bluuebunny/crossref_metadata_2025 huggingface dataset:
The Desmoteplase in Acute Ischemic Stroke Trial (DIAS)
Authors: Hacke Werner , Albers Greg , Al-Rawi Yasir , Bogousslavsky Julien , Davalos Antonio , Eliasziw Michael , Fischer Michael , Furlan Anthony , Kaste Markku , Lees Kennedy R. , Soehngen Mariola , Warach Steven
Published: November 2004

Background and Purpose—

Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI.

Methods—

DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 μg/kg, 90 μg/kg, and 125 μg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days.

Results—

Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (
P
=0.0012) were observed with desmoteplase (125 μg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 μg/kg;
P
=0.757) and 60.0% (125 μg/kg;
P
=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (
P
=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion.

Conclusions—

Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 μg/kg.
Response-Selection-Related Parietal Activation during Number Comparison
Authors: Göbel Silke M. , Johansen-Berg Heidi , Behrens Tim , Rushworth Matthew F. S.
Published: November 2004

Neuroimaging studies of number comparison have consistently found activation in the intraparietal sulcus (IPS). Recently, it has been suggested that activations in the IPS vary with the distance between the numbers being compared. In number comparison, the smaller the distance between a number and the reference the longer the reaction time (RT). Activations in the right or left IPS, however, have also been related to attentional and intentional selection. It is possible, therefore, that activity in this region is a reflection of the more basic stimulus and response-selection processes associated with changes in RT. This fMRI experiment investigated the effect of numerical distance independently from RT. In addition, activations during number comparison of single-digit and double-digit stimuli were compared. During number comparison blocks, subjects had to indicate whether digits were greater or smaller than a reference (5 or 65). In control blocks, they were asked to perform a perceptual task (vertical line present/absent) on either numerical or nonnumerical stimuli. Number comparison versus rest yielded a large bilateral parietal-posterior frontal network. However, no areas showed more activation during number comparison than during the control tasks. Furthermore, no areas were more active during comparison of numbers separated by a small distance than comparisons of those separated by a large distance or vice versa. A left-lateralized parietal-posterior frontal network varied significantly with RT. Our findings suggest that magnitude and numerical-distance-related IPS activations might be difficult to separate from fundamental stimulus and response-selection processes associated with RT changes. As is the case with other parameters, such as space, magnitude may be represented in the context of response selection in the parietal cortex. In this respect, the representation of magnitude in the human IPS may be similar to the representation of magnitude in other nonhuman primates.
Matter in Plotinus's Normative Ontology
Authors: Schäfer Christian
Published: November 2004

To most interpreters, the case seems to be clear: Plotinus identifies matter and evil, as he bluntly states in Enn. I.8[51] that 'last matter' is 'evil', and even 'evil itself'. In this paper, I challenge this view: how and why should Plotinus have thought of matter, the sense-making εσχατον of his derivational ontology from the One and Good, evil? A rational reconstruction of Plotinus's tenets should neither accept the paradox that evil comes from Good, nor shirk the arduous task of interpreting Plotinus's texts on evil as a fitting part of his philosophy on the whole. Therefore, I suggest a reading of evil in Plotinus as the outcome of an incongruent interaction of matter and soul, maintaining simultaneously that neither soul nor matter are to be considered as bad or evil. When Plotinus calls matter evil, he does so metonymically denoting matter's totally passive potentiality as perceived by the toiling soul trying to act upon it as a form-bringer. As so often, Plotinus is speaking quoad nos here rather than referring to 'matter per se ' (for Plotinus, somewhat of an oxymoron) which, as mere potentiality (and nothing else) is not nor can be evil. In short: matter is no more evil than the melancholy evening sky is melancholy – not in itself (for it isn't), but as to its impression on us who contemplate it. As I buttress this view, it will also become clear that matter cannot tritely be considered to be the αυτο κακον as a prima facie -reading of Enn. I.8[51] might powerfully suggest, but that the αυτο κακο&ν, far from being a principle of its own, has to be interpreted within the dynamics of Plotinus's philosophical thinking as a unique, though numerously applicable flaw-pattern for all the single κακα(hence the Platonic αυτο). To conclude, I shall offer a short outlook on the consistency of this interpretation with Plotinus's teaching on the soul and with the further Neoplatonic development of the doctrine of evil.
On Volterra Dislocations of Finitely Deforming Continua
Authors: Casey James
Published: November 2004

In the context of finite deformations, a purely kinematical treatment of Volterra dislocations is presented. These dislocations correspond to deformations that have a jump discontinuity across a singular surface in a fixed reference configuration of the continuum, but whose right Cauchy-Green deformation tensor field is continuous and has second partial derivatives that are continuous. Analytical and geometrical proofs of Weingarten's theorem for finite deformations are given. Tune-dependent Volterra dislocations are also considered.
Wave Stability for Constrained Materials in Anisotropic Generalized Thermoelasticity
Authors: Leslie D. J. , Scott N. H.
Published: November 2004

In generalized thermoelasticity Fourier's law of heat conduction in the classical theory of thermoelasticity is modified by introducing a relaxation time associated with the heat flux. Equations are derived for the squared wave speeds of plane harmonic body waves propagating through anisotropic generalized thermoelastic materials subject to thermomechanical constraints of an arbitrary nature connecting deformation with either temperature or entropy. In contrast to the classical case, it is found that all wave speeds remain finite for large frequencies. As in the classical case, it is found that with temperature-defonnation constraints one unstable and three stable waves propagate in any direction but with deformation-entropy constraints there are three stable waves and no unstable ones. Many special cases are discussed including purely thermal and purely mechanical constraints.
Thermoelastic Small-Amplitude Wave Propagation in Nonlinear Elastic Multilayers
Authors: Gei Massimiliano , Bigoni Davide , Franceschni Giulia
Published: November 2004

A framework for thermoelastic analysis of wave propagation in multilaminated structures is given. The elastic material is subject to an arbitrary, homogeneous deformation and to a condition of uniform temperature. Small-amplitude vibrations are analyzed starting from this state, in a fully coupled thermomechanical formulation.
Beyond the Country House
Authors: Deckha Nityanand
Published: November 2004

While many critics hold historic conservation or preservation in contempt for its complicity in gentrification, this article explores its continuing relevance as an aesthetic politics of everyday life. Interweaving vignettes taken from interviews with conservationists in London, the history of institutionalized heritage in Britain, as well as theories on aesthetics and everyday life in postmodern late capitalism, this article demonstrates the contradictory nature of conservation's aesthetic politics. Although conservationists normalize architectural and social histories, the author argues that they also mobilize a 'spatial politics of affect', appreciating the expressive, and potentially insurgent, power of material objects in the face of an increasingly banal everyday life under late capitalism. Finally, the author suggests that conservationists begin considering how Black and Asian Britons are injecting new spatial uses that offer new avenues for the relevance of conservation's aesthetic politics to Britain's increasingly culturally hybrid everyday life.
Value of imprint cytology for ultrasound-guided transthoracic core biopsy
Authors: Liao W-Y. , Jerng J-S. , Chen K-Y. , Chang Y-L. , Yang P-C. , Kuo S-H.
Published: November 2004

The aim of this study was to investigate the possible additional diagnostic information provided by imprint cytology when performing ultrasound-guided transthoracic core biopsy and to evaluate whether it could optimise the biopsy procedure.

A total of 155 transthoracic core biopsies with touch imprint smears were performed under ultrasound guidance, with 127 malignant and 28 benign lesions. The imprint smears were stained using Riu's method and interpreted by a cytopathologist. These were compared with the histopathology of core biopsy specimens and the final diagnosis of malignantversusbenign disease.

The overall diagnostic accuracy of imprint cytology was 94% (146 out of 155). Histopathological analysis showed an overall accuracy of 94% (146 out of 155), with a sensitivity of 94% (119 out of 127) and negative predictive value of 79% (27 out of 34). The combination of these two methodologies had an increased overall accuracy and negative predictive value of 98% (152 out of 155) and 90% (28 out of 31), respectively. The results of imprint cytology and histopathology were in agreement in 143 patients (92%).

In conclusion, imprint cytology of ultrasound-guided transthoracic core biopsy is a sensitive procedure for diagnosing peripheral thoracic lesions, and it may increase the diagnostic accuracy and cancer negative prediction of biopsy alone. With an on-site approach, imprint cytology may help to assess the adequacy of biopsy specimens and optimise the biopsy procedure.
Airway remodelling assessed by sputum and high-resolution computed tomography in asthma and COPD
Authors: Vignola A.M. , Paganin F. , Capieu L. , Scichilone N. , Bellia M. , Maakel L. , Bellia V. , Godard P. , Bousquet J. , Chanez P.
Published: November 2004

It is not known whether sputum elastase, metalloproteinase (MMP)-9 and tissue-inhibitor metalloproteinase (TIMP)-1 are related to structural changes of the airways, as assessed by high-resolution computed tomography (HRCT) scan.

The relationships between these markers and the magnitude of structural changes of the airways in asthma and chronic obstructive pulmonary disease (COPD) were assessed. Induced sputum and HRCT scan were performed in 30 asthmatics (14 mild and 16 severe) and in 12 patients with COPD.

A greater extent of HRCT scan abnormalities was found in COPD than in severe and mild asthmatics. HRCT scan abnormalities correlated with the degree of airway obstruction in COPD and in severe asthma. HRCT scan abnormalities also correlated with the levels of sputum elastase both in COPD and in severe asthma. HRCT scan abnormalities were associated with sputum MMP-9/TIMP-1 ratio in mild asthma, severe asthma and COPD.

In conclusion, this study demonstrates that sputum elastase and the metalloproteinase-9/tissue-inhibitor metalloproteinase-1 ratio are associated with the magnitude of high-resolution computed tomography scan abnormalities of the airways in asthma and chronic obstructive pulmonary disease, and suggests that the levels of these markers reflect the extent of structural changes of the airways.
Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid
Authors: Betsuyaku T. , Kuroki Y. , Nagai K. , Nasuhara Y. , Nishimura M.
Published: November 2004

Surfactant protein (SP)-A and SP-D are collagen-like glycoproteins that are synthesised in the distal pulmonary epithelium. This study examined the effects of ageing and long-term smoking on SP-A and SP-D in the lungs. The possible links to the development of pulmonary emphysema were also investigated.

Sequential lavage was performed in young and middle-aged or elderly nonsmokers and asymptomatic current smokers with various smoking histories. Middle-aged or elderly smokers were further categorised according to the presence of emphysema by high-resolution computed tomography. Levels of SP-A and SP-D in bronchial lavage (BL) fluid and in bronchoalveolar lavage (BAL) fluid were quantified by ELISA.

Significant decreases in SP-A were seen with age in nonsmokers in BL fluid, but not in BAL fluid. Middle-aged or elderly smokers with emphysema had lower levels of SP-A in both BL and BAL fluids when compared with young subjects, and in BL fluid when compared with middle-aged or elderly smokers without emphysema. SP-D did not change with age alone, however, it was decreased in middle-aged or elderly smokers when compared with similarly aged nonsmokers.

In conclusion, surfactant protein-A may decrease with age alone or due to the cumulative effects of long-term smoking and development of emphysema, while surfactant protein-D decreases due to long-term smoking.
Noninvasive monitoring of respiratory mechanics during sleep
Authors: Farré R. , Montserrat J.M. , Navajas D.
Published: November 2004

The sleep apnoea–hypopnoea syndrome is characterised by recurrent obstructions of the upper airway, resulting in sleep disruption and arterial oxygen desaturations. Noninvasive assessment of respiratory mechanics during sleep is helpful in facilitating the diagnosis and treatment of patients with sleep apnoea–hypopnoea syndrome. This series summarises the different tools that are currently available to noninvasively assess respiratory mechanics during sleep breathing disturbances. These techniques are classified according to the main variable monitored: ventilation, breathing effort or airway obstruction. Changes in patient ventilation are assessed by recording flow or volume signals by means of pneumotachographs, thermistors or thermocouples, nasal prongs or thoraco-abdominal bands. Common tools to noninvasively assess breathing efforts are the thoraco-abdominal bands and the pulse transit time technique. Upper airway obstruction is noninvasively characterised by its upstream resistance and its critical pressure or by means of the forced oscillation technique. Given the technical and practical limitations of each technique, combining different tools improves the reliability and robustness of patient assessment during sleep.
On the nature ofMycobacterium tuberculosis-latent bacilli
Authors: Cardona P-J. , Ruiz-Manzano J.
Published: November 2004

Mycobacterium tuberculosis-latent bacilli are microorganisms that adaptto stressful conditions generated by the infected host against them. By slowing metabolism or becoming dormant, they may counterbalance these conditions and appear as silent to the immune system. Moreover, the dynamic turnover of the infected cells provokes a constant reactivation of the latent bacilli when the environmental conditions are favourable, or an activation after being dormant in necrotic and fibrotic lesions for a long period of time. Since there is noin vivonorin vitroevidence for quick resuscitation of dormant bacilli, the current authors strongly favour the possibility that latent tuberculosis infection can be maintained for no longer than ∼10 yrs, which is, nowadays, a time period very close to that considered for “primary” tuberculosis. This concept may also be helpful for newer epidemiological considerations regarding the real impact of reinfection in tuberculosis.
Vasoactive intestinal peptide receptors in the airways of smokers with chronic bronchitis
Authors: Miotto D. , Boschetto P. , Bononi I. , Zeni E. , Cavallesco G. , Fabbri L.M. , Mapp C.E.
Published: November 2004

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the regulation of airway mucus secretion. The biological functions of VIP are mediated through two receptors, the vasoactive intestinal peptide receptor type 1 (VPAC1R) and type 2 (VPAC2R). The aim of this study was to quantify the expression of both VPAC1R and VPAC2R in the central airways of smokers with chronic bronchitis.

Surgical specimens were obtained from 33 smokers undergoing thoracotomy for localised pulmonary lesions: 23 smokers with symptoms of chronic bronchitis and 10 asymptomatic smokers with normal lung function.

By using immunohistochemical and microscopic analysis, an increased expression of VPAC1R, but not VPAC2R, was found in bronchial epithelium, bronchial glands and vessels of smokers with symptoms of chronic bronchitis compared with asymptomatic smokers. Smokers with symptoms of chronic bronchitis also had an increased number of mononuclear cells positive for both VPAC1R and VPAC2R in the bronchial submucosa.

In conclusion, the expression of type 1 and type 2 vasoactive intestinal peptide receptors is increased in the central airways of smokers with chronic bronchitis, suggesting their possible involvement in the pathogenesis of chronic bronchitis.
Diagnostic stability in a Dutch psychosis incidence cohort
Authors: Veen Natalie D. , Selten Jean-Paul , Schols Diede , Laan Winfried , Hoek Hans W. , van der Tweel Ingeborg , Kahn René S.
Published: November 2004

Background

No study outside the UK has examined the diagnostic stability of psychotic disorders in a population-based sample.

Aims

To determine diagnostic stability in a Dutch population-based psychosis incidence cohort, to examine the frequencies of diagnostic shifts to and from schizophrenic disorders and to report the revised relative risks of schizophrenic disorders for immigrants.

Method

A 30-month follow-up study assessed the cohort (n=181) by means of face-to-face diagnostic interviews.

Results

Diagnostic stability of schizophrenic disorders was high (91%), but lower for other psychotic disorders. At follow-up, the initial diagnosis was adjusted to schizophrenic disorder more often than that the reverse occurred. Almost half (49%) of the patients who were not initially diagnosed as having a schizophrenic disorder received this diagnosis at follow-up. The relative risks for most immigrant groups were stable.

Conclusions

Schizophrenic disorders are underdiagnosed, rather than overdiagnosed, at first presentation.
Socio-economic differentials in mental disorders and suicide attempts in Australia
Authors: Taylor Richard , Page Andrew , Morrell Stephen , Carter Greg , Harrison James
Published: November 2004

Background

Responses to mental disorders usually focus on treatment; socio-economic conditions are less likely to be considered.

Aims

To examine social determinants of mental disorders and attempted suicide in Australia.

Method

Data from the 1997 Australian National Survey of Mental Health and Wellbeing (n=10 641) were used to estimate associations between socio-economic status, mental disorders and attempted suicide. Logistic regression was used to adjust for age, urban/rural residence and country of birth. Socio-economic status differentials in suicide attempts were also adjusted for mental disorders.

Results

Significant increasing gradients from high to low levels of education and occupational status (employed) were evident for affective disorders and anxiety disorders in both men and women and for substance use disorders in men. Similar gradients were found for suicide attempts, which decreased after adjusting for mental disorders, but remained significant in the working-age employed.

Conclusions

These findings suggest social causation of mental disorders and suicide attempts, and the need for social and economic responses beyond provision of mental health services.
Suicide in custody
Authors: Fruehwald Stefan , Matschnig Teresa , Koenig Franz , Bauer Peter , Frottier Patrick
Published: November 2004

Background

Few risk factors and indicators of vulnerability for suicide in custody are known so far.

Aims

A case-control study was conducted to investigate the relevance of criminal history, psychiatric morbidity and social integration to suicide in prison.

Method

For every suicide that occurred in an Austrian correctional institution between 1975 and 1999, two controls matched for correctional institution, gender, nationality, age, custodial status and time of admission were selected. Psychiatric characteristics, previous suicidal behaviour, criminal history and indicators of social integration were compared.

Results

Of 250 recorded suicides, 220 personal files were available and matched to 440 controls. The most important predictors for suicide in custody were a history of suicidality (status following attempted suicide and suicide threat), psychiatric diagnosis, psychotropic medication, a highly violent index offence and single-cell accommodation.

Conclusions

A significant finding is the importance of suicidal behaviour as an indicator of risk of suicide in correctional institutions, which until now has been a matter of debate. This study demonstrates the need for staff to take suicidal behaviour as seriously in custodial settings as in any other circumstances.
People with learning disabilities in a low secure in-patient unit: comparison of offenders and non-offenders
Authors: Reed Suzie , Russell Ailsa , Xenitidis Kiriakos , Murphy Declan G. M.
Published: November 2004

Background

People with learning disability who exhibit challenging behaviour are frequently segregated from services and local teams are often reluctant to receive them back into their care. This situation is worse in those whose challenging behaviour includes a forensic history, but the difference between those labelled as challenging and those treated as offenders is not clear, and there is a lack of evidence about treatment effectiveness.

Aims

To test between-group differences in aggression and treatment outcome in people with learning disability and challenging behaviour, with and without a forensic history.

Method

Clinical records of 86 former in-patients (45 offenders and 41 non-offenders) of a specialist unit were compared on measures of behavioural disturbance and placement outcome.

Results

People in the offenders group were significantly less likely to be aggressive to others and to use weapons, but significantly more likely to harm themselves compared with the non-offenders group. Both groups had a significant reduction in their challenging behaviour during admission, and there was no significant difference in treatment outcome.

Conclusions

The negative reputation of people with learning disabilities who offend needs to be reconsidered.
Tissue Collection for Correlative Studies in Childhood Cancer Clinical Trials: Ethical Considerations and Special Imperatives
Authors: Anderson Barry D. , Adamson Peter C. , Weiner Susan L. , McCabe Mary S. , Smith Malcolm A.
Published: November 2004

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.
Complementary and Alternative Medicine Use by Patients Enrolled Onto Phase I Clinical Trials
Authors: Dy Grace K. , Bekele Lishan , Hanson Lorelei J. , Furth Alfred , Mandrekar Sumithra , Sloan Jeff A. , Adjei Alex A.
Published: November 2004

Purpose

To describe the prevalence, clinical characteristics, and pattern of use of complementary and alternative medicine (CAM) in patients enrolled onto phase I trials.

Patients and Methods

Questionnaires were administered to 108 patients with advanced malignancies enrolled onto phase I chemotherapy trials at the Mayo Clinic Comprehensive Cancer Center (Rochester, MN). CAM was classified into two modalities, pharmacologic and nonpharmacologic. Clinical and demographic data, including age, sex, and prior cancer treatment, were subsequently obtained from patient charts and examined for any correlation with CAM use, using χ2 analysis.

Results

One hundred two survey forms were returned. Among respondents, 88.2% (90 of 102) had used at least one CAM modality; 93.3% (84 of 90) and 53.3% (48 of 90) had used pharmacologic and nonpharmacologic CAM, respectively; and 46.7% (42 of 90) used both modalities. Vitamin and mineral preparations constituted 89.3% (75 of 84) of all pharmacologic CAM used. Intake was highest for vitamins E (48.8% [41 of 84]) and C (38.1% [32 of 84]), and 71.4% (60 of 84) of respondents took nonvitamin/mineral agents. Green tea (29.8% [25 of 84]), echinacea (13.1% [11 of 84]), and essiac (9.5% [8 of 84]) were the most popular. Prayer and spiritual practices were the most commonly used nonpharmacologic CAM, accounting for 52.1% (25 of 48). Chiropractors, the most frequently visited nontraditional medicine practitioners, were consulted by only 10% (9 of 90) of those who practiced CAM. Both CAM modalities were used more frequently by women (53.5% [23 of 43]) than men (40.4% [19 of 47]).

Conclusion

CAM use is common among patients in phase I trials and should be ascertained by investigators, because some of the agents used may interact with investigational agents and affect adverse effects and/or efficacy.
Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies
Authors: Zimmerman Todd M. , Harlin Helena , Odenike Olatoyosi M. , Berk Seth , Sprague Evie , Karrison Theodore , Stock Wendy , Larson Richard A. , Ratain Mark J. , Gajewski Thomas F.
Published: November 2004

Purpose

Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.

Patients and Methods

The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.

Results

Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).

Conclusion

Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.
Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate Cancer
Authors: Shuch Brian , Mikhail Maryann , Satagopan Jaya , Lee Peng , Yee Herman , Chang Caroline , Cordon-Cardo Carlos , Taneja Samir S. , Osman Iman
Published: November 2004

Purpose

The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors.

Patients and Methods

We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage ≥ T3, n = 72; Gleason score < 7, n = 110; Gleason score ≥ 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically.

Results

EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003).

Conclusion

Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.
Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196
Authors: Sparano Joseph A. , Bernardo Patricia , Stephenson Patricia , Gradishar William J. , Ingle James N. , Zucker Stanley , Davidson Nancy E.
Published: November 2004

Purpose

To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy.

Patients and Methods

One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.

Results

When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).

Conclusion

Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.
Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy
Authors: Huang Eugene H. , Tucker Susan L. , Strom Eric A. , McNeese Marsha D. , Kuerer Henry M. , Buzdar Aman U. , Valero Vicente , Perkins George H. , Schechter Naomi R. , Hunt Kelly K. , Sahin Aysegul A. , Hortobagyi Gabriel N. , Buchholz Thomas A.
Published: November 2004

Purpose

To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy.

Patients and Methods

We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation.

Results

Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage ≥ IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P ≤ .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage ≥ IIIB disease, clinical T4 tumors, and four or more positive nodes (P ≤ .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively.

Conclusion

After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.
Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)
Authors: Blaney Susan M. , Bernstein Mark , Neville Kathleen , Ginsberg Jill , Kitchen Brenda , Horton Terzah , Berg Stacey L. , Krailo Mark , Adamson Peter C.
Published: November 2004

Purpose

To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.

Patients and Methods

An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.

Results

Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2 dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% ± 7.6% at the 1.2 mg/m2/dose and 76.5% ± 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses.

Conclusion

Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.
Properties of classes of life distribution based on the conditional variance
Authors: Stoyanov Jordan , Al-Sadi M. H. M.
Published: November 2004

We consider two classes of life distribution, VD and VI, the members of which are defined in terms of the conditional variance σ2(t) of the remaining lifetime of a system: a life distribution F belongs to VD if is a decreasing function and to VI if is increasing. We study closure properties of these classes under relevant reliability operations such as mixing, convolution and formation of coherent systems. We show, for example, that the class VD is not closed under convolution or mixing, and that the class VI is not closed under formation of coherent systems.
The use of the variogram in construction of stationary time series models
Authors: Ma Chunsheng
Published: November 2004

This paper studies a class of stationary covariance models, in both the discrete- and the continuous-time domains, which possess a simple functional formγ(τ+τ0)+γ(τ−τ0)− 2γ(τ), whereτ0is a fixed lag andγ(τ) is an intrinsically stationary variogram, and include the fractional Gaussian noise of Kolmogorov (1940) and a stochastic volatility model of Barndorff-Nielsen and Shephard (2001), (2002) as special cases. Properties of the class, and interesting special cases with long memory, are studied. We also characterize the covariance function via the variogram.
Numerical integration using V-uniformly ergodic Markov chains
Authors: Mathé Peter
Published: November 2004

We study numerical integration based on Markov chains. Our focus is on establishing error bounds uniformly on classes of integrands. Since in general state space the concept of uniform ergodicity is too restrictive to cover important cases, we analyze the error of V-uniformly ergodic Markov chains. We place emphasis on the interplay between ergodicity properties of the transition kernel, the initial distributions and the classes of integrands. Our analysis is based on arguments from interpolation theory.
On pair and tuple formation under independent Poisson or renewal arrival processes
Authors: Borovkov K.
Published: November 2004

We present several results refining and extending those of Neuts and Alfa on weak convergence of the pair-formation process when arrivals follow two independent Poisson processes. Our results are obtained using a different, more straightforward, and apparently simpler probabilistic approach. Firstly, we give a very short proof of the fact that the convergence of the pair-formation process to a Poisson process actually holds in total variation (with a bound for convergence rate). Secondly, we extend the result of the theorem to the case of multiple labels: there aredindependent arrival Poisson processes, and we are looking at the epochs whend-tuples are formed. Thirdly, we extend the original (weak convergence) result to the case when arrivals follow independent renewal processes (this extension is also valid for thed-tuple formation).
Infinite divisibility of infinite sums of lower records: a simple proof
Authors: Iksanov Aleksander M.
Published: November 2004

Let {Xn, n = 0, 1,…} be the sequence of the lower records for an arbitrary underlying distribution μ on [0, ∞). We show that is equal in distribution to where {τi, i = 1, 2,…} is a Poisson flow of unit intensity and g is a right-continuous and nonincreasing function defined by μ. This observation allows us to extend results of Bose et al. and simplify their proofs.
Some fluctuation identities for Lévy processes with jumps of the same sign
Authors: Zhou Xiaowen
Published: November 2004

We consider a two-sided exit problem for a Lévy process with no positive jumps. The Laplace transform of the time when the process first exits an interval from above is obtained. It is expressed in terms of another Laplace transform for the one-sided exit problem. Applications of this result are discussed. In particular, a new expression for the solution to the two-sided exit problem is obtained. The joint distribution of the minimum and the maximum values of such a Lévy process is also studied.
The mean comparison theorem cannot be extended to the Poisson case
Authors: Večeř Jan , Xu Mingxin
Published: November 2004

In this paper, we show that the mean comparison theorem, which is valid for Brownian motion, cannot be extended to Poisson processes. A counterexample in the Poisson case for which the mean comparison theorem does not hold is provided.
On the multifractal spectrum of the branching measure on a Galton–Watson tree
Authors: Mörters Peter , Shieh Narn-Rueih
Published: November 2004

Suppose that μ is the branching measure on the boundary of a supercritical Galton–Watson tree with offspring distribution N such that E[N log N] < ∞ and P{N = 1} > 0. We determine the multifractal spectrum of μ using a method different from that proposed by Shieh and Taylor, which is flawed.
A Gd–Ag Coordination Polymer with Porous Structure via Hydrothermal Synthesis: [Gd2Ag2(pydc)4(H2O)4]n
Authors: Liang Yucang , Cao Rong , Su Weiping , Hong Maochun
Published: December 2004

A Gd-Ag coordination polymer [Gd2Ag2(pydc)4(H2O)4]n (pydc = pyridine-2,5-dicarboxylate) with lamellar structure was prepared by the hydrothermal reaction of Gd2O3, AgNO3, H2pydc and H2O in a molar ratio of 1 : 4 : 5 : 3100 at 170 °C and characterized by single-crystal X-ray diffraction analysis.
Solvent-Free Robinson Annelation Reaction
Authors: Miyamoto Hisakazu , Kanetaka Shotaro , Tanaka Koichi , Yoshizawa Kazuhiro , Toyota Shinji , Toda Fumio
Published: December 2004

Solvent-free Robinson annelation reaction proceeded at room temperature to give corresponding cyclohexenones.
Effect of the Atoms in Outermost Layers upon Friction Behavior of Organized Molecular Films of Comb-polymers Containing Fluorocarbon Chains
Authors: Fujimori Atsuhiro , Araki Tohru , Nakahara Hiroo
Published: December 2004

Several newly synthesized comb-polymers with fluorocarbon side-chains have been found to form stable monolayers on the water surface, which could be deposited on solid substrates as the Z-films. Friction behavior of the Z-films measured by atomic force microscopy has been clearly affected by the atom (–F/–H) of ends of the fluorocarbon chains exposed in the outermost layers of the polymer as well as those of the corresponding monomer Z-films.
Health services research in Australia: an investigation of its current status
Authors: Haas Marion
Published: November 2004

Objectives

The objectives of this audit were to document the current status of health services research (HSR) in Australia in terms of inputs and outputs. Inputs were defined as the number of organised centres or groups undertaking HSR, the extent to which HSR was being developed and the funding available for HSR. Outputs were measured as the number of peer-reviewed papers.

Methods

Centres or groups were identified via the membership of the HSRAANZ and a web-based search. Information from annual reports and/or other published sources was used to determine the extent of capacity building and available funding. The tables of contents of 21 journals published over a 10-year period were searched for articles reporting Australian HSR.

Results

Eighteen groups were identified that undertook HSR as their predominant activity, while twelve were involved in HSR as a collaborative activity. No HSR-specific training (in terms of under- or postgraduate degrees) was identified, although more than 400 postgraduate students were being supervised in the university departments where HSR groups were situated. Between 1998 and 2001, more than AU$13 million was awarded for HSR, most of it by the National Health and Medical Research Council (NHMRC). Over the past 10 years, 482 articles about Australian health services have been published in the peer-reviewed journals audited.

Conclusions

Although HSR is widespread in Australia, no specific training appears to be available to build capacity. Overall, HSR is not well-funded especially by organisations outside the NHMRC or Australian Research Council. Thus, it is not surprising that the output of Australian HSR, in terms of peer-reviewed articles, is slight.