bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Bisphosphonates as Adjuvant Therapy for Operable Breast Cancer
Authors: Powles Trevor , McCroskey Eugene , Paterson Alexander
Published: October 2006

Bone is the most common site of metastatic spread from primary operable breast cancer, causing pain, fractures, and hypercalcemia. This spread depends on the release of osteolytic substances by the cancer cells, which activate osteoclasts to cause bone resorption. The osteoclasts also release growth factors that can act back on the cancer cells to activate growth. This vicious circle thereby facilitates the growth of metastases in bone, thus making this a preferential site for relapse. Agents, such as the bisphosphonates, which block osteoclast function, have been shown to reduce the progression of established bone metastases. The oral bisphosphonate clodronate (1,600 mg/d) is effective for treatment of patients with bone metastases. When used as adjuvant therapy, given to patients with operable breast cancer for 2 years, clodronate has been reported to significantly reduce the risk of bone metastases during the 2-year study period [19 clodronate patients versus 35 placebo patients; hazard ratio (HR), 0.546; P = 0.03] and 5-year study period (51 clodronate patients versus 73 placebo patients; HR, 0.692; P = 0.04) with a significant reduction in mortality (HR, 0.768; P = 0.048). This benefit, together with the low toxicity and safety of clodronate, supports its use as additional adjuvant therapy for patients with primary breast cancer. Further, similarly designed trials are under way to establish the optimal duration of therapy, the efficacy in stage I disease, and the relative potential of other bisphosphonates, particularly the more powerful aminobisphosphonates, such as ibandronate and zoledronate.
Advances in Treating Metastatic Bone Cancer: Summary Statement for the First Cambridge Conference
Authors: Lipton Allan , Berenson James R. , Body Jean-Jacques , Boyce Brendan F. , Bruland Oyvind S. , Carducci Michael A. , Cleeland Charles S. , Clohisy Denis R. , Coleman Robert E. , Cook Richard J. , Guise Theresa A. , Pearse Roger N. , Powles Trevor J. , Rogers Michael J. , Roodman G. David , Smith Matthew R. , Suva Larry J. , Vessella Robert L. , Weilbaecher Katherine N. , King Laura
Published: October 2006

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.
Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics
Authors: Lagas Jurjen S. , Vlaming Maria L. , van Tellingen Olaf , Wagenaar Els , Jansen Robert S. , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H.
Published: October 2006

Purpose: P-glycoprotein (P-gp; ABCB1) efficiently transports lipophilic amphipathic drugs, including the widely used anticancer drug paclitaxel (Taxol). We found previously that human multidrug resistance protein 2 (MRP2; ABCC2) also transports paclitaxel in vitro, and although we expected that paclitaxel pharmacokinetics would be dominated by P-gp, the effect of Mrp2 was tested in vivo.

Experimental Design: We generated and characterized Mdr1a/1b/Mrp2−/− mice, allowing assessment of the distinct roles of Mrp2 and Mdr1a/1b P-gp in paclitaxel pharmacokinetics.

Results: Surprisingly, the effect of Mrp2 on i.v. administration of paclitaxel was as great as that of P-gp. The area under plasma concentration-time curve (AUC)i.v. in both Mrp2−/− and Mdr1a/1b−/− mice was 1.3-fold higher than in wild-type mice, and in Mdr1a/1b/Mrp2−/− mice, a 1.7-fold increase was found. In spite of this similar effect, Mrp2 and P-gp had mostly complementary functions in paclitaxel elimination. Mrp2 dominated the hepatobiliary excretion, which was reduced by 80% in Mrp2−/− mice. In contrast, P-gp dominated the direct intestinal excretion, with a minor role for Mrp2. The AUCoral of paclitaxel was 8.5-fold increased by Mdr1a/1b deficiency but not affected by Mrp2 deficiency. However, in the absence of Mdr1a/1b P-gp, additional Mrp2 deficiency increased the AUCoral another 1.7-fold.

Conclusions: Thus far, Mrp2 was thought to mainly affect organic anionic drugs in vivo. Our data show that Mrp2 can also be a major determinant of the pharmacokinetic behavior of highly lipophilic anticancer drugs, even in the presence of other efficient transporters. Variation in MRP2 activity might thus directly affect the effective exposure to paclitaxel, on i.v. administration, but also on oral administration, especially when P-gp activity is inhibited.
The Hedgehog Signaling Pathway in Cancer
Authors: Evangelista Marie , Tian Hua , de Sauvage Frederic J.
Published: October 2006

The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis, and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer. A comprehensive understanding of Hh signaling during development will undoubtedly shed light into the mechanism of Hh in cancer progression and identify potential targets for therapeutic intervention.
Activation of Potassium Channels by Tempol in Arterial Smooth Muscle Cells From Normotensive and Deoxycorticosterone Acetate-Salt Hypertensive Rats
Authors: Xu Hui , Jackson William F. , Fink Gregory D. , Galligan James J.
Published: October 2006

Large-conductance Ca
2+
-activated potassium (BK) channels modulate vascular tone. Tempol, an O
2
−
dismutase mimetic, causes vasodilation via activation of vascular BK channels. In this study, we investigated the mechanisms underlying tempol-induced activation of BK channels in mesenteric arterial (MA) myocytes from sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In sham myocytes, whole-cell patch clamp studies showed that tempol enhanced peak outward currents (
I

o

). This effect was larger in DOCA-salt myocytes. Tempol caused a leftward shift in the activation curve for

I
o

in sham and DOCA-salt myocytes. In DOCA-salt myocytes, the peak

I
o

at +80 mV did not differ from sham myocytes, but iberiotoxin (BK channel blocker) caused a larger reduction of

I
o

in DOCA-salt compared with sham myocytes. Iberiotoxin but not 4-aminopyridine blocked the

I
o

activated by tempol. Tiron, another O
2
−
scavenger, had no effect on
I

o

. Using inside-out patches, we found that tempol caused a 4-fold increase in open probability (P
o
) of BK channels but did not change the mean channel open time in sham and DOCA-salt myocytes. Tempol did not change single channel conductance in sham or DOCA-salt myocytes. Western blot and immunocytochemical studies revealed that BK channel α-subunit expression was increased in DOCA-salt MA compared with sham MA. The data indicate that tempol directly activates BK channels by increasing channel P
o
. We conclude that upregulation of the BK channel α-subunit protein and tempol-induced increases in BK channel P
o
contribute to the enhanced depressor response caused by tempol in DOCA-salt hypertensive rats.
Induction of Oral Tolerance to Oxidized Low-Density Lipoprotein Ameliorates Atherosclerosis
Authors: van Puijvelde G.H.M. , Hauer A.D. , de Vos P. , van den Heuvel R. , van Herwijnen M.J.C. , van der Zee R. , van Eden W. , van Berkel T.J.C. , Kuiper J.
Published: October 2006

Background—

Oxidation of low-density lipoprotein (LDL) and the subsequent processing of oxidized LDL (oxLDL) by macrophages results in activation of specific T cells, which contributes to the development of atherosclerosis. Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis.

Methods and Results—

Tolerance to oxLDL and malondialdehyde-treated LDL (MDA-LDL) was induced in LDL receptor
−/−
mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis. Oral tolerance to oxLDL resulted in a significant attenuation of the initiation (30% to 71%;
P
<0.05) and progression (45%;
P
<0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4
+
CD25
+
Foxp3
+
cells in spleen and mesenteric lymph nodes, and these cells specifically responded to oxLDL with increased transforming growth factor-β production. Tolerance to oxLDL also increased the mRNA expression of Foxp3, CTLA-4, and CD25 in the plaque. In contrast, tolerance to MDA-LDL did not affect atherogenesis.

Conclusions—

OxLDL-specific T cells, present in LDL receptor
−/−
mice and important contributors in the immune response leading to atherosclerotic plaque, can be counteracted by oxLDL-specific CD4
+
CD25
+
Foxp3
+
regulatory T cells activated via oral tolerance induction to oxLDL. We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis.
Impaired Regulatory T-Cell Response and Enhanced Atherosclerosis in the Absence of Inducible Costimulatory Molecule
Authors: Gotsman Israel , Grabie Nir , Gupta Rajat , Dacosta Rosa , MacConmara Malcolm , Lederer James , Sukhova Galina , Witztum Joseph L. , Sharpe Arlene H. , Lichtman Andrew H.
Published: October 2006

Background—

T-cell–mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses.

Methods and Results—

Bone morrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor–deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4
+
T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4
+
T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-γ and tumor necrosis factor-α than T cells from control mice, which suggests a lack of regulation. FoxP3
+
regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3
+
Treg and impaired in vitro Treg suppressive function compared with control mice.

Conclusions—

ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
Effect of Coronary Stenosis on Adjacent Bed Flow Reserve
Authors: Pacella John J. , Villanueva Flordeliza S.
Published: October 2006

Background—

During coronary stenosis, flow reserve in the adjacent nonstenotic bed decreases, but the microvascular mechanisms are unknown. Because myocardial contrast echocardiography (MCE) assesses microvascular physiology, we used it to relate flow reserve to intramyocardial blood volume in the adjacent bed.

Methods and Results—

A noncritical left anterior descending (LAD) stenosis was created in 10 dogs. MCE was performed and myocardial blood flow was measured with neutron-activated microspheres and flow probes. Data were collected at baseline, hyperemia, and hyperemia and stenosis. Hyperemia was induced with an A
2A
receptor agonist. MCE acoustic intensity in the LAD and left circumflex (LCx) regions were fit to the following: y=A(1-e
−βt
), where A, β, and A×β reflect intramyocardial blood volume, red cell velocity, and flow, respectively. During hyperemia alone, LCx probe and microsphere flows and MCE-derived red cell velocity increased from baseline (30±14 versus 125±62 mL/min,
P
<0.0005; 1.5±0.5 versus 6.6±2.0 mL · min
−1
· g
−1
,
P
<0.0005; and 0.53±0.14 versus 0.96±0.45 second
−1
,
P
=0.030, respectively); intramyocardial blood volume was unchanged. LAD stenosis during hyperemia decreased LCx probe flow (125±62 versus 110±57 mL/min;
P
<0.05), microsphere flow (6.6±2.0 versus 4.2±2.1 mL · min
−1
· g
−1
;
P
<0.0005), and MCE-derived flow (0.57±0.29 versus 0.45±0.33 second
−1
;
P
=0.032). LCx bed intramyocardial blood volume concurrently increased (0.61±0.14 versus 0.70±0.15;
P
<0.01).

Conclusions—

Coronary stenosis impairs flow reserve in the adjacent nonstenotic bed, in which intramyocardial blood volume increases. MCE suggests compensatory recruitment of microvascular anastomotic collateral networks that augment stenotic bed flow reserve, but at the expense of the adjacent bed. Adjacent bed collateral microcirculation thus participates in the regulation of collateral flow and appears functionally significant during coronary stenosis.
Myocardial Infarct–Sparing Effect of Adenosine A2AReceptor Activation Is due to Its Action on CD4+T Lymphocytes
Authors: Yang Zequan , Day Yuan-Ji , Toufektsian Marie-Claire , Xu Yaqin , Ramos Susan I. , Marshall Melissa A. , French Brent A. , Linden Joel
Published: October 2006

Background—We previously used adenosine A2Areceptor (A2AR) knockout (KO) mice and bone marrow transplantation to show that the infarct-sparing effect of A2AR activation at reperfusion is primarily due to effects on bone marrow–derived cells. In this study we show that CD4+but not CD8+T lymphocytes contribute to myocardial ischemia/reperfusion injury.

Method and Results—After a 45-minute occlusion of the left anterior descending coronary artery and reperfusion, T cells accumulate in the infarct zone within 2 minutes. Addition of 10 μg/kg of the A2AR agonist ATL146e 5 minutes before reperfusion produces a significant reduction in T-cell accumulation and a significant reduction in infarct size (percentage of risk area) measured at 24 hours. In Rag1 KO mice lacking mature lymphocytes, infarct size is significantly smaller than in C57BL/6 mice. Infarct size in Rag1 KO mice is increased to the level of B6 mice by adoptive transfer of 50 million CD4+T lymphocytes derived from C57BL/6 or A2AR KO but not interferon-γ KO mice. ATL146e completely blocked the increase in infarct size in Rag1 KO mice reconstituted with B6 but not A2AR KO CD4+T cells. The number of neutrophils in the reperfused heart at 24 hours after infarction correlated well with the number of lymphocytes and infarct size.

Conclusions—These results strongly suggest that the infarct-sparing effect of A2AR activation is primarily due to inhibition of CD4+T-cell accumulation and activation in the reperfused heart.
Outcomes of 6906 Patients Undergoing Percutaneous Coronary Intervention in the Era of Drug-Eluting Stents
Authors: Williams David O. , Abbott J. Dawn , Kip Kevin E.
Published: October 2006

Background—

The DEScover Registry was designed to characterize patients selected for drug-eluting stents (DES) in routine clinical practice and their outcomes in the United States.

Methods and Results—

From January to June 2005, data were collected on 6906 patients who underwent percutaneous coronary intervention at 140 medical centers. Baseline characteristics and outcomes were compared on the basis of treatment with ≥1 bare-metal (BMS; n=397), sirolimus-eluting (SES; n=3873), or paclitaxel-eluting (PES; n=2636) stent. Clinical characteristics and the types of lesion treated for BMS patients differed substantially from those treated with DES, but minimal differences were noted between DES patients receiving SES or PES. At 1 year, the unadjusted cumulative incidence of death/myocardial infarction was higher in BMS than in DES patients (9.0% versus 5.2%;
P
=
0.002) but similar in SES and PES patients (5.2% versus 5.3%;
P
=0.64). After adjustment, risk of death/MI was not significantly lower in DES- compared with BMS-treated patients (adjusted hazard ratio, 0.74; 95% confidence interval, 0.52 to 1.07). Although target vessel revascularization occurred less often in DES patients (9.5% versus 6.0%;
P
=0.007), rates were similar between SES and PES patients (6.3% versus 5.5%;
P
=0.20). Rates of stent thrombosis were similar among BMS (0.8%), SES (0.5%), and PES (0.8%) patients.

Conclusions—

In DEScover, differences in patient selection were observed between BMS and DES patients but not between SES and PES patients. DES use resulted in lower rates of clinically driven repeat revascularization with similar rates of stent thrombosis. These observations confirm the effectiveness and safety of both SES and PES in unselected patients.
Civic Responsibility and Patterns of Voluntary Participation Around the World
Authors: Haddad Mary Alice
Published: October 2006

This article seeks to explain why different types of volunteer organizations are prevalent in different countries. It hypothesizes that patterns of volunteer participation are a function of citizen attitudes toward governmental and individual responsibility for caring for society. Those countries (e.g., Japan)—where citizens think that governments should be responsible for dealing with social problems—will tend to have higher participation in embedded volunteer organizations, such as parent-teacher associations. Those countries (e.g., the United States)—where citizens think that individuals should take responsibility for dealing with social problems—will tend to have more participation in nonembedded, organizations, such as Greenpeace. These hypotheses are tested statistically using membership data from eight organizations in 68 countries. Alternative explanations, such as levels of income, education, urbanization, and prevalence of working women, are also tested. Citizen attitudes about individual and governmental responsibility are best able to explain the prevalence of different types of volunteer organizations found in different countries.
Sexual health services and education: Young people’s experiences and preferences
Authors: Reeves C , Whitaker R , Parsonage R K , Robinson C A , Swale K , Bayley L
Published: October 2006

Objective To examine young people’s requirements and perceptions of sexual health services and education in the context of their experience of sexual relationships and knowledge of sexual health.

Design A questionnaire based cohort study.

Setting Three hundred and sixty Year 11 students (aged 15-16 years) surveyed in three Secondary Schools.

Method The study received ethical approval from The North Wales Central Ethics Committee. School nurses distributed questionnaires in classroom conditions to all students present on the survey day.

Results Eighty-six per cent of the cohort responded. Those young people who reported being sexually active (153, 45 per cent) thought most sexual education topics should be taught around six months earlier than non-sexually active respondents. Of those accessing sexual health services, 90 per cent were happy with the services received, however, only 44 per cent of sexually active males and 76 per cent of sexually active females had sought advice. That clinics had a ‘friendly atmosphere and staff easy to talk to’ ranked highest and ‘only people of your own age using the clinic’ ranked lowest on a list of important features for a sexual health clinic.

Conclusion Planners should consult young people and develop services in line with their needs. Sexual health education should be taught earlier in the school curriculum, with flexibility over when some information is accessed. There is little evidence for the assumption upon which much work in this field is based; that most young people prefer a specifically young person’s sexual health clinic.
Effect of Long-chain Branching on the Foaming of Polypropylene with Azodicarbonamide
Authors: Stange Jens , Münstedt Helmut
Published: October 2006

In this article the influence of long-chain branching on the foaming behavior of polypropylene (PP) is investigated. Different branching contents are achieved by blending a linear PP (L-PP) and a long-chain branched PP (LCB-PP). Whereas, the L-PP does not exhibit any strain hardening in laboratory stretching experiments, blends with amounts of the LCB-PP higher than 2 wt% already show a pronounced strain-hardening behavior. The strain hardening increased with a growing amount of the long-chain branched PP. A laboratory scale foaming apparatus based on a capillary rheometer is developed for the foaming experiments. In foaming tests with azodicarbonamide as chemical blowing agent, a significant improvement of the foaming behavior with respect to a higher expansion ratio, a lower amount of connected cells, and a more homogeneous cell size distribution is found with increasing content of the LCB-PP up to a concentration of 50 wt%. At this concentration, the foaming behavior of the LCB-PP is reached. The results demonstrate that low amounts of long-chain branching can significantly improve the optimal foaming process of PPs with a chemical blowing agent, and that additions of the linear material up to 50 wt% to the LCB-PP do not have any influence on the favorable foaming performance of the long-chain branched PP.
Selective Adsorption and Steric Recognition by Molecularly Imprinted Polymers: a Study on Molecular Self-Assembly and its Effect on Selectivity
Authors: Zhang Daonian , Li Songjun , Huang Jun , Luo Gang
Published: October 2006

This article presents an interesting study on molecular self-assembly and its effect on steric recognition by molecularly imprinted polymers. With S-naproxen as the template and acrylamide as the functional monomer, the self-assembly appears to play important roles in the selective adsorption, affecting not only the adsorption amount but also the enantioselective recognition. Both of them become evident by the change of monomer–template ratio. An increase in the monomer–template ratio will result in a higher level of adsorption. The best selectivity for steric recognition is, however, shown at an optimal composition (corresponding to the saturation interaction of monomer and template). A higher or lower monomer–template ratio leads to a dramatic decrease in this selectivity. Related information indicates that this may be a result from the matched arrangement between the binding sites and the template, which makes the binding sites capable of selectively recognizing the imprint species.
Thermal Conductivity of UltemTM/Carbon Nanofiller Blends
Authors: Ghose S. , Working D. C. , Connell J. W. , Smith J. G. , Watson K. A. , Delozier D. M. , Sun Y. P. , Lin Y.
Published: October 2006

In an effort to improve polymer thermal conductivity (TC), UltemTM 1000 was compounded with nano-fillers of carbon allotropes. As-received and modified multiwalled carbon nanotubes (MWCNTs), vapor-grown carbon nanofibers (CNF) and expanded graphite (EG) were investigated. Functionalization of MWCNTs was performed to improve the TC compatibility between the resin and MWCNTs. It was postulated that this may provide an improved interface between the MWCNT and the polymer which would result in enhanced TC. The nano-fillers were mixed with UltemTM 1000 inthemeltandinsolution at concentrations ranging from 5 to 40 wt.%. Ribbons were extruded from the blends to form samples where the nano-fillers were aligned to some degree in the extrusion direction. Samples were also fabricated by compression molding resulting in random orientation of the nano-fillers. Thermal properties of the samples were evaluated by differential scanning calorimetry (DSC) and thermal gravimetric analyzer (TGA). Tensile properties of aligned samples were determined at room temperature. As expected, increased filler loading led to increased modulus and decreased elongation with respect to the neat polymer. The degree of dispersion and alignment of the nano-fillers was determined by high-resolution scanning electron microscopy (HRSEM). The HRSEM of the ribbons revealed that the MWCNTs and CNFs were predominantly aligned in the flow direction. The TC of the samples was measured using a NanoflashTM instrument. Since the MWCNTs and CNF are anisotropic, the TC was expected to be different in the longitudinal (parallel to the nanotube and fiber axis) and transverse (perpendicular to the nanotube and fiber axis) directions. The largest TC improvement was achieved for aligned samples when the measurement was performed in the direction of MWCNT and CNF alignment (i.e. longitudinal axis). Unaligned samples also showed a significant improvement in TC and may be potentially useful in applications when it is not possible to align the nano-filler. The results of this study will be presented.
Synthesis and Study of Arylenevinylene and Aryleneimine-Type Polymers Containing N-Hexyl-3.6-Carbazolyl Groups
Authors: Conduruta Daniel , Antonoaia Nicoleta Cristina , Grigoras Mircea , Ivanoiu Maria
Published: October 2006

Two monomers with preformed Schiff base and arylenevinylene structure and final bromine substituents were synthesized by coupling of 3-formyl-6-bromo-N-hexyl-carbazole with 1,4-phenylenediamine and tetraethyl-p-xylylene diphosphonate, respectively. These compounds were used to synthesize arylenimine and arylenevinylene polymers containing N-hexyl 3,6-carbazolylydiyl units in the main chain by dehalogenative coupling reactions via organometallic reductive catalysis (Ni°.bipy). The polymers were characterized by spectral methods (Fourier transform-infrared, 1H NMR, UV-vis and fluorescence) as well as gel permeation chromatography and differential scanning calorimetry.
Polyketanils: Preparation of π-Conjugated Polymer Bases from p-dibenzoylbenzene with Various Diamines. Protonation with DL-Camphor-10-sulfonic Acid
Authors: Iwan Agnieszka , Kasperczyk Janusz , Kaczmarczyk Bozena , Janeczek Henryk , Jurusik Jan , Mazurak Zbigniew , Sek Danuta
Published: October 2006

New luminescent materials - aromatic polyketanils (PKs) containing p-phenylene and biphenylene linkages in the backbone and electron-donating side-group substitutions have been synthesized via melt polycondensation (180°C, 24 h). Their structures were confirmed by elemental and spectral Fourier transform infrared, 13Cand 1H NMR, and ultraviolet-visible (UV-vis) analysis. All the PKs were solution-processable and thermally stable, making them potential candidate materials for applications in microelectronics and aerospace. These ketanil polymers showed high thermal stability and well-defined glass transition temperatures ( Tg). The temperature at which the polymers lose 10% of their weight ( T10) ranged from 420 to 520°C. Depending on the polymer structure, PKs showed Tg values in the range of 133 to 244°C. Moreover, the polymers emit either blue radiation or green radiation depending on the mutual presence of conjugated and saturated chain segments. The HOMO/LUMO energy gap of the polymers was in the range of 2.74-2.19 eV. The photoluminescence properties of the PKs after protonation with DL-camphor-10-sulfonic acid (CSA) were tested. The structure formation of (PKs)1(CSA)2 complexes are discussed on the basis of 1HNMRspectroscopy.
Modification of Polysulfones by Carboxylic Acids
Authors: Hoffmann Thorsten , Pospiech Doris , Kretzschmar Bernd , Reuter Uta , Häußler Liane , Eckert Franziska , Perez-Graterol Raul , Sandler Jan K.W. , Altstädt Volker
Published: October 2006

The modification of aromatic polysulfones (PSU) in the melt in continuous mixing aggregates (on the small-scale: twin-screw microcompounder; on the large-scale: twin-screw extruder) by low-molecular weight dicarboxylic acids is presented. Owing to the drastic conditions experienced by the melt in the extruder operating at 320 °C, chain scission of the polysulfones as well as the formation of reactive groups attached to the PSU chains was expected, using either trimellitic acid anhydride or terephthalic acid as dicarboxylic acids. However, no functional groups indicating a reaction between the PSU and the carboxylic acids were detected in the melt-processed PSU compounds. Nevertheless, the resulting thermal and mechanical properties of the PSU compounds were influenced remarkably by the carboxylic acids due to their different mixing behavior with the PSU melt. The tensile stiffness and strength of the compounds were significantly increased in comparison with the PSU reference. PSU compounds containing the trimellitic acid anhydride (at concentrations exceeding 5.7 wt.%) showed a particularly high strength at break, while all compounds had a lower toughness in comparison with the neat PSU.
Challenges in the design and conduct of a randomized study of two interventions for liquid aspiration
Authors: Brandt Diane K , Hind Jacqueline A , Robbins JoAnne , Lindblad Anne S , Gensler Gary , Gill Gary , Baum Herb , Lilienfeld David , Logemann Jeri A ,   Communication Sciences and Disorders Clinical Trials Research Group (CSDRG)
Published: October 2006

Background Liquid aspiration during swallowing has been linked to pneumonia, the most common cause of infectious death in the elderly. This paper examines the key issues in the design and implementation of the first multisite, randomized behavioral trial in dysphagia in an aging population. The study evaluated two commonly used treatments with respect to short-term and long-term management of liquid aspiration and subsequent pneumonia in dysphagic geriatric participants with dementia and/or Parkinson's disease.

Methods Discussed are lessons learned during the conduct of this trial and include (1) ethical and methodological design issues, (2) pragmatic implementation of procedures and forms, (3) importance of multiple communication and monitoring strategies, (4) response to funding issues, and (5) changes in staff and facilities.

Results In order to complete this trial the researchers were required to provide more support than anticipated in tasks such as completion of regulatory requirements by sites, supplementing site staff to identify potential study participants using a ‘circuit rider’ approach, continued recruitment of new sites and staff throughout the course of the trial, adapting forms and procedures and managing within economic constraints in a changing trial environment.

Limitations Many of the challenges faced by the researchers were not anticipated when the study began. Successful strategies are described for these unanticipated difficulties, based on retrospective evaluation.

Conclusions Successful conduct of clinical trials in long-term care environments that are heavily impacted by changes extraneous to the trial design and with staff typically new to clinical trials is possible but success depends on logistical flexibility.
Centralized medical monitoring in phase III clinical trials: the National Surgical Adjuvant Breast and Bowel Project (NSABP) experience
Authors: Soran A , Nesbitt L , Mamounas E P , Lembersky B , Bryant J , Anderson S , Brown A , Passarello M
Published: October 2006

Background There is a need for data quality assurance procedures in phase III cancer trials. At the National Surgical Adjuvant Breast and Bowel Project (NSABP) ‘real-time’ systems have been developed for quality assurance and study monitoring: (1) manual review and triage of data forms by data managers at the time of submission; (2) computerized edit checking of all submitted data forms; (3) systematic review of eligibility, treatment compliance and toxicity in the first 100 patients of a new protocol; (4) prospective centralized medical review of all reported serious adverse events, treatment failures, second primary cancers and deaths; (5) quarterly review and approval of study summary data files by project statistician; and (6) on-site auditing.

Purpose To assess the utility of an additional final comprehensive review of all patient records to confirm eligibility, disease status and vital status prior to manuscript submission.

Methods Four phase III NSABP studies, which had been monitored using the triagebased quality assurance program described above, were selected for analysis ( n = 7972). Charts for 5965 patients were identified that had not been previously medically reviewed for protocol events of recurrence, second primary cancer or death. Submitted source documents and data forms of these 5965 NSABP patient records underwent medical review to verify patient eligibility, disease status and vital status.

Results This final comprehensive review found no additional treatment failures or deaths, identified seven additional cases of ineligibility, was time-intensive requiring enormous use of expensive resources, and was therefore judged not to add significantly to the integrity of the database.

Limitations Our findings are influenced by the procedures the NSABP employs for quality assurance and study monitoring for Phase III clinical trials and may have limited generalizability to other settings.

Conclusion In the presence of multiple quality assurance and data monitoring systems, the rare discrepancies found between the data forms and source documentation does not support the routine use of a final comprehensive chart review for phase III trials at the NSABP Biostatistical Center.
Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer
Authors: Liénard J-L , Quinaux E , Fabre-Guillevin E , Piedbois P , Jouhaud A , Decoster G , Buyse M , on behalf of the European Association for Research in Oncolo
Published: October 2006

Purpose To provide empirical evidence on the impact of on-site initiation visits on the following outcomes: patient recruitment, quantity and quality of data submitted to the trial coordinating office, and patients' follow-up time.

Patients and methods This methodological study was performed as part of a randomized trial comparing two combination chemotherapies for adjuvant treatment of breast cancer. Centers participating to the trial were randomized to either receive systematic on-site visits (Visited group), or not (Non-visited group).

Results The study was terminated after two years, while the main randomized trial continued. Of the 135 centers that had expressed an interest in the trial, only 69 randomized at least one patient (35/68 in the Visited group, 34/67 in the Nonvisited group). Almost two-thirds of the patients were entered by 17 centers (10 in the Visited group, seven in the Non-visited group) that accrued more than 10 patients each. None of the prespecified outcomes favored the group of centers submitted to on-site initiation visits (ie, mean number of queries par patient: 6.1 ± 9.7 versus 5.4 ± 6.4, respectively for the Visited and Non-visited groups). Spontaneous transmittal of case report forms, although required by protocol, was low in both randomized groups (mean number of pages per patient: 1.5 ± 2.0 versus 2.1 ± 2.3, respectively), with investigators submitting about one-third of the expected forms on time (29% and 39%, respectively).

Limitations This study could not evaluate the impact of repeated on-site visits on clinical outcomes.

Conclusion Systematic on-site initiation visits did not contribute significantly to this clinical trial.
Reasons for participation and non-participation in a randomized controlled trial: postal questionnaire surveys of women eligible for TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears)
Authors: Sharp L , Cotton S C , Alexander L , Williams E , Gray N M , Reid J M
Published: October 2006

Background Better understanding of motivators for, and barriers to, participation in randomized controlled trials (RCTs) in different study populations and settings has the potential to improve participation of historically under-represented groups (eg, women) in future trials.

Purpose To investigate reasons why women agreed, or declined, to participate in a RCT.

Methods In two postal questionnaire-based studies, we investigated women's reasons for participation or non-participation in TOMBOLA, a RCT comparing management policies for low-grade cervical abnormalities. Four-hundred and ninety-two TOMBOLA participants (response rate 56%) completed questionnaires on reasons for participation. One-hundred and thiry-seven women (38%) who declined TOMBOLA participation completed questionnaires on reasons for this.

Results Eighty percent of women reported that one of their reasons for attending their TOMBOLA recruitment appointment was worries about their smear result. Ninety-four percent participated in the RCT because it was a worthwhile contribution to the cervical screening programme and other women; for 70% this was the most important reason. These proportions did not vary by socio-demographic factors. Thirty-two percent thought participation would result in better care. The most common reason for non-participation was preference for follow-up from the woman's GP. Logistical issues (eg, inconvenient appointments, travel time, arranging time off work or child-care) were commonly cited. Fourteen percent were too frightened to participate; this was unrelated to the grade of the recruitment smear. Limitations Response rates were not high, but there was little evidence of response bias. Structured questionnaires were used.

Conclusions Future research should address how best to deliver information to ensure different social groups appreciate potential benefits of RCT participation and provide reassurance regarding fears about participation. Simple strategies (eg, appealing to the altruism of potential participants or offering flexible recruitment clinic locations and times) might enhance RCT recruitment rates. This in turn would ensure best use of research resources thus bringing the greatest benefits to participants and the population.
Kamphaugite-(Y) from La Cabrera massif, Spain: a low-temperature hydrothermal Y-REE carbonate
Authors: González del Tánago J. , La Iglesia A. , Delgado A.
Published: October 2006

Kamphaugite-(Y) occurs as white to cream-coloured spherical to semi-spherical aggregates of radial crystals in the La Cabrera granitic pluton (Spanish Central System). It mainly occurs on the free surfaces of alkali feldspar, quartz, calcite, kainosite-(Y) and laumontite, and inside miarolitic cavities. La Cabrera kamphaugite-(Y) has an average composition of Ca0.94Y0.89REE0.21(CO3)2 [F0.05(OH)0.95]·1.19H2O. Negative δ13CV-PDB values (–14 to –15‰) indicate a meteoric carbon source. Textural relations between kamphaugite-(Y) and coexisting minerals, its relatively high δ18OV-SMOW values (+25 to +26‰), and the occurrence of laumontite inclusions in kamphaugite-(Y), point to a genesis at < 50°C during very low-temperature post-magmatic hydrothermal activity.
Sazhinite-(La), Na3LaSi6O15(H2O)2, a new mineral from the Aris phonolite, Namibia: Description and crystal structure
Authors: Cámara F. , Ottolini L. , Devouard B. , Garvie L. A. J. , Hawthorne F. C.
Published: October 2006

Sazhinite-(La) is a new mineral from the Aris phonolite, Windhoek, Namibia. It occurs in vesicles within the phonolite, together with other species crystallized from late-stage hydrothermal fluids: natrolite, aegirine, microcline, apophyllite, sphalerite, analcime, fluorite, villiaumite, hydroxylapatite, galena, makatite, quartz, eudialyte, kanemite, tuperssuatsiaite and korobitsynite. Sazhinite-(La) forms small euhedral crystals up to 1 mm long and 0.4 mm wide, elongated along [001] and flattened on (010), exhibiting the forms {h0l}, {100} and {001}. It has good cleavage parallel to {010} and {001}. Twinning was not observed. Crystals are brittle with a Mohs hardness of 3, creamy white with a white streak, vitreous to pearly lustre, and translucent to transparent. In plane-polarized light, crystals are colourless with a = Z, b = Y, c = X. It is biaxial positive with α = 1.524, β = 1.528, γ = 1.544, all ±0.002, 2Vz(obs) = 46(1)°, and 2Vz(calc.) = 53.6°.

Sazhmite-(La) is orthorhombic Pmm2, a = 7.415(2), b = 15.515(3), c = 7.164(1) Å, and V = 824.2 Å3. One crystal was studied by X-ray diffraction, electron microprobe and secondary ion mass spectrometry (SIMS) microanalysis, leading to the average composition (Na2.87K0.02Sr0.01)Σ2.90 [La0.41Ce0.35Pr0.02Nd0.04(Sm,Gd,Dy,Er,Yb)Σ0.01Th0.09U0.01Y0.01Zr0.01Ca0.08Li0.01]Σ1.04 (S15.87S0.06B0.01) (O14.86F0.14).(H2O)2.

Weighted full-matrix least-squares refinement on 3369 reflections yielded Rall = 3.8%. The structure is built of corrugated [Si6O15]6- layers linked by [7]-coordinated REE and R4+ cations. This framework leaves channels that contain three [5]- and [6]-coordinated Na cations per formula unit that compensate for the residual charge on the silicate layers. The SIMS analyses confirm a Na content of 3 atoms per formula unit, leading to an ideal formula of Na3LaSi6O15(H2O)2. The third Na atom is bonded to H2O groups and therefore the total content of both Na and H2O may be reduced to 2 and 1 per formula, respectively. The depletion in Na allows for the entrance of high-charge cations such as Th4+.
The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules
Authors: Chintala Sreenivasulu , Tan Jian , Gautam Rashi , Rusiniak Michael E. , Guo Xiaoli , Li Wei , Gahl William A. , Huizing Marjan , Spritz Richard A. , Hutton Saunie , Novak Edward K. , Swank Richard T.
Published: October 2006

Platelet dense granules are lysosome-related organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosome-related organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. The platelet-dense granule defect is rescued in BAC transgenic mice containing the normal Slc35d3 gene. Thus, Slc35d3, an orphan member of a nucleotide sugar transporter family, specifically regulates the contents of platelet-dense granules. Unlike HPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency.
ProFAT: a web-based tool for the functional annotation of protein sequences
Authors: Bradshaw Charles Richard , Surendranath Vineeth , Habermann Bianca
Published: October 2006

Background

The functional annotation of proteins relies on published information concerning their close and remote homologues in sequence databases. Evidence for remote sequence similarity can be further strengthened by a similar biological background of the query sequence and identified database sequences. However, few tools exist so far, that provide a means to include functional information in sequence database searches.

Results

We present ProFAT, a web-based tool for the functional annotation of protein sequences based on remote sequence similarity. ProFAT combines sensitive sequence database search methods and a fold recognition algorithm with a simple text-mining approach. ProFAT extracts identified hits based on their biological background by keyword-mining of annotations, features and most importantly, literature associated with a sequence entry. A user-provided keyword list enables the user to specifically search for weak, but biologically relevant homologues of an input query. The ProFAT server has been evaluated using the complete set of proteins from three different domain families, including their weak relatives and could correctly identify between 90% and 100% of all domain family members studied in this context. ProFAT has furthermore been applied to a variety of proteins from different cellular contexts and we provide evidence on how ProFAT can help in functional prediction of proteins based on remotely conserved proteins.

Conclusion

By employing sensitive database search programs as well as exploiting the functional information associated with database sequences, ProFAT can detect remote, but biologically relevant relationships between proteins and will assist researchers in the prediction of protein function based on remote homologies.
A prospective study to assess the value of MMP-9 in improving the appropriateness of urgent referrals for colorectal cancer
Authors: Ryan Angela V , Wilson Sue , Wakelam Michael JO , Warmington Sally A , Dunn Janet A , Hobbs Richard FD , Martin Ashley , Ismail Tariq
Published: October 2006

Background

Bowel cancer is common and is a major cause of death. Most people with bowel symptoms who meet the criteria for urgent referral to secondary care will not be found to have bowel cancer, and some people who are found to have cancer will have been referred routinely rather than urgently. If general practitioners could better identify people who were likely to have bowel cancer or conditions that may lead to bowel cancer, the pressure on hospital clinics may be reduced, enabling these patients to be seen more quickly. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with such conditions, and this can be measured from a blood sample. This study aims to find out whether measuring MMP-9 levels could improve the appropriateness of urgent referrals for patients with bowel symptoms.

Methods

People aged 18 years or older referred to a colorectal clinic will be asked to complete a questionnaire about symptoms, recent injuries or chronic illnesses (these can increase the level of matrix metalloproteinases) and family history of bowel cancer. A blood sample will be taken from people who consent to take part to assess MMP-9 levels, and the results of examination at the clinic and/or investigations arising from the clinic visit will be collected from hospital records. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the resulting diagnosis. The combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined.

Discussion

Although guidelines are in place to facilitate referrals to colorectal clinics, symptoms alone do not adequately distinguish people with malignancy from people with benign conditions. This study will establish whether MMP-9 could assist this process. If this were the case, measurement of MMP-9 levels could be used by general practitioners to assist in the identification of people who were most likely to have bowel cancer or conditions that may lead to bowel cancer, and who should, therefore, be referred most urgently to secondary care.