bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase separation rates of aqueous two‐phase systems: Correlation with system properties
Authors: Asenjo J. A. , Mistry S. L. , Andrews B. A. , Merchuk J. C.
Published: October 2002

The kinetics of phase separation in aqueous two‐phase systems have been investigated as a function of the physical properties of the system. Two distinct situations for the settling velocities were found, one in which the light, organic‐rich (PEG) phase is continuous and the other in which the heavier, salt‐rich (phosphate) phase is continuous. The settling rate of a particular system is a crucial parameter for equipment design, and it was studied as a function of measured viscosity and density of each of the phases as well as the interfacial tension between the phases. Interfacial tension increases with increasing tie line length. A correlation that describes the rate of phase separation was investigated. This correlation, which is a function of the system parameters mentioned above, described the behavior of the system successfully. Different values of the parameters in the correlation were fitted for bottom‐phase‐continuous and top‐phase‐continuous systems. These parameters showed that density and viscosity play a role in the rate of separation in both top continuous‐ and bottom continuous‐phase regions but are more dominant in the continuous top‐phase region. The composition of the two‐phase system was characterized by the tie line length. The rate of separation increased with increasing tie line length in both cases but at a faster rate when the bottom (less viscous) phase was the continuous phase. These results show that working in a continuous bottom‐phase region is advantageous to ensure fast separation. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 217–223, 2002.
Low‐temperature electron microscopy for the study of polysaccharide ultrastructures in hydrogels. II. Effect of temperature on the structure of Ca2+‐alginate beads
Authors: Serp D. , Mueller M. , von Stockar U. , Marison I. W.
Published: October 2002

Calcium alginate beads were thermally treated at temperatures ranging from 25°C to 130°C for periods of up to 30 minutes. Important modifications to the structure of the alginate beads were shown to be a function of the temperature and period of incubation at each temperature. Modifications to the alginate beads included reduction in size, mechanical resistance, and molecular weight cut‐off with increasing temperature and incubation period. Thus, heating 700 μm calcium alginate beads for 20 min at 130°C resulted in a 23% reduction in diameter, 70% increase in mechanical resistance, and 67% reduction in molecular weight cut‐off.

Incubation of calcium alginate beads containing 2 × 106 kDa blue dextran for 20 min at 130°C resulted in no detectable loss of either dye or alginate. This indicates the shrinkage of the beads was due to re‐arrangement of the alginate chains within the beads, coupled with loss of water. This hypothesis was verified by direct visual observation of calcium alginate beads before and after thermal treatment using cryo‐scanning electron microscopy (cryo‐SEM). Unlike other microscopy methods cryo‐SEM offers the advantage of extremely rapid freezing which preserves the original structure of the alginate network. As a result cryo‐SEM is a powerful tool for studies of hydrogel and capsule structure and formation.

Differential scanning calorimetry (DSC) showed that the water entrapped in 2% alginate beads was present in a single state, irrespective of the thermal treatment. This result is attributed to the low alginate concentration used to form the beads. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 253–259, 2002.
Modeling aerobic carbon source degradation processes using titrimetric data and combined respirometric–titrimetric data: Experimental data and model structure
Authors: Gernaey Krist , Petersen Britta , Nopens Ingmar , Comeau Yves , Vanrolleghem Peter A.
Published: October 2002

Experimental data are presented that resulted from aerobic batch degradation experiments in activated sludge with simple carbon sources (acetate and dextrose) as substrates. Data collection was done using combined respirometric–titrimetric measurements. The respirometer consists of an open aerated vessel and a closed non‐aerated respiration chamber for monitoring the oxygen uptake rate related to substrate degradation. The respirometer is combined with a titrimetric unit that keeps the pH of the activated sludge sample at a constant value by addition of acid and/or base. The experimental data clearly showed that the activated sludge bacteria react with consumption or production of protons during aerobic degradation of the two carbon sources under study. Thus, the cumulative amount of added acid and/or base could serve as a complementary information source on the degradation processes. For acetate, protons were consumed during aerobic degradation, whereas for dextrose protons were produced. For both carbon sources, a linear relationship was found between the amount of carbon source added and the amount of protons consumed (in case of acetate: 0.38 meq/mmol) or produced (in case of dextrose: 1.33 meq/mmol) during substrate degradation. A model taking into account substrate uptake, CO2 production, and NH3 uptake for biomass growth is proposed to describe the aerobic degradation of a CxHyOz‐type carbon source. Theoretical evaluation of this model for reference parameters showed that the proton effect due to aerobic substrate degradation is a function of the pH of the liquid phase. The proposed model could describe the experimental observations with both carbon sources. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 741–753, 2002.
Cell‐Surface display of heterologous proteins: From high‐throughput screening to environmental applications
Authors: Chen Wilfred , Georgiou George
Published: October 2002

A variety of expression systems for the display of either short peptides or fully folded proteins on E.coli and, to a lesser extent, on Gram‐positive bacteria have been developed. The expression of proteins on the surface of microbial cells has proved extremely important for numerous applications ranging from combinatorial library screening and protein engineering, to whole cell biocatalysts and adsorbants for bioremediation purposes. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 496–503, 2002.
Influences on registered nurses' decision‐making in cases of suspected child abuse
Authors: Nayda Robyn
Published: October 2002

This paper reports on the factors influencing decision‐making for a group of 10 South Australian community nurses in cases of suspected child abuse. Each nurse participated in a structured interview. The data were organized into themes, using the computer program NUD*IST. Factors having an impact on the nurses' decisions to report included: the type of suspected abuse, making moral judgements and decision‐making, the consequences of reporting, and the impact versus the outcomes of reporting. Most significantly, the community nurses based many of their decisions on their estimation of the kind of intervention likely to be undertaken by children's protection services. Copyright © 2002 John Wiley & Sons, Ltd.
Using the lenses of critically reflective teaching in the community college classroom
Authors: Brookfield Stephen D.
Published: October 2002

Critically reflective teaching asks community college teachers to discover and research the assumptions they make about teaching and learning by using the four lenses available to them: students’ eyes, colleagues’ perceptions, educational literature, and teachers’ autobiographical experiences as learners. Viewing classroom practice through these four lenses helps teachers make more informed judgments and take more informed actions, in community college classrooms.
Cardiac catheterization in morbidly obese patients
Authors: McNulty Patrick H. , Ettinger Steven M. , Field John M. , Gilchrist Ian C. , Kozak Mark , Chambers Charles E. , Gascho Joseph A.
Published: October 2002

The safety and findings of cardiac catheterization and coronary angiography in morbidly obese patients with suspected coronary heart disease (CHD) have not been fully examined in the modern era. From a database of 4,978 patients undergoing diagnostic cardiac catheterization, we identified 110 with morbid obesity (body mass ≥ 145 kg and body mass index ≥ 40 kg/m2). Relative to all the other patients in this database, morbidly obese patients had a lower prevalence of CHD (45% vs. 72%; P < 0.05), reflecting a higher prevalence of false positive noninvasive tests. Overall, noninvasive tests were only 75% sensitive and 39% specific for CHD in this group. Use of radial access (66%) and femoral closure devices (24%) was much more frequent in the morbidly obese cohort. Complications were no more frequent in the morbidly obese group, with major (0 vs. 0.9%) and minor (4.7% vs. 3.5%) adverse outcomes being similar to the rest of the database. We conclude that cardiac catheterization using the radial artery or a femoral closure device is a safe and effective method of evaluating CHD in morbidly obese patients. In contrast, noninvasive testing is frequently not definitive and may be misleading. Cathet Cardiovasc Intervent 2002;56:174–177. © 2002 Wiley‐Liss, Inc.
One core laboratory at two international sites, is that feasible? An inter‐core laboratory and intra‐observer variability study
Authors: Tuinenburg Joan C. , Koning Gerhard , Hekking Ellen , Desjardins Colette , Harel François , Bilodeau Luc , van Weert Anton W.M. , Lespérance Jacques , Reiber Johan H.C.
Published: October 2002

To assess the magnitude of differences in QCA outcomes between two cooperating core laboratories in a single trial, we have carried out an inter‐core laboratory variability study. Two QCA experts at the Montreal Heart Institute and Heart Core Leiden both analyzed 32 lesions (pre‐ and post‐intervention) in accordance with previously agreed upon standard operating procedures. One of the experts analyzed the whole image set twice to determine the intraobserver variability. The inter‐core laboratory differences in the acute gain (n = 31 pairs) are non‐significant. The systematic errors of the individual measurements (n = 63 analyses) show an excellent intraclass correlation coefficient of reliability (>75%), except for the stent length (67.7%). The corresponding random errors are small. In general, the intra‐observer systematic and random errors are both slightly smaller than those for the inter‐core laboratory study. QCA analyses in clinical trials can be carried out in core laboratories at two different locations if and only if highly standardized conditions are maintained. Cathet Cardiovasc Intervent 2002;56:333–340. © 2002 Wiley‐Liss, Inc.
Potential emerging therapeutic strategies to prevent restenosis in the peripheral vasculature
Authors: Schainfeld Robert M.
Published: October 2002

Despite the availability of antiplatelet and antithrombotic therapies, recent advances in catheter and stent technology and improved operator skill, restenosis remains the most frequent problem associated with percutaneous and surgical revascularization interventions for both coronary and peripheral arterial disease. Prevention of restenosis in the coronary vasculature has been demonstrated with cilostazol, trapidil, probucol, tranilast, nitric oxide donors, and clopidogrel. Given the similarities in revascularization procedures and in the pathophysiology of restenosis, it is possible that these results may be extrapolated to the setting of restenosis in the peripheral vasculature, making trials with these agents imperative. Several new agents have shown promising preliminary results for the prevention of restenosis in the peripheral vasculature, including cilostazol, low‐molecular‐weight heparins, and elastase. Several nonpharmacologic treatment modalities are also under study to prevent peripheral and coronary restenosis and have shown favorable initial results. These include endovascular radiation brachytherapy, arterial gene therapy, photoangioplasty, and several novel treatment delivery systems. Cathet Cardiovasc Intervent 2002;56:421–431. © 2002 Wiley‐Liss, Inc.
MRI findings in a case of transient cortical blindness after cardiac catheterization
Authors: Zwicker Jocelyn C. , Sila Cathy A.
Published: October 2002

The magnetic resonance imaging findings in a case of transient cortical blindness (TCB) after cardiac catheterization are described for the first time. In addition, a literature review of TCB, comparison with reversible posterior leukoencephalopathy, and a hypothesis regarding the pathophysiology of TCB are presented. Cathet Cardiovasc Intervent 2002;57:47–49. © 2002 Wiley‐Liss, Inc.
Initial experience with intratherapeutics intrastent doublestrut LD stents in patients with congenital heart defects
Authors: Rutledge Jennifer M. , Mullins Charles E. , Nihill Michael R. , Grifka Ronald G. , Vincent Julie A.
Published: October 2002

Limitations of the currently available balloon‐expandable stainless steel (BE‐SS) stents for use in patients with congenital heart defects (CHD) include inflexibility, significant shortening with expansion, sharp ends, and limited sizes. These limitations increase risk and greatly effect success of stent placement in these patients. The recently approved IntraStent DoubleStrut LD (IS‐LD) stents are BE‐SS stents designed to address such limitations. We report our initial experience with IS‐LD stents in patients with CHD. Using standard techniques, 36 stents were implanted in 22 patients whose median age was 11 years (range, 1.4–35 years) and weight was 33 kg (range, 9–96.8 kg). Lesions stented included aortic coarctation (4), branch pulmonary arteries (19), inferior or superior vena cava (11), Mustard baffle (1), and Fontan baffle (1). All attempts at stent placement were successful. Hemodynamic assessment and angiography was performed pre‐ and poststent placement in all patients. Intravascular ultrasound was performed in four patients. Stenosis diameter increased from 5.7 ± 0.6 mm (mean ± SD) to 11.6 ± 0.5 mm (P < 0.001). Stents did not shorten significantly with dilation (median percent shortening, 3.8%; P > 0.1). Complications included stent recoil (2), stent migration (1), and stent distortion (1). IS‐LD stents are a safe and effective treatment for the majority of vascular stenoses in patients with CHD. Stent recoil at large diameters may limit its usefulness in selected lesions. Follow‐up studies are required to determine the long‐term performance of IS‐LD stents. Cathet Cardiovasc Intervent 2002;56:541–548. © 2002 Wiley‐Liss, Inc.
Catheter closure of perimembranous ventricular septal defects using the new Amplatzer membranous VSD occluder: Initial clinical experience
Authors: Hijazi Ziyad M. , Hakim Fakhri , Haweleh A. Abu , Madani Awni , Tarawna Walid , Hiari Aktham , Cao Qi‐Ling
Published: October 2002

The surgical closure of membranous ventricular septal defects (VSDs) is associated with morbidity and low mortality. Six patients with VSDs located in the membranous part of the ventricular septum underwent an attempt of catheter closure using a new device specifically designed for the membranous septum. Patients ranged in age from 3.5 to 19 years (median, 10.5 years) and in weight from 15 to 45 kg (median, 29 kg). One patient with associated pulmonary valve stenosis had shortness of breath. The median Qp/Qs ratio was 1.6 (range, 1.1–3) and the median left ventricle end‐diastolic dimension (LVEDD) was 44 mm (range, 38–52 mm). The devices were deployed via the femoral vein using 7–8 Fr sheaths. There was immediate complete closure in all patients. One patient developed trivial aortic regurgitation. There were no other complications. The median fluoroscopy time was 15.5 min (range, 10.3–53.4 min). At 24 hr, all patients were doing well. The median LVEDD decreased to 38 mm (range, 34–47 mm). One patient continued to have trace aortic regurgitation. All patients were discharged home after 24 hr. Transcatheter occlusion of membranous VSDs is safe and effective. Further clinical trials are underway to assess the long‐term safety and results. Cathet Cardiovasc Intervent 2002;56:508–515. © 2002 Wiley‐Liss, Inc.
Multivariate methods in pharmaceutical applications
Authors: Gabrielsson Jon , Lindberg Nils‐Olof , Lundstedt Torbjörn
Published: October 2002

This review covers material published within the field of pharmacy in the last five years. Articles concerning experimental design, optimization and applications of multivariate techniques have been published, from factorial designs to multivariate data analysis, and the combination of the two in multivariate design. The number of publications on this topic testifies to the good results obtained in the studies. Much of the published material highlights the usefulness of experimental design, with many articles dealing with optimization, where much effort is spent on getting useful results. Examples of multivariate data analysis are comparatively few, but these methods are gaining in use. The employment of multivariate techniques in different applications has been reviewed. The examples in this review represent just a few of the possible applications with different aims within pharmaceutical applications. A number of companies are using experimental design as a standard tool in preformulation and in combination with response surface modeling. The properties of e.g. a tablet can be optimized to fulfill a well‐specified aim such as a specific release profile, hardness, disintegration time etc. However, none of the companies apply multivariate methods in all steps of the drug development process. As this is still very much a growing field, it is only a question of time before experimental design, optimization and multivariate data analysis are implemented throughout the entire formulation process, from performulation to multivariate process control. Copyright © 2002 John Wiley & Sons, Ltd.
‘Stretch’ vs ‘slice’ methods for representing three‐way structure via matrix notation
Authors: Harshman Richard A. , Hong Sungjin
Published: October 2002

A three‐way array must be represented in two‐way form if its structure is to be described and manipulated by means of matrix notation. Historically, two methods, here called ‘array stretching’ and ‘array slicing’, have been used. More recently, however, array slicing has often been overlooked, resulting in a loss of mathematical flexibility. ‘Stretching’ involves matricizing (unfolding) the three‐way array and applying one's mathematical operations to the resulting two‐way matrix; this results in expressions that are often quite useful for parameter estimation but which are relatively long and require practice to interpret properly. ‘Slicing’ involves taking a representative two‐way subarray and applying operations to it; this often gives compact and easily understood expressions but requires the introduction of extra matrix names and becomes awkward if the array is not ‘slicewise regular’. In this paper the advantages of each approach are demonstrated and compared by applying them to a set of models from the Tucker and Parafac families. In addition, we show how slicewise representation can be improved by using (i) angle brackets to eliminate the need for extra diagonal matrices, and (ii) ‘encapsulated summation’ notation to allow representation of array structure that is orderly but not slicewise regular. Copyright © 2002 John Wiley & Sons, Ltd.
Mixture modelling of medical magnetic resonance data
Authors: Wehrens Ron , Simonetti Arjan W. , Buydens Lutgarde M. C.
Published: October 2002

In clinical decision making, (semi‐)automatic unsupervised classification of data for diagnostic purposes is becoming more and more important. This paper describes the application of mixture modelling, a clustering where multivariate Gaussians are used to describe clusters in the data, toin vivonuclear magnetic resonance data of patients with brain tumours. Images as well as localized spectra are analysed. The method is able to automatically generate meaningful classifications. Moreover, the results of clustering both the image and spectral data are in close agreement. Copyright © 2002 John Wiley & Sons, Ltd.
Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans
Authors: Nicklasson Marie , Björkman Sven , Roth Bodil , Jönsson Maria , Höglund Peter
Published: October 2002

Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)‐ and (S)‐M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)‐ and (S)‐M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl‐L‐tartaric acid anhydride. The metabolism of pentoxifylline to (R)‐M1 in suspensions of hemolysed erythrocytes followed simple Michaelis‐Menten kinetics (Km = 11 mM), while that to (S)‐M1 was best described by a two‐enzyme model (Km = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)‐M1 is 15 times higher than that of the (R)‐enantiomer. Back‐conversion of M1 to pentoxifylline was 3–4 times faster for the (S)‐ than for the (R)‐enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010–0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019–0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)‐enantiomer both in vitro and in vivo. Chirality 14:643–652, 2002. © 2002 Wiley‐Liss, Inc.
Yeast polypeptide chain release factors eRF1 and eRF3 are involved in cytoskeleton organization and cell cycle regulation
Authors: Valouev Igor A. , Kushnirov Vitaly V. , Ter‐Avanesyan Michael D.
Published: October 2002

Termination of translation in eukaryotes is controlled by two interacting polypeptide chain release factors, eRF1 and eRF3. eRF1 recognizes nonsense codons UAA, UAG, and UGA, while eRF3 stimulates polypeptide release from the ribosome in a GTP‐ and eRF1‐dependent manner. In the yeast Saccharomyces cerevisiae, eRF1 and eRF3 are encoded by the SUP45 and SUP35 genes, respectively. Here we show that in yeast shortage of any one of the release factors was accompanied by a reduction in the levels of the other release factor and resulted in a substantial increase of nonsense codon readthrough. Besides, repression of the genes encoding these factors caused different effects on cell morphology. Repression of the SUP35 gene caused accumulation of cells of increased size with large buds. This was accompanied by the disappearance of actin cytoskeletal structures, impairment of the mitotic spindle structure, and defects in nuclei division and segregation in mitosis. The evolutionary conserved C‐terminal domain of eRF3 similar to the elongation factor EF‐1α was responsible for these effects. Repression of the SUP45 gene caused accumulation of unbudded cells with 2C and higher DNA content, indicating that DNA replication is uncoupled from budding. The data obtained suggest that eRF1 and eRF3 play additional, nontranslational roles in the yeast cell. Cell Motil. Cytoskeleton 52:161–173, 2002. © 2002 Wiley‐Liss, Inc.
Distribution of the class II β‐tubulin in developmental and adult rat tissues
Authors: Arai Katsuhiko , Shibutani Makoto , Matsuda Hiroshi
Published: October 2002

During a screen of monoclonal antibodies raised against a cytoskeletal preparation of neonatal rat cerebrum, we have identified a monoclonal antibody, MAb58A, that is specific for the class II β‐tubulin isotype. Immunoscreening of a rat brain cDNA library using MAb58A yielded the cDNA retaining a class II‐specific nucleotide sequence. The specificity of MAb58A to the class II β‐tubulin isotype was confirmed by immunoreactivity to synthetic peptides corresponding to isotype‐specific sequence of class I, II, III, IVa, or IVb. Further, the results of an immunoassay against a series of overlapping octapeptides derived from a class II‐specific region revealed that the antibody epitope was a heptapeptide that consists of Glu‐Glu‐Glu‐Glu‐Gly‐Glu‐Asp (EEEEGED). Immunoblot analysis revealed that the class II isotype represented a significant portion of β‐tubulin present in the adrenal gland, brain, and testis of adult rats. In fetal tissues, this isotype was detected in skeletal muscle, as well as in the brain. Immunohistochemically, MAb58A reacted predominantly with components of the developing rat nervous system, such as migrating neuroblasts, peripheral nerves and ganglion cells, and sensory organs. MAb58A‐immunoreactivity was also found in developing skeletal and smooth muscle cells, chondrocytes, and vascular endothelia. In adults, MAb58A‐immunoreactivity was remarkably diminished, but persisted in peripheral nerves and ganglion cells, chondrocytes, and capillary components. Together, our results demonstrate that MAb58A is specific for the class II β‐tubulin isotype, which may retain an embryonic nature in both neuronal and non‐neuronal tissues. Cell Motil. Cytoskeleton 52:174–182, 2002. © 2002 Wiley‐Liss, Inc.
Characterization of nuclear βII‐tubulin in tumor cells: A possible novel target for taxol
Authors: Xu Keliang , Ludueña Richard F.
Published: October 2002

As the subunits of microtubules, α‐ and β‐tubulins have been thought to only exist in the cytoplasm where they are incorporated into microtubules. However, the βII isotype of tubulin has recently been observed in the nuclei of rat kidney mesangial cells [Walss et al., 1999: Cell Motil. Cytoskeleton 42:274–284]. In this study, we detected nuclear βII‐tubulin in rat C6 glioma cells, human T98G glioma cells, human MCF‐7 breast carcinoma cells, human MDA‐MB‐435 breast carcinoma cells, and human Hela cervix carcinoma cells. In addition, nuclear βII‐tubulin in these cells was found to exist as αβII dimers instead of assembled microtubules and appeared to be particularly concentrated in the nucleoli. Several anti‐tubulin drugs were used to treat C6 cells to determine their influence on nuclear βII‐tubulin. Taxol, a tubulin drug with higher specificity for βII‐tubulin than for other β‐tubulin isotypes, irreversibly decreased nuclear βII content in a concentration‐dependent manner in C6 cells. Meanwhile, cells were found to be apoptotic as was suggested by the presence of multiple micronuclei and DNA fragmentation. On the other hand, no depletion of nuclear βII‐tubulin was observed when C6 cells were incubated with colchicine or nocodazole, two anti‐tubulin drugs with higher specificity for the αβIV isotype, supporting the hypothesis that drugs with higher specificity for βII‐tubulin deplete nuclear βII‐tubulin. Cell Motil. Cytoskeleton 53:39–52, 2002. © 2002 Wiley‐Liss, Inc.
7‐hydroxytryptophan, a novel, specific, cytotoxic agent for carcinoids and other serotonin‐producing tumors
Authors: Walther Diego J. , Peter Jens‐Uwe , Bader Michael
Published: October 2002

BACKGROUND

Carcinoids and small cell lung carcinomas stimulate their growth in an autocrine manner by releasing serotonin, an effect that is blocked by selective serotonergic receptor antagonists that, unfortunately, exert undesirable side effects on serotonergic central nervous function. Moreover, conventional chemotherapeutic agents, such as streptozocin, fluorouracil, cyclophosphamide, and doxorubicin, which target tumor cells directly, have produced disappointing results in the treatment of patients with these tumors in the advanced stage. Therefore, there is still a need for more specific and potent chemotherapeutic agents in the fight against serotonin‐producing tumors.

METHODS

The authors synthesized 7‐hydroxytryptophan to test its chemotherapeutic value in cell culture, using a system consisting of serotonin‐producing and nonproducing cell lines.

RESULTS

The authors chose tryptophan hydroxylase, the rate‐limiting enzyme of serotonin biosynthesis, which is expressed highly in small cell lung carcinomas and carcinoids, as a target for the induction of cellular suicide by chemotherapy. They found that this otherwise substrate specific enzyme was capable of metabolizing in situ a harmless tryptophan analogue, 7‐hydroxytryptophan, to a potent toxin, 5,7‐dihydroxytryptamine, a conversion blocked by the specific tryptophan hydroxylase inhibitor parachlorophenylalanine.

CONCLUSIONS

These data suggest that 7‐hydroxytryptophan may be a highly specific chemotherapeutic compound against serotonin‐producing tumors that also interferes with the autocrine capabilities of serotonin synthesis. Cancer 2002;94:3135–40. © 2002 American Cancer Society.

DOI 10.1002/cncr.10592
Hepatocyte growth factor is associated with poor prognosis of malignant gliomas and is a predictor for recurrence of meningioma
Authors: Arrieta Oscar , Garcia Esperanza , Guevara Patricia , Garcia‐Navarrete Roberto , Ondarza Rodolfo , Rembao Daniel , Sotelo Julio
Published: October 2002

BACKGROUND

Hepatocyte growth factor (HGF) is a cytokine that participates in multiple cell functions; it promotes proliferation, motility, and morphogenesis of epithelial cells. Some malignant tumors, such as breast carcinoma, bronchogenic carcinoma, and multiple myeloma, overexpress it and its receptor. Hepatocyte growth factor is also present in normal astrocytes; therefore, it is important to investigate whether HGF participates in the pathophysiology of malignant gliomas and other brain tumors. Intratumoral concentration of HGF in human intracranial neoplasms was measured and correlated with prognosis, tumor recurrence, vasogenic edema, cell proliferation index, and vascular density.

METHODS

Hepatocyte growth factor concentration was measured in 62 intracranial tumors, including 16 anaplasic astrocytomas (AA), 16 glioblastoma multiformes (GM), 11 meningiomas, 9 hypophyseal adenomas, 7 oligodendrogliomas, and 3 cordomas, and in 4 samples of nonneoplastic brain tissue. The following parameters were correlated with HGF values: survival and tumor recurrence, cell proliferation index and vascular density as determined by immunohistopathologic analysis, and peritumoral edema as seen by magnetic resonance imaging.

RESULTS

Hepatocyte growth factor concentration (pg/mL) was significantly higher in malignant gliomas (AA and GM) than in adenomas, oligodendrogliomas, and nonneoplastic brain tissue, but it was similar to that of meningiomas. Mean survival of patients with AA was 16.5 ± 3.6 months and for patients with GM 12.3 ± 1.3 months. Hepatocyte growth factor concentration was higher in GM than in AA (15,844 ± 2504 vs. 7499 ± 1703, P = 0.0375) and was correlated with the cell proliferation index and with poor prognosis. Likewise, mean tumoral concentration of HGF was higher in meningiomas that relapsed than in those without recurrence (22,887 ± 6489 vs. 2090 ± 497, P = 0.008).

CONCLUSIONS

Intratumoral concentration of HGF in gliomas is associated with malignancy and poor prognosis. High HGF is also found in meningiomas and is related with long term recurrence. The current findings suggest that the routine measurement of HGF may be used as a predictive factor for planning therapeutic strategies in both malignant gliomas and meningiomas. The potential use of HGF inhibitors or antagonists for therapy of these tumors should be explored. Cancer 2002;94:3210–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10594
Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis
Authors: Ando Eiji , Tanaka Masatoshi , Yamashita Fumihiko , Kuromatsu Ryoko , Yutani Shigeru , Fukumori Kazuta , Sumie Shuji , Yano Yoichi , Okuda Koji , Sata Michio
Published: October 2002

BACKGROUND

The prognosis of patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor. The aim of this study was to elucidate the efficacy of hepatic arterial infusion chemotherapy (HAIC) for patients with advanced HCCs.

METHODS

Forty‐eight HCC patients with PVTT were treated by HAIC via a subcutaneously implanted injection port. Of these, 14 had PVTT in the second portal branch and 34 patients had PVTT in the first portal branch or in the main portal trunk. One course of chemotherapy consisted of daily cisplatin (7 mg/m2 for 1 hour on Days 1–5) followed by 5‐fluorouracil (170 mg/m2 for 5 hours on Days 1–5). Patients were scheduled to receive four serial courses of HAIC. Responders were defined as having either a complete response (CR) or partial response (PR) and nonresponders were defined as exhibiting stable disease or progressive disease. The prognosis after HAIC and factors related to survival were analyzed.

RESULTS

Following HAIC, 4 and 19 patients exhibited a CR and PR, respectively (response rate = 48%). The 1, 2, 3, and 5‐year cumulative survival rates of 48 patients treated with HAIC were 45%, 31%, 25%, and 11%, respectively. Median survival periods for 23 responders and 25 nonresponders were 31.6 (range, 8.3–76.9) months and 5.4 (1.9–29.0) months, respectively. Therapeutic effect (P < 0.001) and hepatic reserve capacity (P = 0.021) were identified as significant prognostic factors by univariate analysis. Multivariate analysis identified only therapeutic effect as being significantly related to survival.

CONCLUSIONS

HAIC using low‐dose cisplatin and 5‐fluorouracil may be a useful therapeutic option for patients with advanced HCC with PVTT. HCC patients with PVTT who respond to HAIC could certainly have survival benefits. Cancer 2002;95:588–95. © 2002 American Cancer Society.

DOI 10.1002/cncr.10694
Standards of care for anemia management in oncology
Authors: Langer Corey J. , Choy Hak , Glaspy John A. , Colowick Alan
Published: October 2002

BACKGROUND

Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum‐based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally.

METHODS

A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment.

RESULTS

The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50–60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin‐α]). Darbepoetin‐α represents a new generation of erythropoiesis‐stimulating proteins. Biochemically distinct from epoetin‐α, darbepoetin‐α has a greater sialic acid content and biologic half‐life than epoetin‐α, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer‐related anemia have shown that darbepoetin‐α has a threefold longer half‐life than epoetin‐α, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin‐α in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting.

CONCLUSIONS

Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin‐α into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer‐related anemia. Cancer 2002;95:613–23. © 2002 American Cancer Society.

DOI 10.1002/cncr.10712
Hepatocellular carcinoma in elderly patients
Authors: Teratani Takuma , Ishikawa Takashi , Shiratori Yasushi , Shiina Shuichiro , Yoshida Haruhiko , Imamura Masatoshi , Obi Shuntaro , Sato Shinpei , Hamamura Keisuke , Omata Masao
Published: October 2002

BACKGROUND

The age of patients with hepatocellular carcinoma (HCC) has been increasing worldwide. The objective of this study was to assess the efficacy and safety of percutaneous ethanol injection therapy (PEIT) in elderly patients with HCC.

METHODS

The authors retrospectively analyzed 653 patients who were treated with PEIT between 1985 and 1997. One hundred thirty‐seven patients were age ≥ 70 years, 90 of 137 patients (66%) were male, and 106 of 137 patients (77%) were positive for hepatitis C virus antibodies. Both survival rates and standardized mortality ratios (SMRs) related to the causes of death were compared between patients age ≥ 70 years and patients age < 70 years.

RESULTS

With the exception of greater maximum tumor size in elderly patients age ≥ 70 years, the clinical features of tumors and underlying liver disease were similar to those of patients age < 70 years The survival rates after PEIT in patients age ≥ 70 years were 83%, 52%, and 27% at 1 year, 3 years, and 5 years, respectively. These results were comparable to the rates for patients age < 70 years (1 year, 90%; 3 years, 65%; and 5 years, 40%). In addition, there was no difference in mortality from extrahepatic disease between the two groups (9.8% for patients age ≥ 70 years vs. 9.4% for patients age < 70 years; P > 0.999). The SMR of patients age ≥ 70 years who died of causes related to extrahepatic disease (SMR, 0.56; 95% confidence interval [95%CI], 0.18–1.30) was lower compared with the SMR of patients age < 70 years (SMR, 1.75; 95%CI, 1.07–2.71). The SMR of patients age ≥ 70 years who died of causes related to liver disease (SMR, 115; 95%CI, 84.1–153.0) was similar to that of patients age < 70 years (SMR, 120; 95%CI, 103.0–138.0).

CONCLUSIONS

These results provide support for the treatment of patients with HCC age ≥ 70 years by tumor ablation using PEIT. Cancer 2002;95:816–23. © 2002 American Cancer Society.

DOI 10.1002/cncr.10735
Provider case volume and outcome in the evaluation and treatment of patients with mammogram‐detected breast carcinoma
Authors: McKee Mark D. , Cropp Michael D. , Hyland Andrew , Watroba Nancy , McKinley Brian , Edge Stephen B.
Published: October 2002

BACKGROUND

Practice volume may affect the outcome of patients with breast carcinoma. Defining factors that influence the relation of volume and outcome for the diagnosis and treatment of breast carcinoma is important, because breast carcinoma is common, and care is decentralized.

METHODS

Community‐wide diagnosis and treatment of mammogram‐detected breast carcinoma was examined using claims data from a single insurer representing 25% of the regional population. Among 1001 mammogram‐directed breast biopsies, the rate of breast carcinoma diagnosed by stereotactic core needle biopsy (SCNB) or excisional biopsy with needle localization (EBNL) and the rate at which breast‐conserving surgery (BCS) was used were analyzed. Outcome and practice volume were examined for surgeons, radiologists, and medical centers.

RESULTS

Two hundred twenty‐four tumors were diagnosed by EBNL (604 diagnoses) and SCNB (397 tumors), for a 22.4% positive biopsy rate. The median number of procedures per physician was one. Positive biopsy rates for radiologists, surgeons, and medical centers did not correlate with practice volume. Positive biopsy rates for high‐volume physician providers and medical centers ranged from 9% to 46%. The BCS rate was 45% and 64% for surgeons treating one or more than one claim, respectively. Tumor stage and surgeon case volume were the only independent predictors of BCS (P < 0.05).

CONCLUSIONS

There is wide variation in diagnosis and treatment outcomes for patients with mammogram‐detected breast carcinoma. Overall, practice volume was correlated with the use of BCS but not with the rate of positive biopsy. A wide variation in the positive biopsy rate among high‐volume providers and medical centers suggests that volume of practice is not a surrogate for quality in the diagnosis of breast carcinoma. Cancer 2002;95:704–12. © 2002 American Cancer Society.

DOI 10.1002/cncr.10737
Nitric oxide synthase histochemistry in insect nervous systems: Methanol/formalin fixation reveals the neuroarchitecture of formaldehyde‐sensitive NADPH diaphorase in the cockroach Periplaneta americana
Authors: Ott Swidbert R. , Elphick Maurice R.
Published: October 2002

Formaldehyde‐insensitive NADPH diaphorase (NADPHd) activity is used widely as a histochemical marker for neuronal nitric oxide synthase (NOS). However, in several insects including the cockroach Periplaneta americana, NOS is apparently formaldehyde‐sensitive; NADPHd fails to reveal neuron morphology and results in faint generalized staining. Here we have used a novel fixative, methanol/ formalin (MF), to reveal for the first time the neuroarchitecture of NADPHd in the cockroach, with intense selective staining occurring in neurons throughout the brain and thoracic ganglia. Immunocytochemical and histochemical analysis of cockroach and locust nervous systems indicated that neuronal NADPHd after MF fixation can be attributed to NOS. However, NADPHd in locust glial and perineurial cells was histochemically different from that in neurons and may thus be due to enzymes other than NOS. Histochemical implications of species‐specific enzyme properties and of the transcriptional complexity of the NOS gene are discussed. The present findings suggest that MF fixation is a valuable new tool for the comparative analysis of the neuroarchitecture of NO signaling in insects. The Golgi‐like definition of the staining enabled analysis of the NADPHd architecture in the cockroach and comparison with that in the locust. NADPHd in the tactile neuropils of the thoracic ganglia showed a similar organization in the two species. The olfactory glomeruli of the antennal lobes were in both species densely innervated by NADPHd‐positive local interneurons that correlated in number with the number of glomeruli. Thus, the NADPHd architectures appear highly conserved in primary sensory neuropils. In the cockroach mushroom bodies, particularly dense staining in the γ‐layer of the lobes was apparently derived from Kenyon cells, whereas extrinsic arborizations were organized in domains across the lobes, an architecture that contrasts with the previously described tubular compartmentalization of locust mushroom bodies. These divergent architectures may result in different spatiotemporal dynamics of NO diffusion and suggest species differences in the role of NO in the mushroom bodies. J. Comp. Neurol. 448:165–185, 2002. © 2002 Wiley‐Liss, Inc.
γ‐Aminobutyric acidB receptors and the development of the ventromedial nucleus of the hypothalamus
Authors: Davis Aline M. , Henion Timothy R. , Tobet Stuart A.
Published: October 2002

γ‐Aminobutyric acid (GABA) is a highly abundant neurotransmitter in the brain and the ligand for GABAA, GABAB, and GABAC receptors. Unlike GABAA and GABAC receptors, which are chloride channels, GABAB receptors are G‐protein linked and alter cell‐signaling pathways. Electrophysiological studies have found GABAB receptors in cultured embryonic hypothalamus, but the distribution of these receptors remains unknown. In the present study, we examined the expression of GABAB receptors in the ventromedial nucleus of the hypothalamus (VMH) during embryonic mouse development. GABAB receptors were present in the VMH at all ages examined, from embryonic day 13 to postnatal day 6. Using a brain slice preparation, we examined the effect of GABAB receptor activation on cell movement in the embryonic VMH as the nucleus forms in vitro. The GABAB receptor agonist baclofen decreased the rate of cell movement in a dose‐dependent manner. Baclofen reduced cell movement by up to 56% compared with vehicle‐treated controls. The percentage of cells moving per field and the angles of cell movement were not affected. With our previous findings of GABAA receptor activation, it is likely that GABA influences VMH development via multiple mechanisms. J. Comp. Neurol. 449:270–280, 2002. © 2002 Wiley‐Liss, Inc.
Pulvinar and other subcortical connections of dorsolateral visual cortex in monkeys
Authors: Weller Rosalyn E. , Steele Gregory E. , Kaas Jon H.
Published: October 2002

The present study used injections of neuroanatomical tracers to determine the subcortical connections of the caudal and rostral subdivisions of the dorsolateral area (DL) and the middle temporal crescent area (MTC) in owl monkeys (Aotus trivirgatus), squirrel monkeys (Saimiri sciureus), and macaque monkeys (Macaca fascicularis and M. radiata). Emphasis was on connections with the pulvinar. Patterns of corticopulvinar connections were related to subdivisions of the inferior pulvinar (PI) defined by histochemical or immunocytochemical architecture. Connections of DL/MTC were with the PI subdivisions, PICM, PICL, and PIp; the lateral pulvinar (PL); and, more sparsely, the lateral portion of the medial pulvinar (PM). In squirrel monkeys, there was a tendency for caudal DL to have stronger connections with PICL than PICM and for rostral DL/MTC to have stronger connections with PICM than PICL. In all three primates, DL/MTC had reciprocal connections with the pulvinar and claustrum; received afferents from the locus coeruleus, dorsal raphe, nucleus annularis, central superior nucleus, pontine reticular formation, lateral geniculate nucleus, paracentral nucleus, central medial nucleus, lateral hypothalamus, basal nucleus of the amygdala, and basal nucleus of Meynert/substantia innominata; and sent efferents to the pons, superior colliculus, reticular nucleus, caudate, and putamen. Projections from DL/MTC to the nucleus of the optic tract were also observed in squirrel and owl monkeys. Similarities in the subcortical connections of the dorsolateral region, especially those with the pulvinar, provide further support for the conclusion that the DL regions are homologous in the three primate groups. J. Comp. Neurol. 450:215–240, 2002. © 2002 Wiley‐Liss, Inc.