bluuebunny/crossref_metadata_2025 huggingface dataset:
A Physiologically Based Pharmacokinetic Model of Docetaxel Disposition: from Mouse to Man
Authors: Bradshaw-Pierce Erica L. , Eckhardt S. Gail , Gustafson Daniel L.
Published: May 2007

Purpose: Docetaxel (Taxotere), an important chemotherapeutic agent with shown activity in a broad range of cancers, is being investigated for use in combination therapies and as an antiangiogenic agent. Docetaxel exhibits a complex pharmacologic profile with high interpatient variability. Pharmacokinetic models capable of predicting exposure under various dosing regimens would aid the rational development of clinical protocols.

Experimental Design: A pharmacokinetic study of docetaxel at 5 and 20 mg/kg was carried out in female BALB/c mice. Tissues were collected at various time points and analyzed by liquid chromatography-tandem mass spectrometry. Time course tissue distribution and pharmacokinetic data were used to build and validate a physiologically based pharmacokinetic (PBPK) model in mice. Specific and nonspecific tissue partitioning, metabolism, and elimination data were coupled with mouse physiologic variables to develop a PBPK model that describes docetaxel plasma and tissue pharmacokinetic. The PBPK model was then modified with human model variables to predict the plasma distribution of docetaxel.

Results: Resulting simulation data were compared with actual measured data obtained from our pharmacokinetic study (mouse), or from published data (human), using pharmacokinetic variables calculated using compartmental or noncompartmental analysis to assess model predictability.

Conclusions: The murine PBPK model developed can accurately predict plasma and tissue levels at the 5 and 20 mg/kg doses. The human PBPK model is capable of estimating plasma levels at 30, 36, and 100 mg/m2. This will enable us to develop and test various dosing regimens (e.g., metronomic schedules and combination therapies) to achieve specific tissue and plasma concentrations to maximize therapeutic benefit while minimizing toxicity.
Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer
Authors: Takimoto Chris H. , Hammond-Thelin Lisa A. , Latz Jane E. , Forero Leonardo , Beeram Muralidhar , Forouzesh Bahram , de Bono Johann , Tolcher Anthony W. , Patnaik Amita , Monroe Pamela , Wood Leslie , Schneck Karen B. , Clark Romnee , Rowinsky Eric K.
Published: May 2007

Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability.

Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1.

Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation.

Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.
SOM230, A New Somatostatin Analogue, Is Highly Effective in the Therapy of Growth Hormone/Prolactin-Secreting Pituitary Adenomas
Authors: Fedele Monica , De Martino Ivana , Pivonello Rosario , Ciarmiello Andrea , Del Basso De Caro M. Laura , Visone Rosa , Palmieri Dario , Pierantoni Giovanna M. , Arra Claudio , Schmid Herbert A. , Hofland Leo , Lombardi Gaetano , Colao Annamaria , Fusco Alfredo
Published: May 2007

Purpose: We have previously shown that transgenic mice ubiquitously overexpressing the HMGA2 gene develop growth hormone/prolactin-secreting pituitary adenomas. This animal model has been used to evaluate the therapeutic efficacy of SOM230, a somatostatin analogue with high affinity for the somatostatin receptor subtypes 1, 2, 3, and 5, on the growth of the pituitary adenomas.

Experimental Design: Four groups of 3- and 9-month-old HMGA2 transgenic mice were treated for 3 months with a continuous s.c. injection of two different dosages of SOM230 (5 or 50 μg/kg/h), one dose of octreotide, corresponding to that used in human therapy, and a placebo, respectively. The development of the tumor before and after therapy was monitored by magnetic resonance imaging of the pituitary region and evaluation of the serum prolactin levels.

Results: The highest dose of SOM230 induced a drastic regression of the tumor, whereas octreotide was not able to induce any significant tumor regression, although tumor progression was significantly slowed down. No significant differences were observed between the animals treated with the lowest dose of SOM230 and those receiving placebo.

Conclusions: These results clearly support the efficacy of the SOM230 treatment in human pituitary adenomas secreting prolactin based on the dramatic tumor shrinkage and fall in prolactin levels. This beneficial effect could be of crucial clinical usefulness in patients bearing tumors resistant to dopaminergic drugs.
Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease
Authors: Mena Salvador , Benlloch María , Ortega Angel , Carretero Julian , Obrador Elena , Asensi Miguel , Petschen Ignacio , Brown Bob D. , Estrela José M.
Published: May 2007

Purpose: Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions.

Experimental Design: Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an l-glutamine–enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-α, and IFN-γ were administered as a combination therapy.

Results: Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P < 0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities.

Conclusions: Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.
Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1α Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells
Authors: Tang Xudong , Zhang Qunzhou , Nishitani Junko , Brown Jimmy , Shi Shihong , Le Anh D.
Published: May 2007

Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression.

Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated.

Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol.

Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α–dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α–mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.
Insulin Treatment in Cancer Cachexia: Effects on Survival, Metabolism, and Physical Functioning
Authors: Lundholm Kent , Körner Ulla , Gunnebo Lena , Sixt-Ammilon Petra , Fouladiun Marita , Daneryd Peter , Bosaeus Ingvar
Published: May 2007

Purpose: The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care.

Experimental Design: One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 ± 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat.

Results: Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 ± 139 days (mean ± SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients (P < 0.03).

Conclusion: Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.
Relationship between Survival and Edema in Malignant Gliomas: Role of Vascular Endothelial Growth Factor and Neuronal Pentraxin 2
Authors: Carlson Marc R.J. , Pope Whitney B. , Horvath Steve , Braunstein Jerome G. , Nghiemphu Phioanh , Tso Cho-Lea , Mellinghoff Ingo , Lai Albert , Liau Linda M. , Mischel Paul S. , Dong Jun , Nelson Stanley F. , Cloughesy Timothy F.
Published: May 2007

Purpose: Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood.

Experimental Design: Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival.

Results and Conclusions: VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P < 0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P < 0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P = 0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P < 0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.
Serum Concentrations of Uric Acid and the Metabolic Syndrome Among US Children and Adolescents
Authors: Ford Earl S. , Li Chaoyang , Cook Stephen , Choi Hyon K.
Published: May 2007

Background—

The association between concentrations of uric acid and the metabolic syndrome in children and adolescents remains incompletely understood. The objective of this study was to examine how these 2 were associated in a nationally representative sample of US children and adolescents.

Methods and Results—

We performed a cross-sectional analysis of 1370 males and females aged 12 to 17 years using data from the National Health and Nutrition Examination Survey 1999–2002. The prevalence of the metabolic syndrome was <1% among participants in the lowest quartile of serum concentration of uric acid, 3.7% in the second quartile, 10.3% in the third quartile, and 21.1% in the highest quartile. Compared with the lowest 2 quartiles of uric acid together (≤291.5 μmol/L), the odds ratios were 5.80 (95% confidence interval, 3.22 to 10.46) for those in the third quartile (>291.5 to ≤339 μmol/L or >4.9 to ≤5.7 mg/dL) and 14.79 (95% confidence interval, 7.78 to 28.11) for those in the top quartile (>339 μmol/L) after adjustment for age, sex, race or ethnicity, and concentrations of C-reactive protein. Starting with the lowest quartile of concentration of uric acid, mean concentrations of serum insulin were 66.2, 66.7, 79.9, and 90.9 pmol/L for ascending quartiles, respectively (
P
for trend <0.001).

Conclusions—

Among US children and adolescents, serum concentrations of uric acid are strongly associated with the prevalence of the metabolic syndrome and several of its components.
Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E–Deficient Mice
Authors: Bot Ilze , de Jager Saskia C.A. , Zernecke Alma , Lindstedt Ken A. , van Berkel Theo J.C. , Weber Christian , Biessen Erik A.L.
Published: May 2007

Background—

Mast cells are major effector cells in allergy and host defense responses. Their increased number and state of activation in perivascular tissue during atherosclerosis may point to a role in cardiovascular disorders. In the present study, we investigated the contribution of perivascular mast cells to atherogenesis and plaque stability in apolipoprotein E–deficient mice.

Methods and Results—

We show here that episodes of systemic mast cell activation during plaque progression in mice leads to robust plaque expansion. Targeted activation of perivascular mast cells in advanced plaques sharply increases the incidence of intraplaque hemorrhage, macrophage apoptosis, vascular leakage, and CXCR2/VLA-4–mediated recruitment of leukocytes to the plaque. Importantly, treatment with the mast cell stabilizer cromolyn does prevent all the adverse phenomena elicited by mast cell activation.

Conclusions—

This is the first study to demonstrate that mast cells play a crucial role in plaque progression and destabilization in vivo. We propose that mast cell stabilization could be a new therapeutic approach to the prevention of acute coronary syndromes.
Inductionless or Limited Shock Testing Is Possible in Most Patients With Implantable Cardioverter- Defibrillators/Cardiac Resynchronization Therapy Defibrillators
Authors: Day John D. , Doshi Rahul N. , Belott Peter , Birgersdotter-Green Ulrika , Behboodikhah Mahnaz , Ott Peter , Glatter Kathryn A. , Tobias Serge , Frumin Howard , Lee Byron K. , Merillat John , Wiener Isaac , Wang Samuel , Grogin Harlan , Chun Sung , Patrawalla Rob , Crandall Brian , Osborn Jeffrey S. , Weiss J. Peter , Lappe Donald L. , Neuman Stacey
Published: May 2007

Background—

Implantable cardioverter-defibrillators and cardiac resynchronization therapy defibrillators have relied on multiple ventricular fibrillation (VF) induction/defibrillation tests at implantation to ensure that the device can reliably sense, detect, and convert VF. The ASSURE Study (Arrhythmia Single Shock Defibrillation Threshold Testing Versus Upper Limit of Vulnerability: Risk Reduction Evaluation With Implantable Cardioverter-Defibrillator Implantations) is the first large, multicenter, prospective trial comparing vulnerability safety margin testing versus defibrillation safety margin testing with a single VF induction/defibrillation.

Methods and Results—

A total of 426 patients receiving an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator underwent vulnerability safety margin or defibrillation safety margin screening at 14 J in a randomized order. After this, patients underwent confirmatory testing, which required 2 VF conversions without failure at ≤21 J. Patients who passed their first 14-J and confirmatory tests, irrespective of the results of their second 14-J test, had their devices programmed to a 21-J shock for ventricular tachycardia (VT) or VF ≥200 bpm and were followed up for 1 year. Of 420 patients who underwent 14-J vulnerability safety margin screening, 322 (76.7%) passed. Of these, 317 (98.4%) also passed 21-J confirmatory tests. Of 416 patients who underwent 14-J defibrillation safety margin screening, 343 (82.5%) passed, and 338 (98.5%) also passed 21-J confirmatory tests. Most clinical VT/VF episodes (32 of 37, or 86%) were terminated by the first shock, with no difference in first shock success. In all observed cases in which the first shock was unsuccessful, subsequent shocks terminated VT/VF without complication.

Conclusions—

Although spontaneous episodes of fast VT/VF were limited, there was no difference in the odds of first shock efficacy between groups. Screening with vulnerability safety margin or defibrillation safety margin may allow for inductionless or limited shock testing in most patients.
Annual Rate of Transvenous Defibrillation Lead Defects in Implantable Cardioverter-Defibrillators Over a Period of >10 Years
Authors: Kleemann Thomas , Becker Torsten , Doenges Klaus , Vater Margit , Senges Jochen , Schneider Steffen , Saggau Werner , Weisse Udo , Seidl Karlheinz
Published: May 2007

Background—

The number of patients with longer follow-up after implantation of an implantable cardioverter-defibrillator is increasing continuously. Defibrillation lead failure is a typical long-term complication. Therefore, the long-term reliability of implantable cardioverter-defibrillator leads has become an increasing concern. The aim of the present study was to assess the annual rate of transvenous defibrillation lead defects related to follow-up time after lead implantation.

Methods and Results—

A total of 990 consecutive patients who underwent first implantation of an implantable cardioverter-defibrillator between 1992 and May 2005 were analyzed. Median follow-up time was 934 days (interquartile range, 368 to 1870). Overall, 148 defibrillation leads (15%) failed during the follow-up. The estimated lead survival rates at 5 and 8 years after implantation were 85% and 60%, respectively. The annual failure rate increased progressively with time after implantation and reached 20% in 10-year-old leads (
P
<0.001). Lead defects affected newer as well as older models. Patients with lead defects were 3 years younger at implantation and more often female. Multiple lead implantation was associated with a trend to a higher rate of defibrillation lead defects (
P
=0.06). The major lead complications were insulation defects (56%), lead fractures (12%), loss of ventricular capture (11%), abnormal lead impedance (10%), and sensing failure (10%).

Conclusions—

An increasing annual lead failure rate is noted primarily during long-term follow-up and reached 20% in 10-year-old leads. Patients with lead defects are younger and more often female.
Potentiation of Bradykinin Effect by Angiotensin-Converting Enzyme Inhibition Does Not Correlate With Angiotensin-Converting Enzyme Activity in the Rat Mesenteric Arteries
Authors: Sivieri Disney O. , Bispo-da-Silva Luiz B. , Oliveira Eduardo B. , Resende Angela C. , Salgado Maria Cristina O.
Published: May 2007

Angiotensin-converting enzyme (kininase II [ACE]) inhibitors are capable of potentiating bradykinin (BK) effects by enhancing the actions of bradykinin on B2receptors independent of blocking its inactivation. To investigate further the importance of ACE kininase activity on BK-induced vasodilation, we investigated the effect of inhibiting ACE, as well as other kininases, on both BK metabolism and vasodilator effect in preparations that exhibit increased ACE activity. Mesenteric arterial beds obtained from 1-kidney, 1-clip hypertensive rats presented augmented ACE and angiotensin I converting activities compared with normotensive rats. The isolated and perfused mesenteric beds were exposed to BK for 15 minutes in the absence or in the presence of kininase inhibitors; then, the perfusate was collected for analysis of the products of BK metabolism by high-performance liquid chromatography. BK was metabolized to the fragments BK(1-8), BK(1-7), and BK(1-5), and the recovery of intact BK was reduced by 47% in the hypertensive group. Recovery of BK was increased in both groups in the presence of a kininase I inhibitor and in the hypertensive group by neutral endopeptidase 24.11 inhibitor; however, ACE inhibition did not affect BK metabolism in both groups. In contrast, only the ACE inhibitor potentiated the vasodilator effect of BK in a mesenteric bed preconstricted with phenylephrine; the increase in BK effect, nevertheless, was not greater in arteries from hypertensive rats that presented an increased ACE activity when compared with those in the normotensive group. These data demonstrated that ACE inhibitor–induced potentiation of BK vasodilator effects is not related to their actions on BK degradation.
Similar Effects of Treatment on Central and Brachial Blood Pressures in Older Hypertensive Subjects in the Second Australian National Blood Pressure Trial
Authors: Dart Anthony M. , Cameron James D. , Gatzka Christoph D. , Willson Kristyn , Liang Yu-Lu , Berry Karen L. , Wing Lindon M.H. , Reid Christopher M. , Ryan Philip , Beilin Lawrence J. , Jennings Garry L.R. , Johnston Colin I. , McNeil John J. , Macdonald Graham J. , Morgan Trefor O. , West Malcolm J. , Kingwell Bronwyn A.
Published: May 2007

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6±4.7 years (mean±SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145±1 (mean±SEM), 143±1, 72±1, and 70±1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −17±2, −16±2, −9±1, and −7±1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144±2, 144±2, 71±2, and 72±2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −15±2, −17±2, −6±2, and −8±2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.
Enhanced Superoxide Production in Renal Outer Medulla of Dahl Salt-Sensitive Rats Reduces Nitric Oxide Tubular-Vascular Cross-Talk
Authors: Mori Takefumi , O’Connor Paul M. , Abe Michiaki , Cowley Allen W.
Published: May 2007

Studies were conducted to determine whether the diffusion of NO from the renal medullary thick ascending limb (mTAL) to the contractile pericytes of surrounding vasa recta was reduced and, conversely, whether diffusion of oxygen free radicals was enhanced in the salt-sensitive Dahl S rat (SS/Mcwi). Angiotensin II ([Ang II] 1 μmol/L)–stimulated NO and superoxide (O
2
·−
) production were imaged by fluorescence microscopy in thin tissue strips from the inner stripe of the outer medulla. In prehypertensive SS/Mcwi rats and a genetically designed salt-resistant control strain (consomic SS-13
BN
), Ang II failed to increase either NO or O
2
·−
in pericytes of isolated vasa recta. Ang II stimulation resulted in production of NO in epithelial cells of the mTAL that diffused to vasa recta pericytes of SS-13
BN
rats but not in SS/Mcwi rats except when tissues were preincubated with the superoxide scavenger TIRON (1 mmol/L). Ang II resulted in a greater increase of O
2
·−
in the mTAL of SS/Mcwi compared with SS.13
BN
mTAL. The O
2
·−
diffused to adjoining pericytes in tissue strips only in SS/Mcwi rats but not in control SS-13
BN
rats. Diffusion of Ang II-stimulated O
2
·−
from mTAL to vasa recta pericytes was absent when tissue strips from SS/Mcwi rats were treated with the NO donor DETA-NONOate (20 μmol/L). We conclude that the SS/Mcwi rat exhibits increased production of O
2
·−
in mTAL that diffuses to surrounding vasa recta and attenuates NO cross-talk. Diffusion of O
2
·−
from mTAL to surrounding tissue could contribute to reduced bioavailability of NO, reductions of medullary blood flow, and interstitial fibrosis in the outer medulla of SS/Mcwi rats.
Rejected Sacrifice in Greek and Hebrew Religion
Authors:   Naiden
Published: April 2007

Scholars of Greek religion, notably Walter Burkert and Jean-Pierre Vernant, have ignored the few but important examples of sacrifices that meet with rejection, and along with this oversight have minimalized the legal and moral aspect of sacrifice. The same error has led them to overlook the similarity between rejected sacrifice in Greek religion and rejected sacrifice in ancient Judaism, where the same infrequent but important phenomenon occurs. This paper proposes a typology for rejected sacrifice and attempts to balance similarities and differences to be found in Greek and Hebrew practice, notably with respect to sacrifices rejected as punishment for sacrilege.
The Myth of the Golden Fleece
Authors: Bremmer Jan
Published: April 2007

This contribution analyses the Greek myth of the Golden Fleece with special attention to its (possible) Oriental components. The first part of the myth, which is situated in Greece, contains a number of relevant motifs in this respect: the 'desperate housewife' (cf. the Joseph story in Genesis); the king's responsibility of the land (cf. the stories around David in the OT); the scapegoat motif, and the sacrifice of one's own child (cf. Abraham and Isaac). The second part of the myth, which is situated in Colchis, concentrates on the Golden Fleece proper. Recent investigations have argued its connection with the Hittite kurša, and my contribution tries to strengthen this connection. In Greek myth and ritual we can see its development into the Golden Fleece of the Argonauts but also into Athena's aegis; the early history of the Golden Fleece still connects it with Anatolia. The killing of the dragon that guarded the Golden Fleece seems inspired by the defeat of Illuyankaš. Both the kurša and the myth of Illuyankaš played an important role at the Hittite Purulli festival, which may have promoted their combination. The routes of transmission of the Oriental parts of the myth probably were Cilicia, Cyprus and the later Royal Road.
On the Role of Resonant Interactions in the Short-Term Evolution of Deep-Water Ocean Spectra
Authors: Tanaka Mitsuhiro
Published: May 2007

The temporal evolution of the energy spectrum of a field of random surface gravity waves in deep water is investigated by means of direct numerical simulations of the deterministic primitive equations. The detected rate of change of the spectrum is shown to be proportional to the cubic power of the energy density and to agree very well with the nonlinear energy transfer Snl as predicted by Hasselmann. Despite the fact that use of various asymptotic relations that are valid only for t → ∞ or integration with respect to time over a time scale much longer than O[period × (ak)−2] is necessary in the derivation of Hasselmann’s Snl, it is clearly demonstrated that the rate of change of the spectrum given by the numerical simulation agrees very well with Hasselmann’s Snl at every instance of ordinary time scale comparable to the period. The result implies that the four-wave resonant interactions control the evolution of the spectrum at every instant of time, whereas nonresonant interactions do not make any significant contribution even in a short-term evolution. It is also pointed out that the result may call for a reexamination of the process of derivation of the kinetic equation for the spectrum.
The Nonlinear Dynamics of Time-Dependent Subcritical Baroclinic Currents
Authors: Flierl G. R. , Pedlosky J.
Published: May 2007

The nonlinear dynamics of baroclinically unstable waves in a time-dependent zonal shear flow is considered in the framework of the two-layer Phillips model on the beta plane. In most cases considered in this study the amplitude of the shear is well below the critical value of the steady shear version of the model. Nevertheless, the time-dependent problem in which the shear oscillates periodically is unstable, and the unstable waves grow to substantial amplitudes, in some cases with strongly nonlinear and turbulent characteristics. For very small values of the shear amplitude in the presence of dissipation an analytical, asymptotic theory predicts a self-sustained wave whose amplitude undergoes a nonlinear oscillation whose period is amplitude dependent. There is a sensitive amplitude dependence of the wave on the frequency of the oscillating shear when the shear amplitude is small. This behavior is also found in a truncated model of the dynamics, and that model is used to examine larger shear amplitudes. When there is a mean value of the shear in addition to the oscillating component, but such that the total shear is still subcritical, the resulting nonlinear states exhibit a rectified horizontal buoyancy flux with a nonzero time average as a result of the instability of the oscillating shear. For higher, still subcritical, values of the shear, a symmetry breaking is detected in which a second cross-stream mode is generated through an instability of the unstable wave although this second mode would by itself be stable on the basic time-dependent current. For shear values that are substantially subcritical but of order of the critical shear, calculations with a full quasigeostrophic numerical model reveal a turbulent flow generated by the instability. If the beta effect is disregarded, the inviscid, linear problem is formally stable. However, calculations show that a small degree of nonlinearity is enough to destabilize the flow, leading to large amplitude vacillations and turbulence. When the most unstable wave is not the longest wave in the system, a cascade up scale to longer waves is observed. Indeed, this classically subcritical flow shows most of the qualitative character of a strongly supercritical flow. This result supports previous suggestions of the important role of background time dependence in maintaining the atmospheric and oceanic synoptic eddy field.
Satellite Observations of Seasonal and Interannual Changes of Sea Level and Currents over the Scotian Slope
Authors: Han Guoqi
Published: May 2007

Seasonal and interannual sea level and current variations over the Scotian slope are examined using 10 years of Ocean Topography Experiment (TOPEX)/Poseidon (T/P) satellite altimeter data. Geostrophic surface current anomalies normal to ground tracks are derived from the along-track gradients of sea level anomalies. The altimetric current anomalies are combined with a climatological mean circulation field of a finite-element model to construct nominal absolute currents. The seasonal mean results indicate that the sea level is highest in late summer and lowest in late winter and that the surface slope circulation is strong in winter/autumn and weaker in summer/spring. The total transport associated with the westward shelf-edge current and with the eastward slope current, calculated by combining the T/P data with a climatological seasonal mean density field, reveals a substantial seasonal change dominated by the barotropic component. The present analysis reveals prominent interannual changes of the sea level and current anomalies for the study period. The sea level was lowest in 1996/97, when the Gulf Stream was in its most southern position. The mean winter circulation over the Scotian slope was strongest (up to 30 cm s−1 in both the southwestward shelf-edge current and northeastward slope current) in 1998 and weakest (weaker and broader shelf-edge current) in 1996, which may be related to the fluctuation of the equatorward Labrador Current strength and of the Gulf Stream north–south position. The study also suggests that the root-mean-square current magnitude is positively correlated with the occurrence of the Gulf Stream warm-core rings (WCRs) on the interannual scale, while WCR yearly mean kinematic properties seem to have small variations.
Ventilation and Transformation of Labrador Sea Water and Its Rapid Export in the Deep Labrador Current
Authors: Brandt Peter , Funk Andreas , Czeschel Lars , Eden Carsten , Böning Claus W.
Published: May 2007

A model of the subpolar North Atlantic Ocean is used to study different aspects of ventilation and water mass transformation during a year with moderate convection intensity in the Labrador Sea. The model realistically describes the salient features of the observed hydrographic structure and current system, including boundary currents and recirculations. Ventilation and transformation rates are defined and compared. The transformation rate of Labrador Sea Water (LSW), defined in analogy to several observational studies, is 6.3 Sv (Sv ≡ 106 m3 s−1) in the model. Using an idealized ventilation tracer, mimicking analyses based on chlorofluorocarbon inventories, an LSW ventilation rate of 10 Sv is found. Differences between both rates are particularly significant for those water masses that are partially transformed into denser water masses during winter. The main export route of the ventilated LSW is the deep Labrador Current (LC). Backward calculation of particle trajectories demonstrates that about one-half of the LSW leaving the Labrador Sea within the deep LC originates in the mixed layer during that same year. Near the offshore flank of the deep LC at about 55°W, the transformation of LSW begins in January and is at a maximum in February/March. While the export of transformed LSW out of the central Labrador Sea continues for several months, LSW generated near the boundary current is exported more rapidly, with maximum transport rates during March/April within the deep LC.
Effect of Sea Surface Temperature–Wind Stress Coupling on Baroclinic Instability in the Ocean
Authors: Spall Michael A.
Published: May 2007

The impact of the observed relationship between sea surface temperature and surface wind stress on baroclinic instability in the ocean is explored using linear theory and a nonlinear model. A simple parameterization of the influence of sea surface temperature on wind stress is used to derive a surface boundary condition for the vertical velocity at the base of the oceanic Ekman layer. This boundary condition is applied to the classic linear, quasigeostrophic stability problem for a uniformly sheared flow originally studied by Eady in the 1940s. The results demonstrate that for a wind directed from warm water toward cold water, the coupling acts to enhance the growth rate, and increase the wavelength, of the most unstable wave. Winds in the opposite sense reduce the growth rate and decrease the wavelength of the most unstable wave. For representative coupling strengths, the change in growth rate can be as large as ±O(50%). This effect is largest for shallow, strongly stratified, low-latitude flows.
Inclusion in Australia
Authors: Anderson Colin J. K. , Klassen Robert M. , Georgiou George K.
Published: May 2007

This article examines the inclusion-related beliefs and perceived needs of primary teachers in Australia, and proposes ways that school psychologists can help meet these needs. Forced-choice and open-ended survey questions provided quantitative and qualitative data from 162 primary school teachers who were in the midst of implementing an inclusive education program in a large urban/suburban education district in Western Australia. Survey questions focused on beliefs about inclusion, confidence about implementing inclusive practices and attitudes about current and necessary support structures. The majority of teachers perceive benefits (85 percent) as well as drawbacks (95 percent) to teaching in inclusive classrooms. Only 10 percent of teachers noted school psychologists as part of structures that successfully support inclusive practices and only 4 percent of teachers requested additional school psychology time as a support structure needed to boost confidence to teach more inclusively. Qualitative data showed that teachers want more training in specific disabilities as well as additional aide time. We conclude that school psychologists need to be more proactive and involved in providing training, disseminating research, developing behaviour and learning plans and advocating for teachers.
Assessment of Coping Styles and Strategies with School-Related Stress
Authors: Wrzesniewski Kazimierz , Chylinska Joanna
Published: May 2007

A review of the relevant literature indicates a lack of measurement techniques for coping styles and strategies with school-related stress. This study presents the procedure of constructing The Coping with School-related Stress Questionnaire (CSSQ), which makes it possible to investigate dispositional as well as situational aspects of coping. Theoretical assumptions are based on the interactive model of coping with stress, which distinguishes styles and strategies of coping with school-related stress. CSSQ consists of 2 forms: Form A is designed to examine coping styles; Form B is designed to examine strategies of coping with school-related stress. On the basis of several factorial analyses three scales of the CSSQ have been distinguished: task, emotion and avoidance coping. The score is assessed for each scale separately. The psychometric coefficients of CSSQ are satisfactory. CSSQ is designed for adolescents, aged 15—16. Further research concerning its diagnostic qualities among different age groups needs to be conducted.
Peer Relationships, Social Behaviours, Academic Performance and Loneliness in Korean Primary School Children
Authors: Shin Yoolim
Published: May 2007

The purpose of this study was to investigate how different forms of peer relationships offer children unique support for loneliness and to examine the direct as well as indirect effects of social behaviours and academic performance through the mediation of peer relationships on the prediction of loneliness in Korean children. Four hundred and sixty-six children were recruited from a primary school in Korea. Peer nomination, self-reports, and teacher ratings were used to measure social behaviours, peer relationships, academic performance, and loneliness. The results showed that peer relationships, including peer acceptance, the number of friends, and positive friendship quality, uniquely contributed to loneliness. Peer relationships partially mediated between withdrawal and loneliness. Peer acceptance and friendship quality fully mediated the link between academic functioning and loneliness. The findings were discussed with respect to how the social behaviours and academic performance are perceived and valued in Korean culture.
Multidimensional Self-Concept
Authors: Carroll Annemaree , Houghton Stephen , Wood Robert , Perkins Catherine , Bower Julie
Published: May 2007

The present research examined the relationship between self-concept and level of involvement in delinquent activities of 1327 (612 males, 715 females) years 8—12 high school students. Through cluster analysis, participants were identified as having either high or low involvement in delinquent activities from scores on a self-report measure of delinquency. Three multidimensional areas of self-concept (classroom, peer and confidence) were investigated, because of previous findings indicating discrepancies in these three dimensions for adolescent involvement in delinquent activities. Four, two-way multi-variate analyses of variance were conducted across the three self-concept dimensions for Gender, Year Level, and involvement in Delinquent Activities. Students highly involved in delinquent activities reported significantly lower classroom, peer and confidence self-concepts. For gender and year level effects, males reported significantly higher confidence self-concept while females scored significantly higher on peer self-concept. There were significant differences among year levels with a general decline in confidence self-concept with age but for classroom and peer self-concept, no clear age trends were evident. The results indicate the importance of considering multidimensional self-concept when examining adolescents' involvement in delinquent activities and incorporating self-concept enhancement strategies in intervention programs.
The challenges of the Ontario Secondary School Literacy Test for second language students
Authors: Liying Cheng  , Klinger Don A. , Ying Zheng
Published: May 2007

Results from the Ontario Secondary School Literacy Test (OSSLT) indicate that English as a Second Language (ESL) and English Literacy Development (ELD) students have comparatively low success and high deferral rates. This study examined the 2002 and 2003 OSSLT test performances of ESL/ELD and non-ESL/ELD students in order to identify and understand the factors that may help explain why ESL/ELD students failed the test at relatively high rates. The analyses also attempted to determine if there were significant and systematic differences in ESL/ELD students' test performance. The performance of ESL/ELD students was consistently and similarly lower across item formats, reading text types, skills and strategies, and the four writing tasks. Using discriminant analyses, it was found that narrative text type, indirect understanding skill, vocabulary strategy of reading, and the news report writing task were significant predictors of ESL/ELD membership. The results of this study provide direction for further research and instruction regarding English literacy achievement for these second language students within the context of having to complete large-scale English literacy tests designed and constructed for first English language students.
Cooperation Against All Odds
Authors: Tillmar Malin , Lindkvist Lars
Published: May 2007

This article takes an empirical point of departure in a longitudinal study in Tanzania that focuses on the trust formation process in its `bare' form, i.e. in a context where formal institutions are of little help in curbing opportunistic behaviour. The study's framework suggests a knowledge-based view of trust where the interplay between an individual's subjective knowledge or `good reasons' for trusting others and inclination to take a `leap of faith' explains his or her engagement in cooperative activity. The empirical findings show that people do not tend to be gamblers and take a big leap of faith when institutional prerequisites imply bad odds. On the contrary, people instead try hard and imaginatively to create reasons for trusting that are really good. In particular, they favour reasons that are related to control, such as those where sanctions or hostage-like measures come into play. As a result, the findings do not support the argument that the use of control(s) signals distrust and casts doubt over a partner 's good will.