long hospitalisations. It explores the concept of the baby as subject; that is, infants as active, psychic participants in their earliest relationships. It explores therapeutic possibilities with hospitalised infants from an infant mental health perspective. It advocates for family therapists to equip themselves for infant—parent therapeutic work.
Global and local alignments in HIV/AIDS prevention trainings: A case study from Burkina Faso
Authors: Drescher Martina
Published: August 2007

This article presents a linguistic analysis of data from an ongoing research project exploring HIV/AIDS education in West African Burkina Faso. I argue that we can identify different, sometimes even competing, discourses about the disease in prevention interactions. Thus, communication about HIV/AIDS in Burkina Faso—and probably in most of the Sub-Saharan countries—might be characterized by what I will call, with reference to Bakhtin, discursive heteroglossia. There is clear evidence of such discursive heteroglossia, that is, the participants' alignment to local and global HIV discourses, deployed in the communication of health workers. In my analysis of peer educators training sessions, I draw on theoretical and methodological principles from discourse analysis and interactional linguistics. I focus on the linguistic devices and conversational strategies the participants use to indicate the relevance of the local or the global discourses. Three particular devices—namely, metaphors, epistemic and evidential markers, and word explanations—will be examined in a more detailed way. I will also show how the local and the global interweave at different levels of prevention discourse.