bluuebunny/crossref_metadata_2025 huggingface dataset:
Synovial Sarcoma Mimicking Haemophilic Pseudotumour
Authors: Mann Haroon A. , Hilton Andrew , Goddard Nicholas J. , Smith Michael A. , Holloway Brian , Lee Christine A.
Published: September 2006

This is a case of a 36‐year‐old gentleman with haemophilia A who
was presented with an acute atraumatic soft tissue swelling in the
right thigh. Open biopsy was performed with the resultant
diagnosis of a synovial cell sarcoma. Although the clinical
findings were nonspecific they could easily have been found in a
bleeding haemophilic pseudotumour. The findings reported on MRI
scan initially were highly consistent with those present in
patients with mild haemophilia. An important part of orthopaedic
management in haemophilia is concerned with intraarticular and
intramuscular bleeding. Haematomas are common and sarcomas are
rare. However the absence of trauma should alert the clinician to
the possibility that the abnormality may represent haemorrhage
into a tumour and not just haematoma, even in a haemophilic
patient.
Vitamin D Intake and the Risk for Pancreatic Cancer in Two Cohort Studies
Authors: Skinner Halcyon G. , Michaud Dominique S. , Giovannucci Edward , Willett Walter C. , Colditz Graham A. , Fuchs Charles S.
Published: September 2006

Vitamin D and its analogues exhibit potent antitumor effects in many tissues, including the pancreas. Normal and malignant pancreatic tissues were recently shown to express high levels of vitamin D 1-α-hydroxylase, which converts circulating 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D. We examined associations between dietary intake of vitamin D, calcium, and retinol and subsequent risk for pancreatic cancer. We conducted prospective studies in cohorts of 46,771 men ages 40 to 75 years as of 1986 (the Health Professionals Follow-up Study), and 75,427 women ages 38 to 65 years as of 1984 (the Nurses' Health Study), documenting incident pancreatic cancer through the year 2000. Diet was ascertained by semiquantitative food-frequency questionnaire. We identified 365 incident cases of pancreatic cancer over 16 years of follow-up. Compared with participants in the lowest category of total vitamin D intake (<150 IU/d), pooled multivariate relative risks for pancreatic cancer were 0.78 [95% confidence interval (95% CI), 0.59-1.01] for 150 to 299 IU/d, 0.57 (95% CI, 0.40-0.83) for 300 to 449 IU/d, 0.56 (95% CI, 0.36-0.87) for 450 to 599 IU/d, and 0.59 (95% CI, 0.40-0.88) for ≥600 IU/d (Ptrend = 0.01). These associations may be stronger in men than women. After adjusting for vitamin D intake, calcium and retinol intakes were not associated with pancreatic cancer risk. In two U.S. cohorts, higher intakes of vitamin D were associated with lower risks for pancreatic cancer. Our results point to a potential role for vitamin D in the pathogenesis and prevention of pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1688–95)
Maternal Supplement, Micronutrient, and Cured Meat Intake during Pregnancy and Risk of Medulloblastoma during Childhood: A Children's Oncology Group Study
Authors: Bunin Greta R. , Gallagher Paul R. , Rorke-Adams Lucy B. , Robison Leslie L. , Cnaan Avital
Published: September 2006

We conducted a case-control study of medulloblastoma/primitive neuroectodermal tumors of brain (PNET) to pursue findings related to vitamin and mineral supplements, micronutrients, and cured meat consumption during gestation. Mothers of 315 cases ages <6 years at diagnosis in 1991 to 1997 identified from the United States and Canada through the Children's Oncology Group and mothers of 315 controls selected by random-digit dialing were interviewed. In the periconception period of the index pregnancy, case mothers were less likely than control mothers to report use of multivitamins [adjusted odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.4-1.0; P = 0.08] and to be in the highest quartile of iron and folate intake from food and supplements combined (adjusted OR for iron, 0.5; 95% CI, 0.3-0.9; Ptrend = 0.008; adjusted OR for folate, 0.5; 95% CI, 0.3-0.9; Ptrend = 0.007). Case and control mothers had similar intakes of cured meats, although case mothers were more likely to have the combination of high cured meat and low vitamin C intake (OR, 1.5; 95% CI, 1.0-2.3; P = 0.08). The results of the study add to the evidence of a protective role for multivitamins, suggest a possible role for micronutrients early in pregnancy, and generally do not support an association between cured meats and medulloblastoma/PNET. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1660–7)
Familiality in Barrett's Esophagus, Adenocarcinoma of the Esophagus, and Adenocarcinoma of the Gastroesophageal Junction
Authors: Chak Amitabh , Ochs-Balcom Heather , Falk Gary , Grady William M. , Kinnard Margaret , Willis Joseph E. , Elston Robert , Eng Charis
Published: September 2006

Background and Aim: The familial aggregation of Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction, jointly termed familial Barrett's esophagus, may represent a complex genetic trait. The aim of this study was to determine the proportion of patients with these diseases who have familial Barrett's esophagus.

Methods: Information on gastroesophageal reflux symptoms, known risk factors for Barrett's esophagus, and family history of Barrett's esophagus and cancers, was collected at six hospitals using a structured questionnaire from probands with either long-segment Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. Family history of Barrett's esophagus or esophageal cancer in a first- or second-degree relative was determined by reviewing medical records of all relatives reported to be affected.

Results: Seventy one of 411 (17.3%) probands reported an affected first- and/or second-degree relative. Upon review of medical records of the reportedly affected relatives, familial Barrett's esophagus was definitively determined in the case of 30 (7.3%) probands comprising 17 of 276 (6.2%) with Barrett's esophagus, 11 of 116 (9.5%) with adenocarcinoma of the esophagus, and 2 of 21 (9.5%) with adenocarcinoma of the gastroesophageal junction. The diagnosis in the relative reported by the proband to be affected was found not to be Barrett's esophagus or adenocarcinoma in 15 (3.6%) cases. The diagnosis could not be determined in 26 (6.3%) cases in which the proband reported an affected relative. There were no significant differences in age of disease onset, gender, race, or gastroesophageal reflux symptoms between definitive familial Barrett's esophagus probands and nonfamilial probands.

Conclusion: Familial Barrett's esophagus can be confirmed in 7.3% of persons presenting with Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1668–73)
Collection, Processing, and Storage of Biological Samples in Epidemiologic Studies: Sex Hormones, Carotenoids, Inflammatory Markers, and Proteomics as Examples
Authors: Tworoger Shelley S. , Hankinson Susan E.
Published: September 2006

The measurement of biomarkers in blood specimens has become an integral component of many epidemiologic studies and introduces several decision points about specimen collection, processing, and storage for the investigator. We briefly discuss the current state of knowledge for four commonly assessed biomarkers: estrogens and other sex hormones, ascorbic acid and carotenoids, cytokines involved in the inflammatory response, and proteomics. Sex hormones are relatively robust to type of sample collected, delayed processing (if chilled), and long-term storage at <−70°C. Ascorbic acid and carotenoids also are relatively robust to sample type and delayed processing (if chilled); however, the blood sample should not be exposed to sunlight and must be stored at <−70°C to prevent substantial degradation. If ascorbic acid is of primary interest, an acid stabilizer should be added during processing. Less is known for cytokines and proteomics, although initial research suggests that these assays are sensitive to varying collection, processing, and storage methods. Overall, we recommend conducting pilot studies if any nonstandard collection, processing, or storage procedure is used. Finally, decisions about these issues depend primarily on the scientific questions of most interest, cost, flexibility, and resources. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1578–81)
Blood Collection, Shipment, Processing, and Storage
Authors: Vaught Jimmie B.
Published: September 2006

As part of the AACR Annual Meeting Methods Workshop “Sample Collection, Processing, and Storage for Large-Scale Studies: Biorepositories to Support Cancer Research,” blood specimen collection, processing, storage, and dissemination issues were discussed. Whole blood and blood fractions comprise a major portion of biospecimen collections for population-based studies. Although procedures for collecting, processing, storing, and shipping blood components are generally standardized and well documented, several important factors need to be considered before a new study involving blood collection is initiated. Blood is collected from study participants for a variety of purposes, including as a source of DNA, and for a variety of laboratory analyses that may be done on whole blood or blood fractions, including serum, plasma, and lymphocytes. Blood or blood fractions may be shipped to laboratories and biorepositories either at ambient temperature, cooled or frozen, depending on the intended analyses. Blood processing may include fractionation, cryopreservation to preserve the viability of lymphocytes, or purification of nucleic acids. The proper storage conditions depend on a variety of factors, including the intended analyses and whether the specimens will be used within a short period or need to be stored for longer periods. As for all laboratory and biorepository procedures, blood collection, shipment, processing, and storage should be conducted under a strict quality assurance program, including standard operating procedures and regular quality control reviews. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1582–4)
Repression of cell cycle–related proteins by oxaliplatin but not cisplatin in human colon cancer cells
Authors: Voland Carole , Bord Annie , Péleraux Annick , Pénarier Géraldine , Carrière Dominique , Galiègue Sylvaine , Cvitkovic Esteban , Jbilo Omar , Casellas Pierre
Published: September 2006

Oxaliplatin (Eloxatin) is a third-generation platinum derivative with an in vitro and in vivo spectrum of activity distinct from that of cisplatin, especially in colon cancer cells. Here, we studied the molecular basis of this difference on the HCT-116 human colon carcinoma cell line (mismatch repair-deficient, wild-type functional p53). Oxaliplatin inhibited HCT-116 cell proliferation with greater efficacy than cisplatin. At comparable concentrations, cisplatin slowed down the replication phase and activated the G2-M checkpoint, whereas oxaliplatin activated the G1-S checkpoint and completely blocked the G2-M transition. With the aim of finding oxaliplatin-specific target genes and mechanisms differing from those of cisplatin, we established the transcriptional signatures of both products on HCT-116 cells using microarray technology. Based on hierarchical clustering, we found that (a) many more genes were modulated by oxaliplatin compared with cisplatin and (b) among the 117 modulated genes, 79 were regulated similarly by both drugs and, in sharp contrast, 38 genes were dose dependently down-regulated by oxaliplatin and, conversely, up-regulated or unaffected by cisplatin. Interestingly, several cell cycle–related genes encoding proteins involved in DNA replication and G2-M progression belong to this latter group. RNA modulations, confirmed at the protein level, were in accordance with oxaliplatin- and cisplatin-induced cell cycle variations. Beyond the identification of genes affected by both drugs, the identified oxaliplatin-specific target genes could be useful as predictive markers for evaluating and comparing the efficacy and molecular pharmacology of platinum drugs. [Mol Cancer Ther 2006;5(9):2149–57]
The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models
Authors: Ying Han , Biroc Sandra L. , Li Wei-wei , Alicke Bruno , Xuan Jian-Ai , Pagila Rene , Ohashi Yasuhiro , Okada Toshiya , Kamata Yoichi , Dinter Harald
Published: September 2006

The ability of cancer cells to undergo invasion and migration is a prerequisite for tumor metastasis. Rho, a Ras-related small GTPase, and the Rho-associated coiled coil–containing protein kinases (Rho kinases, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Inhibitors of this pathway have been shown to inhibit tumor cell motility and metastasis. Here, we show that fasudil [1-(5-isoquinolinesulfonyl)-homopiperazine], an orally available inhibitor of Rho kinases, and its metabolite 1-(hydroxy-5-isoquinoline sulfonyl-homopiperazine) (fasudil-OH) modify tumor cell morphology and inhibit tumor cell migration and anchorage-independent growth. In addition, we show that fasudil inhibited tumor progression in three independent animal models. In the MM1 peritoneal dissemination model, tumor burden and ascites production were reduced by >50% (P < 0.05). In the HT1080 experimental lung metastasis model, fasudil decreased lung nodules by ∼40% (P < 0.05). In the orthotopic breast cancer model with MDA-MB-231, there were 3-fold more tumor-free mice in the fasudil-treated group versus saline control group (P < 0.01). Fasudil has been approved for the treatment of cerebral vasospasm and associated cerebral ischemic symptoms. In patients, fasudil is well tolerated without any serious adverse reactions. Therefore, the concept of Rho kinase inhibition as an antimetastatic therapy for cancer can now be clinically explored. [Mol Cancer Ther 2006;5(9):2158–64]
Gene therapy with TRAIL against renal cell carcinoma
Authors: Matsubara Hiroki , Mizutani Yoichi , Hongo Fumiya , Nakanishi Hiroyuki , Kimura Yasunori , Ushijima So , Kawauchi Akihiro , Tamura Takahiro , Sakata Tsuneaki , Miki Tsuneharu
Published: September 2006

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells. However, TRAIL is not toxic against most normal cells. We have accordingly examined by in vivo electroporation whether TRAIL induces apoptosis in renal cell carcinoma. In addition, combination treatment with TRAIL and 5-fluorouracil (5-FU) against renal cell carcinoma was also investigated. The NC65 renal cell carcinoma line was used as a target. pCAGGS TRAIL was injected into the NC65 tumors in the right flanks of severe combined immunodeficient mice. Tumors were pulsed with the CUY21 electroporator. Electroporation was done once on day 0 or thrice on days 0, 2, and 4. Apoptosis was determined by terminal deoxyribonucleotide transferase–mediated nick-end labeling assay. When TRAIL gene therapy using in vivo i.t. electroporation was done once only, the growth of NC65 tumors was not inhibited. However, when TRAIL gene therapy was done thrice, growth suppression of the NC65 tumors was observed. Transfection of the TRAIL gene by in vivo electroporation induced apoptosis in NC65 tumors. When NC65 cells were treated with TRAIL gene therapy in combination with 5-FU, stronger growth suppression was obtained. TRAIL gene therapy did not induce liver dysfunction in severe combined immunodeficient mice. This study shows that TRAIL gene therapy induced growth suppression and apoptosis in NC65 tumors without severe side effects, and that combination treatment of NC65 cells with TRAIL gene therapy and 5-FU resulted in higher antitumor activity. These findings suggest that TRAIL gene therapy and/or 5-FU may be effective against renal cell carcinoma without harmful toxic effects. [Mol Cancer Ther 2006;5(9):2165–71]
A novel plant toxin, persin, within vivoactivity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells
Authors: Butt Alison J. , Roberts Caroline G. , Seawright Alan A. , Oelrichs Peter B. , MacLeod John K. , Liaw Tracy Y.E. , Kavallaris Maria , Somers-Edgar Tiffany J. , Lehrbach Gillian M. , Watts Colin K. , Sutherland Robert L.
Published: September 2006

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor–, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland–specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers. [Mol Cancer Ther 2006;5(9):2300–9]
Differential efficacy of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells
Authors: Sivaprasad Umasundari , Abbas Tarek , Dutta Anindya
Published: September 2006

Members of the statin family of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors are being investigated for the therapy and prevention of cancers because of their growth-inhibitory effects on epithelial cells. Some epidemiologic studies show that patients taking statins show a lower incidence of cancer compared with those taking other cholesterol-lowering medication. In contrast, other studies show that statin use does not correlate with cancer risk. To address this discrepancy, we investigated the efficacy of different statins on the PC-3 prostate cancer cell line and the androgen-dependent LNCaP prostate cancer cell line. Clinically used statins, lovastatin, fluvastatin, and simvastatin inhibit proliferation of the two prostate cancer cells by inducing a G1 arrest. Lovastatin induced the arrest at 0.5 μmol/L, a concentration easily reached in the serum after oral administration. Pravastatin, however, was less effective at inhibiting 3-hydroxy-3-methylglutaryl CoA reductase in PC-3 cells and had to be present at 200 times higher concentrations to effect a cell cycle arrest. Another potential source of variability is the different levels of the cyclin-dependent kinase (cdk) inhibitor p27 noted in prostate cancers particularly because statins have been suggested to act through the induction of cdk inhibitors. All three statins (lovastatin, fluvastatin, and simvastatin) inhibited cyclin E/cdk2 kinase leading to hypophosphorylation of Rb, but this inhibition was correlated with a loss of the activating phosphorylation on Thr160 of cyclin E–associated cdk2 and not dependent on the cdk inhibitors p21 and p27. Therefore, p27 status is unlikely to confound the epidemiologic data on the efficacy of statins in prostate cancer. To make definitive conclusions about the efficacy of statins on cancer prevention, however, the epidemiologic studies should take into account the type of statin used and the serum concentrations achieved and ensure that the tested statin inhibits the specific type of cancer in vitro at those concentrations. [Mol Cancer Ther 2006;5(9):2310–6]
Suppression of survivin expression in glioblastoma cells by the Ras inhibitor farnesylthiosalicylic acid promotes caspase-dependent apoptosis
Authors: Blum Roy , Jacob-Hirsch Jasmine , Rechavi Gideon , Kloog Yoel
Published: September 2006

The Ras inhibitor farnesylthiosalicylic acid (FTS) has been shown to induce apoptosis in glioblastoma multiforme, but its mechanism of action was unknown. We show that FTS or dominant-negative Ras, by deregulating extracellular signal-regulated kinase and Akt signaling, decreases survivin gene transcripts in U87 glioblastoma multiforme, leading to disappearance of survivin protein and cell death. FTS affected both Ras-controlled regulators of survivin transcription and Ras-regulated survival signals. Thus, Ras inhibition by FTS resulted in release of the survivin “brake” on apoptosis and in activation of the mitochondrial apoptotic pathway: dephosphorylation of Bad, activation of Bax, release of cytochrome c, and caspase activation. FTS-induced apoptosis of U87 cells was strongly attenuated by forced expression of survivin or by caspase inhibitors. These results show that resistance to apoptosis in glioblastoma multiforme can be abolished by a single Ras inhibitor, which targets both survivin, a critical inhibitor of apoptosis, and the intrinsic mitochondrial apoptotic machinery. [Mol Cancer Ther 2006;5(9):2337–47]
MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death
Authors: Barbieri Eveline , Mehta Parth , Chen Zaowen , Zhang Linna , Slack Andrew , Berg Stacey , Shohet Jason M.
Published: September 2006

Novel therapeutic approaches are urgently needed for high-stage neuroblastoma, a major therapeutic challenge in pediatric oncology. The majority of neuroblastoma tumors are p53 wild type with intact downstream p53 signaling pathways. We hypothesize that stabilization of p53 would sensitize this aggressive tumor to genotoxic chemotherapy via inhibition of MDM2, the primary negative upstream regulator of p53. We used pharmacologic inhibition of the MDM2-p53 interaction with the small-molecule inhibitor Nutlin and studied the subsequent response to chemotherapy in neuroblastoma cell lines. We did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase assays to measure proliferation and apoptosis in several cell lines (IMR32, MYCN3, and JF) treated with combinations of cisplatin, etoposide, and Nutlin. We found consistent and robust decreases in proliferation and increases in apoptosis with the addition of Nutlin 3a to etoposide or cisplatin in all cell lines tested and no response to the inactive Nutlin 3b enantiomer. We also show a rapid and robust accumulation of p53 protein by Western blot in these cells within 1 to 2 hours of treatment. We conclude that MDM2 inhibition dramatically enhances the activity of genotoxic drugs in neuroblastoma and should be considered as an adjuvant to chemotherapy for this aggressive pediatric cancer and for possibly other p53 wild-type solid tumors. [Mol Cancer Ther 2006;5(9):2358–65]
Results of Two Emergency Room Studies
Authors: Moskalewicz Jacek , Świątkiewicz Grażyna , Cherpitel Cheryl J. , Ye Yu
Published: September 2006

The aim of this paper is to examine to what extent cultural differences in male drinking patterns mediate relationships between alcohol and injury in a Polish context. Male patients admitted to emergency rooms located in two culturally different regions were investigated. Data analysis showed significant differences in patients’ socio-demographic characteristics, their drinking patterns as well as their annual alcohol consumption. Logistic regression, however, has not confirmed any impact of site, drinking pattern and their interactions on the risk of injury. The risk of injury tended to decline with age, being more than two times lower for men over 50 years old, and was 2.4 times higher for those with an annual consumption of 12+ liters of pure alcohol.
Endothelial Apoptosis Does Not Determine Symptom Status in Carotid Artery Disease
Authors: Nuotio Krista , Mäyränpää Mikko I. , Saksi Jani , Ijäs Petra , Sairanen Tiina , Carpén Olli , Soinne Lauri , Saimanen Eija , Salonen Oili , Lepäntalo Mauri , Kovanen Petri T. , Kaste Markku , Lindsberg Perttu J.
Published: September 2006

Background: We examined the hypothesis that endothelial denudation in advanced carotid plaques (CPs) occurs by increased apoptosis of endothelial cells (ECs) using scanning electron microscopy (SEM) as well as markers of cellular proliferation and apoptosis in advanced symptomatic CPs (SCPs) and asymptomatic CPs (ACPs). Methods: 93 consecutive patients underwent carotid endarterectomy. Five additional specimens were studied by SEM. We performed TUNEL assays, and immunostaining against Fas receptor (FasR), Fas ligand (FasL), activated caspase 3 (ACA3) and Ki-67. Results: SEM revealed morphological changes consistent with EC detachment. Surprisingly, ACA3 positivity was more pronounced on the endothelium of ACPs (4.6 ± 0.7% of total EC count) than on SCPs (3.3 ± 0.7%, p = 0.049), and was found to correlate positively with nuclear Ki-67 expression (rs = 0.275, p = 0.040). FasL expression was significantly increased on the endothelium of SCPs compared with ACPs (66.4 ± 4.4 vs. 53.9 ± 4.5%, p = 0.047). Conclusions: Absence of increased positivity of apoptotic markers dismisses apoptosis as a dominant mechanism underlying endothelial detachment of SCPs. Rather, increased ACA3 with co-expression of Ki-67 in ACPs might suggest that renewal of endothelium by active cell turnover may contribute to clinically silent evolution of plaques with preserved EC integrity. These observations may assist in designing novel therapies to prevent endothelial decay and symptom generation in advanced carotid artery disease.
Deterioration of Hemiparesis after Recurrent Stroke in the Unaffected Hemisphere: Three Further Cases with Possible Interpretation
Authors: Yamamoto Shiro , Takasawa Masashi , Kajiyama Koji , Baron Jean-Claude , Yamaguchi Takenori
Published: September 2006

Background: The concept of neural reorganization after brain damage is already well established, and many previous studies have successfully reported the translocation of the neural activation in the motor-related cortices during motor tasks using functional imaging modalities. Several primate and human studies have suggested the formation of newly reorganized tracts in the ipsilesional or contralesional hemisphere, but the mechanism for the formation of these tracts is still largely unknown. Methods: Three acute stroke patients who presented with abrupt deterioration of their right-sided hemiparesis due to the infarcts following a recurrent stroke in the originally unaffected hemisphere were studied using magnetic resonance imaging (MRI), MR angiography and single-photon emission CT. The relationship between the neurological symptom on admission and the precise location of the new infarct was carefully investigated from the perspective of reorganization. Results: Diffusion-weighted MRI showed a new subcortical infarct in the right hemisphere contralateral to the initial stroke in all patients. These new lesions involved the thalamus, globus pallidus or corona radiata, sparing the area of the internal capsule. T2-weighed MRI on admission showed an old infarct in the left middle cerebral artery territory, which had caused the original right-sided hemiparesis. Conclusion: It is proposed that the ‘extrapyramidal’ motor pathway in the unaffected hemisphere is associated with poststroke neural reorganization.
Is Fatigue an Independent Factor Associated with Activities of Daily Living, Instrumental Activities of Daily Living and Health-Related Quality of Life in Chronic Stroke?
Authors: van de Port I.G.L. , Kwakkel G. , Schepers V.P.M. , Heinemans C.T.I. , Lindeman E.
Published: September 2006

Background: To determine the longitudinal association of poststroke fatigue with activities of daily living (ADL), instrumental ADL (IADL) and perceived health-related quality of life (HRQoL) and to establish whether this relationship is confounded by other determinants. Methods: A prospective cohort study of stroke patients consecutively admitted for inpatient rehabilitation was conducted. ADL, IADL and HRQoL were assessed in 223 patients at 6, 12 and 36 months after stroke. Fatigue was determined by the Fatigue Severity Scale. Random coefficient analysis was used to analyze the impact of fatigue on ADL, IADL and HRQoL. The association between fatigue and outcome was corrected for potential confounders, i.e. age, gender, comorbidity, executive function, severity of paresis and depression. The covariate was considered to be a confounder if the regression coefficient of fatigue on outcome changed by >15%. Results: Fatigue was significantly related to IADL and HRQoL but not to ADL. The relation between fatigue and IADL was confounded by depression and motor impairment. Depression biased the relation between fatigue and HRQoL, but fatigue remained independently related to HRQoL. Conclusions: Fatigue is longitudinally spuriously associated with IADL and independently with HRQoL. These findings suggest that in examining the impact of poststroke fatigue on outcome, one should control for confounders such as depression.
Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese
Authors: Iwai Naoharu , Kajimoto Kazuaki , Kokubo Yoshihiro , Tomoike Hitonobu
Published: September 2006

The identification of genes that contribute to essential hypertension has been hampered because of a lack of statistical power and problems with multiple testing. In the present study, we performed association analyses between the 161 single nucleotide polymorphisms of 10 candidate genes and hypertension in a Japanese population recruited from the Suita Study (n=3654). We found that 5 polymorphisms in the 3 genes (
SLC9A2
,
UMOD
, and
ELN
) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of
P
<0.05. However, when a Bonferroni correction for multiple testing was applied, none of the polymorphisms were associated with blood pressure levels. We also performed association analyses between these 5 polymorphisms and intermediate phenotypes corresponding with the functions of candidate genes, including the renin/aldosterone profile, plasma uric acid levels, and pulse wave velocity. The
ELN
3′-untranslated region (−/A) polymorphism was found to significantly affect pulse wave velocity, an indicator of arterial stiffness. Associations of the
ELN
3′-untranslated region (−/A) polymorphism with hypertension and pulse wave velocity were reconfirmed in another set of the study population. Thus,
ELN
seems to contribute to blood pressure regulation by affecting arterial stiffness in Japanese.
Role of Endothelin-1 in Exposure to High Altitude
Authors: Modesti Pietro Amedeo , Vanni Simone , Morabito Marco , Modesti Alessandra , Marchetta Matilde , Gamberi Tania , Sofi Francesco , Savia Giulio , Mancia Giuseppe , Gensini Gian Franco , Parati Gianfranco
Published: September 2006

Background—

The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude–associated hypoxia.

Methods and Results—

In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21±7 versus 31±7 mm Hg,
P
<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H
2
OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100±200 versus 1610±590 mL; −6.7±3.5 versus −1.8±4.8 mL/min,
P
<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration.

Conclusions—

The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.
High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P
3
Lysophospholipid Receptor
Authors: Theilmeier Gregor , Schmidt Christoph , Herrmann Jörg , Keul Petra , Schäfers Michael , Herrgott Ilka , Mersmann Jan , Larmann Jan , Hermann Sven , Stypmann Jörg , Schober Otmar , Hildebrand Reinhard , Schulz Rainer , Heusch Gerd , Haude Michael , Lipinski Karin von Wnuck , Herzog Christine , Schmitz Martina , Erbel Raimund , Chun Jerold , Levkau Bodo
Published: September 2006

Background—

All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport–independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury.

Methods and Results—

In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by ≈20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P
3
lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P
3
-deficient mice.

Conclusions—

Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P
3
-mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.
Sex Differences in Major Bleeding With Glycoprotein IIb/IIIa Inhibitors
Authors: Alexander Karen P. , Chen Anita Y. , Newby L. Kristin , Schwartz Janice B. , Redberg Rita F. , Hochman Judith S. , Roe Matthew T. , Gibler W. Brian , Ohman E. Magnus , Peterson Eric D.
Published: September 2006

Background—

Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS); their safe use in women, however, remains a concern. The contribution of dosing to the observed sex-related differences in bleeding is unknown.

Methods and Results—

We explored the relationship between patient sex, GP IIb/IIIa inhibitor use, dose, and bleeding in 32 601 patients with NSTE ACS across 400 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) hospitals, of whom 18 436 were treated. GP IIb/IIIa inhibitor dose was defined as excessive if not reduced when creatinine clearance was <50 mL/min for eptifibatide or <30 mL/min for tirofiban. Major bleeding was defined as a hematocrit drop ≥0.12, need for transfusion, or intracranial bleeding. Major bleeding was adjusted for clinical factors and antithrombotic dose. The risk for bleeding attributable to excess GP IIb/IIIa dose was determined by sex using prevalence and adjusted odds ratios (ORs). Women had higher rates of major bleeding than men among those treated with GP IIb/IIIa inhibitors (15.7% versus 7.3%,
P
<0.0001) and among those not treated (8.5% versus 5.4%,
P
<0.0001). Despite similar serum creatinine levels, creatinine clearance averaged 20 points lower among treated women than men. Treated women were also more likely to receive excess GP IIb/IIIa doses than men (46.4% versus 17.2%,
P
<0.0001; adjusted OR 3.81, 95% confidence interval [CI] 3.39 to 4.27). Excess dosing was associated with increased risk of bleeding in women (OR 1.72, 95% CI 1.30 to 2.28) and men (OR 1.27, 95% CI 0.97 to 1.66); however, bleeding risk attributable to dosing was much higher in women (25.0% versus 4.4%).

Conclusions—

Women experience more bleeding than men whether or not they are treated with GP IIb/IIIa inhibitors; however, because of frequent excessive dosing in women, up to one fourth of this sex-related risk difference in bleeding is avoidable. Appropriate dosing will improve care of all patients with NSTE ACS, with a particular benefit for women.
Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy
Authors: Khoo Michelle S.C. , Li Jingdong , Singh Madhu V. , Yang Yingbo , Kannankeril Prince , Wu Yuejin , Grueter Chad E. , Guan Xiaoqun , Oddis Carmine V. , Zhang Rong , Mendes Lisa , Ni Gemin , C. Madu Ernest , Yang Jinying , Bass Martha , Gomez Rey J. , Wadzinski Brian E. , Olson Eric N. , Colbran Roger J. , Anderson Mark E.
Published: September 2006

Background—Activation of cellular Ca2+signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death.

Methods and Results—We found that activity and expression of a second Ca2+-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to “clamp” CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy.

Conclusions—CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.
(Mis-)Measuring the Relative Pay of Public School Teachers
Authors: Podgursky Michael , Tongrut Ruttaya
Published: September 2006

Statistics on the relative pay of public school teachers are routinely cited by plaintiffs in school finance (“adequacy”) lawsuits. However, comparisons of pay and benefits for public school teachers to those of professional employees in other sectors are complicated by the fact that most teachers work under contracts that are nine or ten months in length rather than a full year. The authors show that this makes household survey data on weekly earnings in the widely used Current Population Survey (CPS-ORG) unreliable. In general, employer-reported data on salaries and benefits such as the National Compensation Survey (NCS) or state administrative data are preferred for this type of comparison. NCS data on weekly earnings in metropolitan labormarkets suggest that pay of public school teachers compares much more favorably to that of nonteachers than CPS-ORG data suggest.
Adequacy Cost Studies: Perspectives on the State of the Art
Authors: Rebell Michael A.
Published: September 2006

In recent years, state legislatures, state education departments, and advocacy groups in more than thirty states have sponsored education adequacy studies, which aim to determine objectively the amount of funding needed to provide all students with a meaningful opportunity for an adequate education. Based on a detailed analysis of judicial and other critiques of the state of the art of “costing-out” studies, this policy brief recommends specific mechanisms for defining the outcome standards for these studies, more precise means for identifying the extent to which students with special needs require extra resources, ways to minimize political bias and manipulations, and the use of “quality education models” to integrate efficiency and accountability considerations into the basic cost analysis. More extensive public engagement and continuing judicial oversight will be necessary to ensure the credibility and legitimacy of the ultimate judgments that result from these studies.
Destination decision sets: A longitudinal comparison of stated destination preferences and actual travel
Authors: Pike Steven
Published: September 2006

There have only been a small number of applications of consumer decision set theory to holiday destination choice, and these studies have tended to rely on a single cross-sectional snapshot of research participants’ stated preferences. Very little has been reported on the relationship between stated destination preferences and actual travel. To what degree then can marketers rely on consumers’ stated attitudes if there is no supporting measure of actual behaviour? The article presents a rare longitudinal examination of destination decision sets, and the first in the context of short break holidays by car in Queensland, Australia. Two questionnaires were administered, three months apart. The first identified destination preferences while the second examined actual travel and revisited destination preferences. The findings indicate a general consistency between attitude and behaviour in the short term. The results support the proposition that the positioning of a destination into a consumer’s decision set represents a source of competitive advantage. A key implication for the destination of interest, which launched a new brand campaign during the period of the project, is that a long-term investment in a clearly differentiated brand message will be required to improve awareness and intent to travel by consumers in the region’s most important market. It is recommended that monitoring decision set composition represents an important and practical indicator of future performance for destination marketers.
Tourist dependent small towns: Understanding competitive advantage
Authors: Runyan Rodney C.
Published: September 2006

This study explores the resources that two distinctly different types of downtown business districts use to gain competitive advantage. Specifically, 267 respondents in four tourist dependent and seven non-dependent small downtowns were surveyed regarding the use of brand image and positioning, as well as business diversity and magnet stores within each respective downtown. T-tests were utilized to determine differences between downtown types, while multiple regression was used to determine which of the four constructs contributed to downtown performance. Analyses indicated that tourist dependent downtowns rated use of brand image, positioning, and business mix significantly higher than non-tourist dependent downtowns, while non-tourist downtowns rated magnet stores as more important to their downtown’s success. Regression analyses found that for both types of downtowns, image was a strong indicator of performance, while business diversity was an indicator for tourist dependent downtowns only. Managerial and research implications are provided to ground these findings in practice.
Understanding the impact of climate change on Scottish tourism
Authors: Yeoman Ian , McMahon-Beattie Una
Published: September 2006

Scottish tourism is forecasted to grow by 50 per cent over the next 10 years but one of the factors that may hinder or facilitate that growth is climatic change. Indeed, many people are now starting to question the impact of such significant growth on the planet. Therefore, this paper assesses the impact of climate change on Scottish tourism in order that policy makers can separate the facts from the myths. The dimensions of climate change such as CO2 emissions, temperature, rainfall, storms, and wind speed are discussed and the implications for Scottish tourism are mapped. Those implications may include the introduction of CO2 allowances for all travellers, more wind farms in rural locations impacting on film tourism or the grouse species disappearing from Scotland. The paper concludes with a number of adaptation strategies that Scottish tourism agencies and business could adopt to mitigate climate change. The importance of this paper lies in understanding how climate change could impact upon a specific destination, in this case Scotland, and in providing a micro analysis of that impact.
Monoclonal immunoglobulin with antitransferrin activity: a rare cause of hypersideremia with increased transferrin saturation
Authors: Alyanakian Marie-Alexandra , Taes Youri , Bensaïd Mimouna , Segovia Berta , Aucouturier Pierre , Rain Jean-Didier , Delanghe Joris , Varet Bruno , Beaumont Carole
Published: September 2006

Two unusual but similar cases of very high serum iron, extremely high transferrin concentrations (5.4 to 6.5 g/L), and increased transferrin saturation are reported. No anemia or microcytosis was observed. The ferritin concentration remained within the normal range, and no iron overload was observed. In one case, the in vivo half-life of 59Fe-labeled transferrin was shown to be prolonged (206 minutes versus 75 minutes for controls). In both patients, a monoclonal IgG was observed in the serum. The association between serum transferrin and monoclonal IgG was demonstrated by Western blot analysis and affinity chromatography. We suggest that the transferrin bound to the monoclonal IgG molecule has a prolonged half-life in the circulation, leading to high transferrin concentrations, and that the increased serum iron values prevent the onset of anemia. The antitransferrin activity of monoclonal antibody should be added to the list of situations accounting for elevated serum iron with elevated transferrin saturation.
miTarget: microRNA target gene prediction using a support vector machine
Authors: Kim Sung-Kyu , Nam Jin-Wu , Rhee Je-Keun , Lee Wha-Jin , Zhang Byoung-Tak
Published: September 2006

Background

MicroRNAs (miRNAs) are small noncoding RNAs, which play significant roles as posttranscriptional regulators. The functions of animal miRNAs are generally based on complementarity for their 5' components. Although several computational miRNA target-gene prediction methods have been proposed, they still have limitations in revealing actual target genes.

Results

We implemented miTarget, a support vector machine (SVM) classifier for miRNA target gene prediction. It uses a radial basis function kernel as a similarity measure for SVM features, categorized by structural, thermodynamic, and position-based features. The latter features are introduced in this study for the first time and reflect the mechanism of miRNA binding. The SVM classifier produces high performance with a biologically relevant data set obtained from the literature, compared with previous tools. We predicted significant functions for human miR-1, miR-124a, and miR-373 using Gene Ontology (GO) analysis and revealed the importance of pairing at positions 4, 5, and 6 in the 5' region of a miRNA from a feature selection experiment. We also provide a web interface for the program.

Conclusion

miTarget is a reliable miRNA target gene prediction tool and is a successful application of an SVM classifier. Compared with previous tools, its predictions are meaningful by GO analysis and its performance can be improved given more training examples.