bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341
Authors: Hideshima Teru , Mitsiades Constantine , Akiyama Masaharu , Hayashi Toshiaki , Chauhan Dharminder , Richardson Paul , Schlossman Robert , Podar Klaus , Munshi Nikhil C. , Mitsiades Nicholas , Anderson Kenneth C.
Published: January 2003

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341–induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
Randomized, Multicenter, Open-Label Study of Pegfilgrastim Compared With Daily Filgrastim After Chemotherapy for Lymphoma
Authors: Vose J.M. , Crump M. , Lazarus H. , Emmanouilides C. , Schenkein D. , Moore J. , Frankel S. , Flinn I. , Lovelace W. , Hackett J. , Liang B.C.
Published: January 2003

Purpose: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 × 109/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed.

Patients and Methods: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 μg/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 μg/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin’s or non-Hodgkin’s lymphoma.

Results: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 μg/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle.

Conclusion: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.
Matched and Mismatched Allogeneic Stem-Cell Transplantation From Unrelated Donors Using Combined Graft-Versus-Host Disease Prophylaxis Including Rabbit Anti–T Lymphocyte Globulin
Authors: Finke Jürgen , Schmoor Claudia , Lang Helmut , Potthoff Karin , Bertz Hartmut
Published: January 2003

Purpose: With improved HLA-typing techniques, it is presently unclear what degree of identity is necessary for successful unrelated-donor stem-cell transplantation (UD SCT). Here, we describe the outcome after matched and mismatched UD SCT using a graft-versus-host disease (GVHD) prophylaxis including high-dose rabbit anti–T lymphocyte globulin (ATG).

Patients and Methods: One hundred adult patients (median age, 37 years; range, 17 to 65 years) with hematologic malignancies underwent transplantation in early disease (first complete remission [CR1] or first chronic phase [CP1]; n = 34) or in advanced disease (second complete remission or second chronic phase, no remission, refractory; n = 66) with nondepleted bone marrow (n = 87) or peripheral-blood–derived (n = 13) stem cells from an HLA-A, HLA-B, HLA-DRB1*, or HLA-DQB1* identical (n = 75) or mismatched (one antigen, n = 21; two to three antigens, n = 4) unrelated donor. GVHD prophylaxis consisted of rabbit ATG before transplantation in addition to cyclosporine and short-course methotrexate.

Results: The cumulative incidence of acute GVHD °II-°IV was 21% (95% confidence interval [CI], 14% to 33%) and 20% (95% CI, 9% to 44%) and acute GVHD °III–°IV was 5.3% (95% CI, 2% to 14%) and 4% (95% CI, 0.6% to 28%) in HLA-matched and HLA-mismatched transplantations, respectively. The risk for extensive chronic GVHD was 43% (95% CI, 32% to 59%) and 44% (95% CI, 26% to 75%) for HLA-matched and HLA-mismatched patients, respectively. The risk of relapse at 4 years was 17% (95% CI, 7% to 43%) and 43% (95% CI, 31% to 60%) for CR1/CP1 and advanced disease patients, respectively. With a median follow-up of 1,068 days (range, 12 to 1,958 days), 3-year disease-free and overall survival for patients who underwent transplantation in CR1/CP1 was 63% (95% CI, 46% to 81%) and 75% (95% CI, 59% to 90%), respectively; and for patients with advanced disease, it was 34% (95% CI, 22% to 46%) and 39% (95% CI, 25% to 53%), respectively.

Conclusion: A certain degree of one antigen mismatching may not compromise the outcome after UD SCT when using this rabbit ATG in addition to standard GVHD prophylaxis regimen.
HER2 Overexpression and Doxorubicin in Adjuvant Chemotherapy for Resectable Breast Cancer
Authors: Moliterni Angela , Ménard Sylvie , Valagussa Pinuccia , Biganzoli Elia , Boracchi Patrizia , Balsari Andrea , Casalini Patrizia , Tomasic Gorana , Marubini Ettore , Pilotti Silvana , Bonadonna Gianni
Published: January 2003

Purpose: Human epidermal growth factor receptor 2 (HER2) overexpression was found to predict a good response in breast carcinoma patients treated with doxorubicin (Adriamycin [ADM]). Evidence from our recent study indicates that node-positive patients respond to cyclophosphamide, methotrexate, and fluorouracil (CMF) regardless of HER2 status. We address the issue of whether therapy regimens including CMF and ADM versus CMF alone have the same therapeutic effect in patients with HER2+ and HER2− tumors in terms of relapse-free survival (RFS) and overall survival (OS).

Methods: Archival specimens of the primary tumors from 506 patients in a prospective clinical trial were stained with the anti-HER2 monoclonal antibody CB11. Originally, patients were randomly allocated to receive either 12 courses of intravenous CMF or eight courses of the same regimen followed by four cycles of ADM. RFS and OS were analyzed by a Cox model taking into account treatment, HER2 status, and the interaction between treatment and HER2 status, adjusting for the effect of other known clinical and biopathologic factors.

Results: Analysis of survival rates indicates a possible differential effect of treatment in the patients grouped according to HER2 status. Improved RFS and OS were observed in the HER2+ subgroup after treatment with CMF plus ADM versus CMF alone. With a median follow-up of 15 years, the hazard ratio (HR) for RFS was 0.83 in HER2+ tumors and 1.22 in HER2− tumors. The effect of treatment was more evident on OS in HER2+ patients (HR = 0.61; CI, 0.32 to 1.16) than in HER2− patients (HR = 1.26).

Conclusion: Our data indicate that adding ADM to CMF might be beneficial for patients with HER2+ tumors.
Prognostic Significance of Reverse Transcriptase Polymerase Chain Reaction for Prostate-Specific Antigen in Metastatic Prostate Cancer: A Nested Study Within CALGB 9583
Authors: Halabi Susan , Small Eric J. , Hayes Daniel F. , Vogelzang Nicholas J. , Kantoff Philip W.
Published: January 2003

Purpose: To determine whether reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating prostate-specific antigen (PSA)-positive cells is a prognostic factor for survival in hormone refractory prostate cancer and to validate the prognostic importance of this test in relation to other known prognostic factors.

Patients and Methods: A single centralized laboratory received and analyzed whole blood for RT-PCR for PSA for a subset of patients enrolled on two Cancer and Leukemia Group B (CALGB) randomized trials (CALGB 9583 and CALGB 9480). Using 9583, a prognostic model was developed and an independent data set (CALGB 9480) was used to validate the fitted model.

Results: Of 162 patients in 9583, 91 (56%) patients were negative for RT-PCR for PSA and 71 (44%) patients were positive. The median survival time was 21 months (95% confidence interval [CI], 18 to 27 months) for RT-PCR-negative patients compared with 11 months (95% CI, 8 to 15 months) for RT-PCR-positive patients (P ≤ .001). In multivariable analysis, the hazard ratio (HR) for death was 1.7 (95% CI, 1.2 to 2.4; P = .006) for positive RT-PCR patients compared with negative RT-PCR patients. A fitted model that incorporated RT-PCR for PSA and other factors was used to classify patients from 9480 into one of two risk groups: low or high. We observed good agreement between the observed and predicted survival probabilities for the two risk groups.

Conclusion: RT-PCR to detect PSA-positive circulating cells is confirmed to be a significant prognostic factor of survival in patients with hormone refractory prostate cancer. This model could be used to stratify patients in randomized phase III trials.
Does Delay in Starting Treatment Affect the Outcomes of Radiotherapy? A Systematic Review
Authors: Huang Jenny , Barbera Lisa , Brouwers Melissa , Browman George , Mackillop William J.
Published: January 2003

Purpose: The objective of this study was to synthesize what is known about the relationship between delay in radiotherapy (RT) and the outcomes of RT.

Methods: A systematic review of the world literature was conducted to identify studies that described the association between delay in RT and the probability of local control, metastasis, and/or survival. Studies were classified by clinical and methodologic criteria and their results were combined using a random-effects model.

Results: A total of 46 relevant studies involving 15,782 patients met our minimum methodologic criteria of validity; most (42) were retrospective observational studies. Thirty-nine studies described rates of local recurrence, 21 studies described rates of distant metastasis, and 19 studies described survival. The relationship between delay and the outcomes of RT had been studied in diverse situations, but most frequently in breast cancer (21 studies) and head and neck cancer (12 studies). Combined analysis showed that the 5-year local recurrence rate (LRR) was significantly higher in patients treated with adjuvant RT for breast cancer more than 8 weeks after surgery than in those treated within 8 weeks of surgery (odds ratio [OR] = 1.62, 95% confidence interval [CI], 1.21 to 2.16). Combined analysis also showed that the LRR was significantly higher among patients who received postoperative RT for head and neck cancer more than 6 weeks after surgery than among those treated within 6 weeks of surgery (OR = 2.89; 95% CI, 1.60 to 5.21). There was little evidence about the impact of delay in RT on the risk of metastases or the probability of long-term survival in any situation.

Conclusion: Delay in the initiation of RT is associated with a decrease in LRR in breast cancer and head and neck cancer. Delays in starting RT should be as short as reasonably achievable.
Impact of Diabetes Mellitus on Outcomes in Patients With Colon Cancer
Authors: Meyerhardt Jeffrey A. , Catalano Paul J. , Haller Daniel G. , Mayer Robert J. , Macdonald John S. , Benson Al B. , Fuchs Charles S.
Published: January 2003

Purpose: To determine the influence of diabetes mellitus on long-term outcomes and treatment-related toxicity among patients with curatively resected colon cancer.

Patients and Methods: This study was a cohort study within a large, randomized adjuvant chemotherapy trial of 3,759 patients with high-risk stage II and stage III colon cancer treated between 1988 and 1992 throughout the United States. In the cohort, 287 patients were identified as having diabetes mellitus. With a median follow-up of 9.4 years, we analyzed differences in overall survival (OS) and colon cancer recurrence as well as treatment-related toxicity between patients with diabetes and those without diabetes.

Results: At 5 years, patients with diabetes mellitus, compared with patients without diabetes, experienced a significantly worse disease-free survival (DFS; 48% diabetics v 59% nondiabetics; P < .0001), OS (57% v 66%; P < .0001), and recurrence-free survival (RFS; 56% v 64%, P = .012). Median survival was 6.0 years and 11.3 years for diabetics and nondiabetics, respectively. Compared with patients without a history of diabetes, those with diabetes had a 42% increased risk of death from any cause (P < .0001) and 21% increased risk for recurrence (P = .05) after adjustment for other predictors of colon cancer outcome. Treatment-related toxicities were similar between the two groups, although patients with diabetes experienced an increase in treatment-related diarrhea.

Conclusion: Patients with diabetes mellitus and high-risk stage II and stage III colon cancer experienced a significantly higher rate of overall mortality and cancer recurrence, even after adjustment for other predictors of colon cancer outcome. These results underscore the need for further research to understand the mechanism that underlies this relation.
Dispositional Optimism Predicts Survival Status 1 Year After Diagnosis in Head and Neck Cancer Patients
Authors: Allison Paul J. , Guichard Christophe , Fung Karen , Gilain Laurent
Published: January 2003

Purpose: The aim of this study was to investigate the hypothesis that, independent of other known prognostic factors, pessimistic head and neck (H&N) cancer patients have a greater risk of being dead 1 year after diagnosis than do optimistic patients.

Patients and Methods: A prospective observational study design was used with a cohort of H&N cancer patients diagnosed during the period from March 1, 1997, to August 31, 1998, at the Centre Hospitalier Universitaire, Clermont-Ferrand, France. Dispositional optimism (DO) was evaluated at baseline using a French version of the Life Orientation Test translated and validated for this study. One-year survival status was collected on all subjects. The analysis of the hypothesized association between DO and 1-year survival was performed using multiple logistic regression analysis, controlling for other sociodemographic and clinical variables.

Results: The sample size was 101 patients, representing all but one of those patients fitting the inclusion criteria who were diagnosed during the recruitment period. Of these, 51 were alive at 1 year after diagnosis, 45 were dead, and five were lost to follow-up. The multivariate analysis was performed on the data from the 96 subjects in whom 1-year survival status was known. Controlling for known predictors of H&N cancer survival, pessimistic subjects (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.01 to 1.24) and those living alone (OR, 4.14; 95% CI, 1.21 to 14.17) were more likely than optimistic subjects and those living with others to be dead at 1 year.

Conclusion: The results of this study of a cohort of French H&N cancer patients indicate that dispositional optimism predicts 1-year survival independent of other sociodemographic and clinical variables.
Phase II Trial of Systemic Continuous Fluorouracil and Subcutaneous Recombinant Interferon Alfa-2b for Treatment of Hepatocellular Carcinoma
Authors: Patt Yehuda Z. , Hassan Manal M. , Lozano Richard D. , Brown Thomas D. , Vauthey J. Nicolas , Curley Steven A. , Ellis Lee M.
Published: January 2003

Purpose: Because cirrhosis is extremely common in hepatocellular carcinoma (HCC) in the United States, and it precludes the use of several chemotherapy agents, this phase II trial of fluorouracil (FU) and recombinant interferon alfa-2b (rIFNα2b) in HCC was launched with the assumption that it could be tolerated by cirrhotics.

Patients and Methods: Forty-three patients with HCC (34), and fibrolamellar HCC (FLHCC; nine) were treated with continuous intravenous (IV) FU (200 mg/m2/d × 21 every 28 days) and subcutaneous (SC) rIFNα2b (4 million U/m2) three times weekly. Survival was determined in all 43 patients, and response could be assessed in 28 HCC and 8 FLHCC patients.

Results: The median ages of the patients were 63.5 and 19 years among HCC and FLHCC patients, respectively. Liver cirrhosis was present among 71% of HCC patients but among none of the FLHCC patients. Nine of 36 (25%; four of 28 [14%] HCC patients; five of eight [62.5%] FLHCC patients) patients in which a response could be assessed had a complete response (CR; one patient with FLHCC and no patients with HCC) or partial response (PR; eight patients [four HCC and four FLHCC patients]). Four HCC patients underwent resection, and two had a histologic CR; one HCC patient with a PR underwent orthotopic liver transplantation. One FLHCC patient also underwent resection without clear margins. Overall median survival was 19.5 months (95% confidence interval [CI], 11.2 to 27.8 months); median survival was 15.5 months (95% CI, 8.5 to 22.5 months) among HCC patients, and that of FLHCC patients was 23.1 months (95% CI, 10.3 to 35.9 months). Overall grade 3 or 4 toxicity included stomatitis (32.6%), fatigue (4.7%), and hematologic toxicity (9.3%).

Conclusion: Continuous IV FU and thrice-weekly SC rIFNα2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.
Management and Outcome Differences in Supraglottic Cancer Between Ontario, Canada, and the Surveillance, Epidemiology, and End Results Areas of the United States
Authors: Groome Patti A. , O’Sullivan Brian , Irish Jonathan C. , Rothwell Deanna M. , Schulze Karleen , Warde Padraig R. , Schneider Ken M. , Mackenzie Robert G. , Hodson D. Ian , Hammond J. Alex , Gulavita Sunil P.P. , Eapen Libni J. , Dixon Peter F. , Bissett Randy J. , Mackillop William J.
Published: January 2003

Purpose: We compared the management and outcome of supraglottic cancer in Ontario, Canada, with that in the Surveillance, Epidemiology, and End Results (SEER) Program areas in the United States.

Methods: Electronic, clinical, and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Stage-stratified analyses compared initial treatment and survival in the SEER areas (n = 1,643) with a random sample from Ontario (n = 265). We also compared laryngectomy rates at 3 years in those patients 65 years and older at diagnosis.

Results: Radical surgery was more commonly used in SEER, with absolute differences increasing with increasing stage: I/II, 17%; III, 36%; and IV, 45%. The 5-year survival rates were 74% in Ontario and 56% in SEER for stage I/II disease (P = .01), 55.7% in Ontario and 46.8% in SEER for stage III disease (P = .40), and 28.5% in Ontario and 29.1% in SEER for stage IV disease (P = .28). Cancer-specific survival results mirrored the overall survival results with the exception of stage IV disease, for which 34.6% of Ontario patients survived their cancer compared with 38.1% in SEER (P = .10). This stage IV difference was more pronounced when we further controlled for possible cause of death errors by restricting the comparison to patients with a single primary cancer (P = .01). Three-year actuarial laryngectomy rates differed. In stage I/II, these rates were 3% in Ontario compared with 35% in SEER (P < 10−3). In stage III disease, the rates were 30% and 54%, respectively (P = .03), and in stage IV disease they were 33% and 64% (P = .002).

Conclusion: There are large differences in the management of supraglottic cancer between the SEER areas of the United States and Ontario. Long-term larynx retention was higher in Ontario, where radiotherapy is widely regarded as the treatment of choice and surgery is reserved for salvage. In stages I to III, survival was similar in the two regions despite the differences in treatment policy. In stage IV, there may be a small survival advantage in the U.S. SEER areas related to the higher use of primary surgery.
HER-2/neu Overexpression and Response to Oophorectomy Plus Tamoxifen Adjuvant Therapy in Estrogen Receptor-Positive Premenopausal Women With Operable Breast Cancer
Authors: Love Richard R. , Duc Nguyen Ba , Havighurst Thomas C. , Mohsin Syed K. , Zhang Qian , DeMets David L. , Allred D. Craig
Published: January 2003

Purpose: Studies evaluating the relationship of HER-2/neu breast tumor status and response to adjuvant endocrine therapy have reached conflicting conclusions about resistance of HER-2/neu-positive tumors to this treatment. We studied 282 patients participating in a randomized controlled trial of adjuvant oophorectomy and tamoxifen or observation who had estrogen receptor-positive tumors and whose tumors were evaluated for HER-2/neu overexpression by immunohistochemistry.

Patients and Methods: Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier disease-free and overall survival estimate methods were used.

Results: HER-2/neu overexpression was a negative prognostic factor for overall survival. In univariate analyses, in HER-2/neu-positive patients, the hazard ratio (HR) for disease-free survival (DFS) with adjuvant endocrine therapy was 0.37 (95% confidence interval [CI], 0.26 to 0.89); for HER-2/neu-negative patients, the corresponding HR for DFS was 0.48 (95% CI, 0.31 to 0.71). The overall survival (OS) data were HR=0.26 (95% CI, 0.07 to 0.92) and HR=0.68 (95% CI, 0.32 to 1.42) for HER-2/neu-positive and HER-2/neu-negative patients, respectively. In multivariate models, the P values for tests of interaction of HER-2/neu status and response to adjuvant endocrine therapy were 0.18 and 0.07 for DFS and OS, respectively. Kaplan-Meier DFS and OS curves and 3-year DFS estimates were consistent in showing greater benefit to the HER-2/neu-positive subgroup given adjuvant treatment.

Conclusion: HER-2/neu overexpression does not adversely and may favorably influence response to adjuvant oophorectomy and tamoxifen treatment in patients with estrogen receptor–positive tumors.
Carbonic Anhydrase IX Expression, a Novel Surrogate Marker of Tumor Hypoxia, Is Associated With a Poor Prognosis in Non–Small-Cell Lung Cancer
Authors: Swinson Daniel E.B. , Jones J. Louise , Richardson Donna , Wykoff Charles , Turley Helen , Pastorek Jaromir , Taub Nick , Harris Adrian L. , O’Byrne Kenneth J.
Published: January 2003

Purpose: To evaluate carbonic anhydrase (CA) IX as a surrogate marker of hypoxia and investigate the prognostic significance of different patterns of expression in non–small-cell lung cancer (NSCLC).

Methods: Standard immunohistochemical techniques were used to study CA IX expression in 175 resected NSCLC tumors. CA IX expression was determined by Western blotting in A549 cell lines grown under normoxic and hypoxic conditions. Measurements from microvessels to CA IX positivity were obtained.

Results: CA IX immunostaining was detected in 81.8% of patients. Membranous (m) (P = .005), cytoplasmic (c) (P = .018), and stromal (P < .001) CA IX expression correlated with the extent of tumor necrosis (TN). The mean distance from vascular endothelium to the start of tumor cell positivity was 90 μm, which equates to an oxygen pressure of 5.77 mmHg. The distance to blood vessels from individual tumor cells or tumor cell clusters was greater if they expressed mCA IX than if they did not (P < .001). Hypoxic exposure of A549 cells for 16 hours enhanced CA IX expression in the nuclear and cytosolic extracts. Perinuclear (p) CA IX (P = .035) was associated with a poor prognosis. In multivariate analysis, pCA IX (P = .004), stage (P = .001), platelet count (P = .011), sex (P = .027), and TN (P = .035) were independent poor prognostic factors.

Conclusion: These results add weight to the contention that mCA IX is a marker of tumor cell hypoxia. The absence of CA IX staining close to microvessels suggests that these vessels are functionally active. pCA IX expression is representative of an aggressive phenotype.
A classification of FASTEX cyclones using a height‐attributable quasi‐geostrophic vertical‐motion diagnostic
Authors: Deveson A. C. L. , Browning K. A. , Hewson T. D.
Published: January 2003

A systematic and objective procedure is developed for applying the simple cyclone classification scheme of Petterssen and Smebye. This method uses a height‐attributable solution of the quasi‐geostrophic ! equation to identify and quantify the relative importance of upper‐ and lower‐tropospheric forcing and also the time trend in the horizontal spacing of the forcing at these two levels. By applying this classification method to a sample of cyclogenesis events, during their maximum intensification stage, from the Fronts and Atlantic Storm‐Track EXperiment field experiment, the Type A and Type B scheme of Petterssen and Smebye is reproduced and extended to include a Type C. Type C consists of upper‐level dominated cyclones that form at high latitudes and in their initial stages resemble comma‐cloud‐type polar lows. Detailed examples of each of the three types are presented. Some cyclones can undergo more than one period of development and it is found that each development period can be classified as a different cyclogenesis category, A or B: these cyclones are classified as hybrid Type A=B. There is some evidence that cyclone forecast accuracy depends on cyclone type, thereby suggesting the potential for this method to be used to assign confidence levels for forecasts of cyclogenesis produced by numerical weather‐prediction models. Type B cyclones appear more difficult to predict, because their development depends, initially, on the interaction between significant features in the upper and lower troposphere. Copyright © 2002 Royal Meteorological Society. T. D. Hewson's contribution is Crown copyright.
The response of CAPE and CIN to tropospheric thermal variations
Authors: Parker D. J.
Published: January 2003

In the absence of moist convection, convective available potential energy (CAPE) and convective inhibition (CIN) both respond to changes in the thermal and humidity profiles of the atmosphere. It is shown that these changes can be understood in terms of a direct effect, involving changes in the profile in the absence of parcel changes, and an indirect effect involving changes in air‐parcel evolution in a developing convective boundary layer. Succinctly, low‐wave‐number (deep) changes in the thermal profile maximize the direct influence on CAPE while higher‐wave‐number (shallower, near‐surface) thermal changes maximize the direct influence on CIN. A simple estimate of the direct influence on CAPE, which is independent of the assumptions relating to choice of parcel ascent, is shown to give accurate results.

The indirect influence comes about as a result of changes in the stability of the profile just above the inversion: the stability acts as a control on the entrainment of dry air into the boundary layer under conditions of surface heating, so that a boundary layer growing into a stable lower troposphere is more humid than one growing into a less stable profile, with significantly higher equivalent potential temperature. Thus, a profile of relatively high stability just above the inversion, typically exhibiting high CIN, will also tend to allow CAPE to build up in the boundary layer quite rapidly, through a suppression of the entrainment under conditions of surface heating and boundary‐layer growth. Thus it may be said that high CIN tends to lead to the accumulation of high CAPE even in the absence of convective downdraught feedbacks. Copyright © 2002 Royal Meteorological Society.
Mechanisms leading to singular‐vector growth for FASTEX cyclones
Authors: Montani A. , Thorpe A. J.
Published: January 2003

Calculations of localized singular vectors (SVs) are performed using the European Centre for Medium‐Range Weather Forecasts prediction model and the dynamical properties responsible for the SVs' growth are investigated. Potential vorticity (PV) diagnostics are used to investigate the dynamical processes responsible for SV growth in terms of total energy and PV. The independent evolution of perturbations initially confined either in the lower or in the upper troposphere is considered in order to identify the more dynamically active regions within an SV. The extent to which balanced‐flow theory, valid in idealized models of non‐normal growth, can be applied during the evolution of SVs is also examined. It is found that the part of the SV located below 500 hPa plays a major role in the interaction processes between the perturbation and the basic‐state fields and is responsible for the SVs' energy growth. SVs are also shown to grow in terms of PV due to SV advection of the basic‐state PV horizontal gradients. Perturbations initially confined at low levels can propagate vertically more efficiently than those localized above 500 hPa and the interaction with the upper‐level basic‐state fields is much more effective, leading to PV growth. If SVs are calculated with the total‐energy norm, their initial state is found to be somewhat out of balance, because of a relative lack of amplitude in the vorticity component. During their evolution, SVs achieve a more balanced configuration. Copyright © 2002 Royal Meteorological Society.
A simple conceptual model of cirrus horizontal inhomogeneity and cloud fraction
Authors: Smith S. A. , Del Genio A. D.
Published: January 2003

A simple conceptual model of horizontal inhomogeneity and cloud amount in cirrus clouds has been formulated on the basis that internal horizontal inhomogeneity in the ice mixing ratio is due to variations in the cloud depth, which are assumed to be Gaussian. The use of such a model was justified by the observed relationship between the normalized variability of cloud depth and both the cloud amount and the normalized variability of the ice‐water mixing ratio (and extinction).

Using radar cloud‐depth data as input, the model reproduced well the in‐cloud ice‐water mixing ratio histograms obtained from horizontal aircraft runs during the FIRE‐II cirrus campaign. For totally overcast cases the histograms were almost Gaussian, but changed as cloud amount decreased to distributions which peaked at the lowest non‐zero ice value and decreased rapidly and monotonically towards higher ice values for cloud amounts below 90%. Cloud amounts and average ice‐water mixing ratios for cases with observed distributions of cloud depth were predicted by the model to within 15% and 31% of the observed values. This model could be used as a starting point in the development of a GCM parametrization of the ice mixing‐ratio probability distribution function and cloud amount, if a means of diagnosing the depth of the saturated layer and the standard deviation of cloud depth from basic large‐scale meteorological parameters could be determined. Copyright © 2002 Royal Meteorological Society.
VHF radar measurements and model simulations of mountain waves over Wales
Authors: Vosper S. B. , Worthington R. M.
Published: January 2003

Very high frequency (VHF) radar measurements of mountain waves over Aberystwyth, Wales, during 29 November 1997 are presented and compared with the predictions made by a three‐dimensional numerical model which is based on the linearized equations of motion. The radar height–time plot of vertical velocity reveals a wave field in the troposphere and lower stratosphere which changes significantly throughout the day. Four separate radiosonde soundings taken during the day are used to represent the steady background flow in the numerical model. In this case the steady‐state model wave fields are shown to compare qualitatively well with the radar measurements and the three‐dimensional information provided by the model is used to help explain the changes in the wave field observed by the radar throughout the day.

The radiosonde profiles are interpolated in time to provide approximate basic‐state data at two‐hour intervals. Model steady‐state vertical‐velocity fields, based on each of these 13 approximate basic‐state profiles are used to generate a model time–height vertical‐velocity plot which is qualitatively similar to that obtained from the radar measurements, indicating that, to a reasonable approximation, the evolving wave field can be regarded as a sequence of independent steady states. This is generally true if the basic‐state flow remains steady over the time taken for wave packets to propagate over several wavelengths. Group‐velocity arguments are used to show that, for typical mountain waves in the troposphere, such time‐scales are generally less than one hour.

Model simulations in which the basic‐state flow is allowed to vary in time continually (based on either the interpolated radiosonde soundings or the radar horizontal‐wind measurements) are conducted. In this case the simulated wave fields are always unsteady; the waves show a tendency to drift in response to changes in the basic‐state wind field. For example, during instances when the wind speed at a given level decreases (whilst the wind direction remains the same) the waves show an upwind phase propagation with a typical phase speed of the order of 1 m s−1. The consequence of this unsteadiness for the propagation of the waves is discussed. Copyright © 2002 Royal Meteorological Society.
Transient and asymptotic perturbation growth in a simple model
Authors: Gelaro Ronald , Reynolds Carolyn A. , Errico Ronald M.
Published: January 2003

The relationship between asymptotic and finite‐interval instabilities in nonlinear, time‐dependent flows is examined in the context of a quasi‐geostrophic model. For a chosen interval and metric, perturbation growth is related to the singular vectors (SVs) of the linear propagator, while long‐term or asymptotic growth is determined by the leading Lyapunov vector (LV), which is independent of metric and grows at the mean rate of the leading Lyapunov exponent. It is shown that the growth rates of the leading LVs vary significantly about their mean values over periods of a few days. For the leading LV, episodes of greater (or lesser) growth correspond to significant variations in vertical structure, and are highly correlated with its projection onto the leading SVs optimized for short (e.g. 24‐hour) intervals. The LV exhibits maximum growth over east Asia and the Pacific, where its projection onto rapidly growing SVs in the vicinity of the Pacific storm track is greatest. For a given 24‐hour interval, the 30 leading SVs at initial time account for only a few per cent of the total variance of the LV, but account for most of its growth. Filtering these leading SV components from the evolving LV structure over successive intervals reduces its mean (asymptotic) growth rate dramatically in a piecewise continuous sense. The results make clear the importance of transient growth in maintaining the positive mean growth rates of the leading LVs, and in determining the asymptotic stability properties of time‐dependent flows. Copyright © 2002 Royal Meteorological Society.
Implementation and validation of a new prognostic large‐scale cloud and precipitation scheme for climate and data‐assimilation purposes
Authors: Lopez Philippe
Published: January 2003

A large‐scale condensation scheme, able to treat separately both atmospheric cloud condensate and precipitation content in a prognostic way, has been implemented and validated in Météo‐France's operational global model, ARPEGE. The proposed scheme can be used for climate simulations and short‐range numerical weather prediction, although it was originally designed for the future variational assimilation of cloud and precipitation observations.

The main originalities of the scheme, compared with other existing schemes having a similar moderate level of complexity, lie in the inclusion of a prognostic variable for rain and snow content, and in the use of a simple semi‐Lagrangian treatment of the fall of precipitation. The calculations of large‐scale condensation/evapora tion and cloud fraction are based on probability‐density functions, and the parametrized microphysical processes that involve precipitation are autoconversion, collection, and evaporation/sublimation.

Various observations, which include satellite data from METEOSAT and from the Defense Meteorological Satellite Program's Special Sensor Microwave Imager, have been used for validating the cloud scheme within three‐dimensional ARPEGE simulations at operational resolution for cases from the Fronts and Atlantic Storm‐Track Experiment. These ARPEGE simulations have also been compared with 10 km runs obtained with the Met Office's Unified Model and with the French Méso‐NH research model. In addition, cloud radar, ceilometer, and lidar observations from the Atmospheric Radiation Measurement project have been utilized for validating the simulation of a synoptic winter cloud system over the southern Great Plains in the USA. The behaviour of the scheme was then assessed at a coarser resolution, with a particular focus on the zonal‐mean radiative budget of the earth and the zonal‐mean cloud cover.

Finally, the question of the sensitivity of the results from the new scheme to various parameters has been addressed, including the time step and the specification of the fall velocities for rain and snow. Copyright © 2002 Royal Meteorological Society.
A refined semi‐Lagrangian vertical trajectory scheme applied to a hydrostatic atmospheric model
Authors: Gospodinov I. , Spiridonov V. , Bénard P. , Geleyn J.‐F.
Published: January 2003

An explicit estimate of the vertical acceleration in a hydrostatic atmospheric model is necessary in order to extend the application of the uniform acceleration two‐time‐level semi‐Lagrangian trajectory scheme of Gospodinov et al. to the vertical direction. It has been diagnosed from the continuity equation. The trajectory scheme proposed, together with the vertical acceleration, has been tested for the so‐called ‘Baltic jet’ case which is dominated by horizontal advection. Enhanced quality has been demonstrated. Copyright © 2002 Royal Meteorological Society.
Design Strategies for Controlling Structural Instabilities
Authors: Gantes Charis J.
Published: January 2003

An overview of buckling behaviour is presented, with emphasis on its analysis and design implications and ways of incorporating these considerations in the design of spatial structures. In the first part of the paper the fundamental stability concepts are briefly reviewed. The major types of instability are presented and typical structures that are prone to fail in such modes are identified. The influence of initial imperfections is discussed, as well as the interaction between different failure modes. In the second part, practical issues pertaining to structural analysis and design are addressed. These include hints to identify potential instability modes and obtain approximate buckling loads by analytical considerations, guidelines for selection of appropriate analysis methods, as well as discussion of pertinent design approaches, code provisions and issues that are not covered by present codes.
Buckling Analysis of Reticulated Shells
Authors: Dulácska Endre , Kollár Lajos
Published: January 2003

The paper presents a comparatively simple method for assessing the global stability of single- and double-layer reticulated shells, assuming rigid connections between the bars. With knowledge of the rigidities of the reticulated shell, a statically equivalent replacement solid shell is established, the buckling of which is extensively treated in the literature. The critical load of this replacement continuum is determined by taking into account the influences of geometric imperfections (eccentricity), plasticity, (local) bar buckling and – in the case of double-layer reticulated shells – of transverse shear deformation. All these are presented in detail for isotropic shells, but the method can also be used for anisotropic ones. Finally, for dimensioning reticulated shells, a unique safety factor based on the theory of probabilities is recommended, which depends on the uncertainties of the various effects. Numerical values for the safety factor are also given. The method proposed provides a transition from shells to plane plates, from surface to bar structures, and from reticulated to solid shells, thus ensuring identical safety levels for all these structures.
Member Buckling with Joint Instability – Design Application
Authors: Hanaor A. , Dallard P. R. B. , Levy R. , Gelberg N.
Published: January 2003

Compression member buckling in association with joint instability was observed in several truss and model tests, involving certain types of prefabricated systems. It was also evident in a recent collapse. The paper presents an analytical procedure for evaluating the influence of the connection stiffness on the member elastic buckling load. The proposed model, which is suitable for implementation with the aid of spreadsheet calculations, is intended as an indication of the sensitivity of the system to joint instability and the need for rigorous stability and non-linear analysis. Some examples are presented, comparing results of the proposed method with analytical and numerical computations and with test results.
Some Design Aspects Peculiar to Space Trusses
Authors: Schmidt Lewis C.
Published: January 2003

This paper considers some aspects of structural design that are largely peculiar to the design of space truss systems, in particular double-layer systems, although the design aspects considered may overlap with conventional structural design as well. The aspects covered herein are joint design, force distributions in space trusses, lack of fit of members, sensitivity to type of compression chord failure, failure mechanisms, possible welding defects in joints, and the use of laboratory models as indicators of real behaviour. Because of the nature of space trusses, with hundreds, if not thousands, of members with a relatively high degree of interaction, their structural design presents its own peculiarities that fall outside conventional structural design. Special attention needs to be given to these topics.
Some Observations on Designing Double Layer Grids
Authors: Marsh Cedric
Published: January 2003

The manner in which three dimensional lattice structures are analysed and designed is reviewed in terms of the reliability of the final design, with a consideration of the consequences arising from the special form of these structures. The wide variety of nodal details and member types makes it difficult to deal with each specific system but the essential behaviour, interactions and the modes of failure are discussed. Although it is held that linear elastic analysis and the application of existing standards will, in general, provide safe structures, there is a need to be aware of those aspects of the performance which are not treated in current codes.
Investigation of risk factors in children with arterial ischemic stroke
Authors: Ganesan Vijeya , Prengler Mara , McShane Michael A. , Wade Angela M. , Kirkham Fenella J.
Published: January 2003

We present data on the known risk factors encountered in children presenting with a first arterial ischemic stroke to a single tertiary center over 22 years. Two hundred twelve patients (54% male; median age, 5 years) were identified. One hundred fifteen (54%) were previously healthy. Cerebral arterial imaging was undertaken in 185 patients (87%) and was abnormal in 79%. Of 104 previously healthy patients investigated with echocardiography, only 8 had abnormal studies. Genetic or acquired conditions causing thrombophilia were rare. Forty percent of patients were anemic, and 21% either had elevated total plasma homocysteine or were homozygous for the t‐MTHFR mutation. Trauma and previous varicella zoster infection were significantly more common in the previously healthy group. There was a significant association between cerebral arterial abnormalities and systolic blood pressure greater than 90th percentile and a trend for an association with varicella within the previous year. Clinical history and examination usually identify underlying risk factors and precipitating triggers for arterial ischemic stroke in childhood. Cerebral arterial imaging is usually abnormal, but echocardiography and prothrombotic screening are commonly negative. Ann Neurol 2003
Assessing the onset of structural change in familial Alzheimer's disease
Authors: Schott Jonathan M. , Fox Nick C. , Frost Chris , Scahill Rachael I. , Janssen John C. , Chan Dennis , Jenkins Rhian , Rossor Martin N.
Published: January 2003

Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3–28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0–7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7–7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms. Ann Neurol 2003;53:000–000
Magnetic resonance cerebral metabolic rate of oxygen utilization in hyperacute stroke patients
Authors: Lee Jin‐Moo , Vo Katie D. , An Hongyu , Celik Azim , Lee Yueh , Hsu Chung Y. , Lin Weili
Published: January 2003

The purpose of this study was to explore the feasibility of obtaining magnetic resonance–measured cerebral metabolic rate of oxygen utilization (MR‐CMRO2) in acute ischemic stroke patients. Seven stroke patients were serially imaged: 4.5 ± 0.9 hours (tp1), 3 to 5 days (tp2), and 1 to 3 months (tp3) after symptom onset. Diffusion‐weighted, perfusion‐weighted, and multiecho gradient‐echo/spin‐echo images were acquired; cerebral blood flow and oxygen extraction fraction maps were obtained from which CMRO2 was calculated as the product of cerebral blood flow and oxygen extraction fraction. The final infarct lesions obtained from tp3 T2‐weighted images and the “penumbra” obtained from the tp1 perfusion‐weighted image–defined lesion were coregistered onto tp1 CMRO2 maps. CMRO2 values in the region of brain that eventually infarcted were reduced to 0.40 ± 0.24 of the respective region on the contralateral hemisphere. The “salvaged penumbra” defined by the area of mismatch between the final infarct and the tp1 perfusion‐weighted lesion demonstrated an average CMRO2 value of 0.55 ± 0.11 of the contralateral hemisphere. Although our results are preliminary and require further evaluation, the ability to obtain in vivo measurements of MR‐CMRO2 noninvasively potentially can provide information for determining brain tissue viability in acute ischemic stroke patients.