bluuebunny/crossref_metadata_2025 huggingface dataset:
From fins to limbs to fins: Limb evolution in fossil marine reptiles
Authors: Caldwell Michael W.
Published: October 2002

Limb osteology and ontogenetic patterns of limb ossification are reviewed for extinct lineages of aquatically adapted diapsid reptiles. Phylogenies including these fossil taxa show that paddle‐like limbs were independently derived, and that the varied limb morphologies were produced by evolutionary modifications to different aspects of the limb skeleton. Ancient marine reptiles modify the limb by reducing the relative size of the epipodials, modifying the perichondral and periosteal surface of elements distal to the propodials, and evolving extremes of hyperphalangy and hyperdactyly. Developmental genetic models illuminate gene systems that may have controlled limb evolution in these animals. © 2002 Wiley‐Liss, Inc.
Impact of industrialization: Comparative study of child health in four sites from medieval and postmedieval England (A.D. 850–1859)
Authors: Lewis Mary E.
Published: October 2002

The morbidity and mortality profiles of 831 non‐adult skeletons from four contrasting sites in medieval and postmedieval England were compared to assess whether urbanization and later industrialization, had a detrimental effect on the health of the inhabitants. Failure in the population's ability to adapt to these environments should be evident in the higher rates of mortality, retarded growth, higher levels of stress, and a greater prevalence of metabolic and infectious disease in the urban groups. Non‐adult skeletons were examined from Raunds Furnells in Northamptonshire, from St. Helen‐on‐the‐Walls and Wharram Percy in Yorkshire, and from Christ Church Spitalfields in London. Results showed that a greater number of older children were being buried at the later medieval sites and that the skeletal growth profiles of the medieval urban and rural children did not differ significantly. A comparison of the growth profiles of St. Helen‐on‐the‐Walls (urban) and Spitalfields (industrial) showed that the Spitalfields children were up to 3 cm shorter than their later medieval counterparts. At Spitalfields, cribra orbitalia and enamel hypoplasias occurred during the first 6 months of life, and 54% of the non‐adults had evidence of metabolic disease. It is argued that differences in the morbidity and mortality of non‐adults from urban and rural environments did exist in the past, but that it was industrialization that had the greatest impact on child health. Environmental conditions, urban employment, socioeconomic status, and changes in weaning ages and infant feeding practices contributed to differences in health in rural, urban, and industrial environments. Am J Phys Anthropol 119:211–223, 2002. © 2002 Wiley‐Liss, Inc.
Assessment of different treatment failure criteria in a cohort of relapsing–remitting multiple sclerosis patients treated with interferon β: Implications for clinical trials
Authors: Río Jordi , Nos Carlos , Tintoré Mar , Borrás Cecilia , Galán Ingrid , Comabella Manuel , Montalban Xavier
Published: October 2002

Clinical trials with interferons in relapsing–remitting multiple sclerosis have shown a modest effect on disability using fixed definitions of treatment failure to measure disease progression. However, in the course of the disease, treatment failure may be influenced by interrater variability and frequent remissions. Thus, the purpose of this study was to assess the clinical usefulness of different treatment failure criteria in a cohort of relapsing–remitting multiple sclerosis patients treated with interferon β. We studied 252 patients with a follow‐up of more than 2 years. We used four different criteria of treatment failure with increasing stringency (1 Expanded Disability Status Scale [EDSS] point increase confirmed at 3 months, 1 EDSS point increase confirmed at 6 months, 1.5 EDSS points increase confirmed at 3 months, and 1.5 EDSS points increase confirmed at 6 months). We divided treatment failure into permanent treatment failure and transient treatment failure. We considered permanent treatment failure when treatment failure was confirmed on the last two scheduled visits and transient treatment failure when treatment failure was not confirmed on these visits at different time points (9, 12, 18, and 24 months). We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the different criteria of treatment failure to identify patients who achieved a high degree of disability after 4 years of follow‐up. Regardless of the stringency of treatment failure definitions, a variable proportion of patients with treatment failure had transient treatment failure depending on the criterion applied. Patients with transient treatment failure had a significantly lower EDSS at entry compared with those with permanent treatment failure or no treatment failure. The number of relapses in patients with transient treatment failure did not differ from that of patients with permanent treatment failure. The criterion of confirmed 1 EDSS point increase at 6 months showed the best sensitivity (76.5%), with satisfactory specificity (89%). Our study shows that a large proportion of patients treated with interferon experience transient treatment failure that may affect outcome interpretation in clinical trials. Using a more strict criterion, as extending time to confirmation of EDSS deterioration, and longer follow‐up may reduce this proportion of patients with transient treatment failure and improve the validity of the results attained in clinical trials.
Imaging the metabolic footprint of Glut1 deficiency on the brain
Authors: Pascual Juan M. , van Heertum Ronald L. , Wang Dong , Engelstad Kristin , De Vivo Darryl C.
Published: October 2002

Cerebral 18F‐fluorodeoxyglucose positron emission tomography in 14 patients with microcephaly, developmental delay, seizures, and mutations of the glucose transporter Glut1 (Glut1 deficiency syndrome) showed distinct abnormalities. Within a global context of diminished cortical uptake, more severe hypometabolism was found in the mesial temporal regions and thalami, accentuating a relative signal increase in the basal ganglia. In contrast, the structure of the brain appeared preserved in patients additionally investigated by magnetic resonance imaging. This metabolic footprint was relatively constant in all patients regardless of age, seizure history, or therapies and therefore constitutes a radiological signature of the disease. The full expression of the signature in the youngest patient (aged 19 months) indicates that the state of haploinsufficiency caused by Glut1 mutation leaves a permanent footprint on the nervous system from its earlier postnatal stages of development. The potential benefit of prompt diagnosis, aided by 18F‐fluorodeoxyglucose positron emission tomography, and early initiation of available therapies is underscored by our results.
Involvement of lysosomes in the pathogenesis of CAG repeat diseases
Authors: Yamada Mitsunori , Tsuji Shoji , Takahashi Hitoshi
Published: October 2002

In CAG repeat diseases, affected neurons possess many cytoplasmic granules immunopositive for expanded polyglutamine stretches. Electron microscopic immunohistochemistry showed that the granules corresponded to lysosomes of primitive type. The results suggest that, in addition to the ubiquitin/proteasome pathway, mutant proteins with expanded polyglutamine stretches are involved in the lysosomal pathway for protein degradation and that this processing mechanism may serve as a target for a new therapeutic approach to CAG repeat diseases.
Photodegradation of thermoplastic elastomeric rubber–polyethylene blends
Authors: Bhowmick Anil K , Heslop J. , White J. R.
Published: October 2002

The photodegradation of a new family of thermoplastic elastomers, based on blends of natural rubber and polyethylene, was studied with laboratory ultraviolet exposures in the unstrained state and under tensile strain (25 and 50%). Strained exposure caused reduction of the strain to failure in subsequent tensile tests. The blends were more resistant to degradation than the natural rubber homopolymer. The introduction of crosslinks (at a low concentration so that the thermoplastic nature of the blends was retained) changed the resistance to photo‐oxidation. Two different crosslinking systems were used. When dicumyl peroxide was used as the crosslinking agent, the resistance to degradation was reduced, whereas the compound containing a sulfur curing system showed improved resistance to photodegradation. Photo‐oxidation rather than ozone degradation was found to be the major cause of breakdown, even with samples held in tension. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2393–2402, 2002
Rheological and morphological properties of high‐density polyethylene and poly(ethylene–octene) blends
Authors: Guimarães Maria José O. C. , Coutinho Fernanda M. B. , Rocha Marisa C. G. , Farah Marcelo , Bretas Rosário E. S.
Published: October 2002

The rheological and morphological properties of blends based on high‐density polyethylene (HDPE) and a commercial ethylene–octene copolymer (EOC) produced by metallocene technology were investigated. The rheological properties were evaluated in steady and dynamic shear experiments at 190°C in shear rates ranging from 90 s−1 to 1500 s−1 and frequency range between 10−1 rad/s and 102 rad/s, respectively. These blends presented a high level of homogeneity in the molten state and rheological behavior was generally intermediate to those of the pure components. Scanning electron microscopy (SEM) showed that the blends exhibit dispersed morphologies with EOC domains distributed homogeneously and with particle size inferior to 2 μm. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2240–2246, 2002
Effects of reprocessing on the structure and mechanical properties of poly(trimethylene terephthalate)
Authors: Ramiro J. , Eguiazábal J. I. , Nazábal J.
Published: October 2002

The effects of reprocessing by extrusion for up to four cycles on the structure and mechanical properties of poly(trimethylene terephthalate) (PTT) were studied. Reprocessing did not change the chemical structure of the polymer but led to both yellowing and molecular weight reduction. Young's modulus and the yield stress of PTT remained constant or decreased with successive extrusion cycles, probably because of the observed slight specific volume increase. The continuous reduction in the break properties due to reprocessing was smaller than that found in similar polyesters and was attributed to the molecular weight reduction. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2775–2780, 2002
Preparation and properties of polyamide 6/polypropylene–vermiculite nanocomposite/polyamide 6 alloys
Authors: Tjong S. C. , Meng Y. Z. , Xu Y.
Published: October 2002

Polypropylene–vermiculite nanocomposites can be achieved by simple melt mixing of maleic anhydride‐modified vermiculite with polypropylene. Maleic anhydride acts either as a compatibilizer for the polymeric matrix or as a swelling agent for the silicate. Compatibilized blends are injection molded directly from polyamide 6 and polypropylene–vermiculite nanocomposites. Scanning electron microscopy observation reveals that a two‐phase structure consisting of polypropylene–vermiculite nanocomposite and polyamide 6 is formed in the blends. The absence of vermiculite reflections in the X‐ray powder diffraction patterns indicates that the polypropylene–vermiculite phase exhibits nanocomposite characteristics. Tensile test shows that the tensile modulus of the polymer alloy tends to increase with increasing polypropylene–vermiculite nanocomposite content. The tensile strength of composite containing 8 wt % vermiculite is higher than that of pure polyamide 6. Finally, the thermal properties of the nanocomposites are determined by dynamic mechanical analysis, differential scanning calorimetry, and thermogravimetric measurements. The effects of maleic anhydride addition on the formation of polypropylene–vermiculite nanocomposite reinforcement and on the mechanical properties of composites are discussed. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2330–2337, 2002
Synthesis of amine‐cured, epoxy‐layered silicate nanocomposites: The influence of the silicate surface modification on the properties
Authors: Kornmann Xavier , Thomann Ralph , Mülhaupt Rolf , Finter Jürgen , Berglund Lars
Published: October 2002

Fluorohectorites were rendered organophilic through the cation exchange of sodium intergallery cations for protonated monoamine, diamine, and triamine oligopropyleneoxides and octadecylamine, benzylamine, and adducts of octadecylamine and benzylamine with diglycidyl ether of bisphenol A (DGEBA). The influence of the silicate surface modification and compatibility on the morphology and thermal and mechanical properties was examined. Surface modification with protonated octadecylamine and its adduct with DGEBA promoted the formation of microscale domains of silicate layers separated by more than 50 Å, as evidenced by transmission electron microscopy and wide‐angle X‐ray scattering. Young's modulus of these two nanocomposites increased parabolically with the true silicate content, whereas conventionally filled composites exhibited a linear relationship. The highest fracture toughness was observed for conventionally filled composites. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2643–2652, 2002
Differences in expectations of outcome mediate African American/white patient differences in “willingness” to consider joint replacement
Authors: Ibrahim Said A. , Siminoff Laura A. , Burant Christopher J. , Kwoh C. Kent
Published: October 2002

Objective

Joint replacement therapy is an effective treatment option for end‐stage osteoarthritis (OA) of the knee and/or hip. There are marked racial/ethnic disparities in the utilization of this procedure. The reasons for these disparities are not known. We sought to determine whether African American patients differ from white patients in their “willingness” to consider joint replacement and to determine the factors that influence this relationship.

Methods

We performed a cross‐sectional survey of 596 elderly, male, African American or white patients with moderate‐to‐severe symptomatic knee or hip OA who were receiving primary care at the Department of Veterans Affairs outpatient clinics.

Results

The groups were similar with respect to age, severity of arthritis measured by the Lequesne Scale and the Western Ontario and McMaster Universities Osteoarthritis Index, and scores on the Charlson Comorbidity Index and Geriatric Depression Scale. Compared with whites, African Americans were less likely to be employed or married or to have attained a high school education, but were more likely to report a median annual household income of <$10,000. They were also less likely than whites to be familiar with joint replacement and more likely to expect a longer duration of hospital course, pain, and functional disability following replacement surgery. African American patients were less “willing” than white patients to consider joint replacement (odds ratio 0.50, 95% confidence interval 0.30–0.84). However, this difference was explained by the between‐group differences in expectations.

Conclusion

African American patients were less likely than white patients to express “willingness” to consider joint replacement if the procedure was needed and recommended. This difference was explained by differences between the groups in their expectations of hospital course, pain, and function following replacement surgery.
Regression to the mean and football wagers
Authors: Lee Marcus , Smith Gary
Published: October 2002

Football performances are an imperfect measure of abilities, and consequently exaggerate differences in abilities. The skills of those football teams that perform the best and the worst are not really that far from average; thus their future performances regress to the mean. Betting data indicate that gamblers do not fully account for this regression. Copyright © 2002 John Wiley & Sons, Ltd.
Good fungi gone bad: The corruption of calcineurin
Authors: Fox Deborah S. , Heitman Joseph
Published: October 2002

Calcineurin is a Ca2+/calmodulin‐activated protein phosphatase that is conserved in eukaryotes, from yeast to humans, and is the conserved target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. Genetic studies in yeast and fungi established the molecular basis of calcineurin inhibition by the cyclophilin A–CsA and FKBP12–FK506 complexes. Calcineurin also functions in fungi to control a myriad of physiological processes including cell cycle progression, cation homeostasis, and morphogenesis. Recent investigations into the molecular mechanisms of pathogenesis in Candida albicans and Cryptococcus neoformans, two fungi that cause life‐threatening infections in humans, have revealed an essential role for calcineurin in morphogenesis, virulence, and antifungal drug action. Novel non‐immunosuppressive analogs of the calcineurin inhibitors CsA and FK506 that retain antifungal activity have been identified and hold promise as candidate antifungal drugs. In addition, comparisons of calcineurin function in both fungi and humans may identify fungal‐specific components of calcineurin‐signaling pathways that could be targeted for therapy, as well as conserved elements of calcium signaling events. BioEssays 24:894–903, 2002. © 2002 Wiley Periodicals, Inc.
The one‐bead two‐compound assay for solid phase screening of combinatorial libraries
Authors: Meldal Morten
Published: October 2002

Fluorescent quenched substrate libraries are a very powerful tool for investigation of protease activity and specificity. Particularly, libraries where the fluorescent resonance energy transfer (FRET) pair is 3‐nitrotyrosine and 2‐amino‐benzamide are easy to prepare by split and combine synthesis to yield a one‐bead one‐compound library format. The solid support is critical for the successful hydrolysis of the resin‐bound substrates. For this purpose, a range of highly porous poly(ethylene glycol) (PEG)‐based resins have been developed. Active substrates yield highly fluorescent beads and these are selected under a fluorescence microscope or isolated on a bead sorter. Edman sequence analysis yields the substrate sequence, the cleavage point, and the degree of conversion. The method gives a complete map of the substrate specificity, and substrates with high affinity for the active site can be selected. These may in turn be used as inhibition indicators in a second solid phase library assay for enzyme inhibition where each single bead is transformed into an assay container. The substrate is attached to temporarily shielded functional groups after completion of inhibitor library synthesis. By using a photolabile linker and ladder synthesis, the active inhibitors may be rapidly identified by mass spectrometry. In each bead, the putative inhibitor competes with the substrate attached for binding to the enzyme, and when the inhibitor binds strongly, the substrate remains intact and quenched. Thus dark beads indicate inhibitors, and these may be isolated using a bead‐sorter and the structure determined by mass spectrometry. A selection of the best substrates and inhibitors should always be resynthesized for solution kinetics and confirmation of the results obtained on solid support. The inhibitor assay is almost free from false positives, which is a consequence of combining the binding of the protease to the inhibitor with observation of activity toward a FRET substrate. The Ki of the identified inhibitors are typically in the nM range. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 93–100, 2002
Multiblock PLS analysis of an industrial pharmaceutical process
Authors: Lopes J.A. , Menezes J.C. , Westerhuis J.A. , Smilde A.K.
Published: October 2002

The performance of an industrial pharmaceutical process (production of an active pharmaceutical ingredient by fermentation, API) was modeled by multiblock partial least squares (MBPLS). The most important process stages are inoculum production and API production fermentation. Thirty batches (runs) were produced according to an experimental planning. Rather than merging all these data into a single block of independent variables (as in ordinary PLS), four data blocks were used separately (manipulated and quality variables for each process stage). With the multiblock approach it was possible to calculate weights and scores for each independent block. It was found that the inoculum quality variables were highly correlated with API production for nominal fermentations. For the nonnominal fermentations, the manipulations of the fermentation stage explained the amount of API obtained (especially the pH and biomass concentration). Based on the above process analysis it was possible to select a smaller set of variables with which a new model was built. The amount of variance predicted of the final API concentration (cross‐validation) for this model was 82.4%. The advantage of the multiblock model over the standard PLS model is that the contributions of the two main process stages to the API volumetric productivity were determined. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 419–427, 2002.
Transcriptional regulation of gene expression by the coding sequence: An attempt to enhance expression of human AChE
Authors: Weill Claire O. , Vorlová Sandra , Berna Nathalie , Ayon Annick , Massoulié Jean
Published: October 2002

In a previous report, Morel and Massoulié showed that Bungarus AChE (bBAChE) is produced more efficiently than rat AChE in various expression systems, mainly because the Bungarus coding sequence exerts a stimulatory effect on transcription (Morel and Massoulié, 2000). They reported that a 5′ Bungarus fragment could partially transfer this property to a CAT expression vector. This appeared to offer the possibility of increasing the production of recombinant proteins. In the present paper, we show that insertion of this fragment in the transcribed region, before the polyadenylation site, may have either stimulatory or inhibitory effects, depending on the vector and on the reporter gene. Since the stimulatory effect of Bungarus coding region could not be attached to a small number of discrete motifs, we reasoned that it might result from a general feature of the sequence. Therefore it might be possible to partially transfer this property to the very homologous human AChE (hHAChE) coding sequence by modifications based on synonymous codons, which increased nucleotide identity between the 5′ fragment (721 nucleotides) of bBAChE and hHAChE from 71% to 85%. The production of human AChE in transfected COS cells was increased nearly 2‐fold with this modified construct, but still remained about 4‐fold smaller than that of Bungarus AChE. There was no change in expression level in transformed Pichia pastoris. We thus confirm that coding sequences can strongly influence gene expression, but in a manner that depends on the context and cannot yet be predicted. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 490–497, 2002.
Modeling acidogenic and sulfate‐reducing processes for the determination of fermentable fractions in wastewater
Authors: Ruel S. Martin , Comeau Y. , Ginestet P. , Héduit A.
Published: October 2002

The biochemical acidogenic potential (BAP) of a wastewater is the maximum concentration of volatile fatty acids (VFAs) that can be measured at the end of an anaerobic fermentation test. A model was constructed to describe the acidogenic reactions occurring during BAP tests and to divide the BAP into organic fractions. The model was calibrated with a set of specific experiments highlighting the role of sulfate‐reducing bacteria on acidogenic processes, which description was necessary for correct parameter identification. The model could describe acidogenic fermentation processes, with or without sulfate reduction, at 20°C, for 13 wastewaters of different origin, composition, and settleability using the same optimized parameters. A simplified version of the model, without sulfate reduction, was able to describe VFA production by the adjustment of only three variables: readily fermentable organic matter (Sf), anaerobically hydrolyzable organic matter (Xf), and heterotrophic acidogenic biomass (Xha), which proved to be coherent with the experimental BAP value. The combination of the BAP test and the model developed in this study resulted in a new reliable tool to characterize wastewater under anaerobic conditions. As VFAs are the main substrates for phosphate‐accumulating organisms (PAOs), the use of organic fractions VFA, Sf, Xf, and Xha in wastewater treatment plant modeling could improve the predictability and optimization of enhanced biological phosphorus removal (EBPR) processes. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 525–536, 2002.
Modeling of the controlled expression of a harmful protein by a three‐plasmid harboring system
Authors: Unzaga T. V. , Díaz‐Ricci J. C. , Rhee J. I. , Hernández M. R. , Schügerl K.
Published: October 2002

A genetically structured mathematical model was developed and used to evaluate the influence of molecular parameters involved in the expression of a harmful recombinant protein (SPA::EcoRI). The system consists of the controlled expression of the endonuclease EcoRI cloned in the plasmid pMTC48. The control is exerted by the lambda CI repressor expressed from the plasmid pRK248cIts. The deleterious effect of the activity of the enzyme EcoRI on the host DNA is prevented by the action of the EcoRI methylase that is expressed constitutively from a third plasmid, pEcoR4. The model includes molecular mechanisms involved in the regulation of the expression of these genes and is used to determine cultural conditions that maximize the production of the recombinant protein. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 544–551, 2002.
Anterior coracoscapular ligament and suprascapular nerve entrapment
Authors: Avery B.W. , Pilon F.M. , Barclay J.K.
Published: October 2002

A reduction in the height of the suprascapular foramen may predispose to entrapment of the suprascapular nerve. In this study, 16 of 27 cadavers (60%) demonstrated a heretofore unreported ligament located on the anterior aspect of the suprascapular foramen. In 11 of the 27 cadavers (41%), the ligament was observed bilaterally. The ligament decreased the foraminal height from the normative value of 5.6 ± 0.4 to 2.3 ± 0.4 mm (mean ± SEM). Because this ligament, for which we propose the term anterior coracoscapular ligament (ACSL), substantially narrows the suprascapular foramen, it should be considered as a possible etiologic factor in suprascapular nerve entrapment. Clin. Anat. 15:383–386, 2002. © 2002 Wiley‐Liss, Inc.
Long‐term renal function preservation after renal artery stenting in patients with progressive ischemic nephropathy
Authors: Rocha‐Singh Krishna J. , Ahuja Ratan K. , Sung Chung‐Hsien , Rutherford Janiece
Published: October 2002

We assessed the long‐term effect of successful renal artery stent revascularization on renal function, blood pressure control, and survival in patients with progressive renal dysfunction due to ischemic nephropathy. Ischemic nephropathy presents a potentially serious risk of complete loss of renal function. Surgical renal revascularization is associated with significant risk of mortality/morbidity in this patient population. The potential role and long‐term effect of renal artery stent revascularization in this patient population is not well defined. A cohort of 51 patients (mean age, 72 years; 52.9% men) with progressive azotemia, defined as a preprocedure serum creatinine (Scr) value of ≥ 1.5 mg/dl and a negative slope of the reciprocal 1/Scr curve during the 12 months preceding revascularization, underwent successful primary stent deployment in 93 atherosclerotic renal artery lesions (42 bilateral, 9 solitary kidneys). Estimated glomerular filtration rate (EGFR) and serum creatinine values, blood pressure, antihypertensive medication requirements, and survival rates were monitored over a mean of 30‐month follow‐up. Renal artery duplex Doppler or renal angiography were performed at a mean of 13 months (range, 7–15 months) to assess stent patency. Stent implantation was successful in 92/93 (98.9%) stenotic renal arteries (mean preprocedure serum creatinine 2.3 ± 0.9 mg/dl; range, 1.5–8.2 mg/dl). Forty‐seven patients were eligible for 30‐month follow‐up of the procedural effect on renal function, blood pressure control, number of antihypertensive medications, and survival. At 1‐year follow‐up, the slope of the 1/Scr curve increased and the EGFR values significantly improved compared to preprocedure values (19.9 ± 6.2 to 26.8 ± 10.1 ml/min; P < 0.0001), serum creatinine decreased from the mean preprocedure value to 1.75 ± 0.69 mg/dl (P < 0.001), with renal function improvement or stabilization observed in 94% of patients; three patients (7.3%) required permanent hemodialysis during the 30‐month follow‐up period. Systolic and diastolic blood pressure significantly decreased (from 177 ± 28 to 148 ± 25 mm Hg and from 92 ± 15 to 78 ± 14 mm Hg, respectively; P < 0.001) with fewer antihypertensive medications required to control blood pressure (3.5 ± 0.9 vs. 1.9 ± 1.3; P < 0.001). The patient survival rate after 30‐month follow‐up was 87%, with three deaths related to end‐stage renal failure. Renal artery stent revascularization reversed progressive renal dysfunction within the first 12 months and maintained the improved level of renal function at 30‐month follow‐up while improving blood pressure control and reducing the number of antihypertensive medication requirements. Renal stent revascularization should be considered a valid therapeutic option for the long‐term treatment of ischemic nephropathy. Cathet Cardiovasc Intervent 2002;57:135–141. © 2002 Wiley‐Liss, Inc.
Enantioselective addition of diethylzinc to aldehydes catalyzed by optically active C2‐symmetrical bis‐β‐amino alcohols
Authors: Xu Qianyong , Zhu Guangming , Pan Xinfu , Chan Albert S.C.
Published: October 2002

The syntheses of new optically active C2‐symmetrical bis‐β‐amino alcohols 1‐6 from (S)‐2‐(1‐hydroxy‐1,1‐diphenylmethyl)‐pyrrolidine are described. Especially attention is focused on bridges, which link the two β‐amino alcohol units. These new chiral ligands have been successfully applied in the catalytic enantioselective addition of diethylzinc to aldehydes to give sec‐alcohols in good yields with up to 95% enantiomeric excess. Chirality 14:716–723, 2002. © 2002 Wiley‐Liss, Inc.
Reflectance circular dichroism of solid‐state chiral coordination compounds
Authors: Bilotti Ivano , Biscarini Paolo , Castiglioni Ettore , Ferranti Francesco , Kuroda Reiko
Published: October 2002

Solid‐state diffuse reflectance circular dichroism (DRCD) spectra of some chiral Λ‐ and Δ‐M[(A⁁A)n]m+ coordination compounds [M(III) = Cr, Co; A⁁A = ethylendiamine (en), O,O′‐2(R)3(R)dimethylethylene dithiophosphate ion, (R,R)bdtp−, sepulchrate (Sep); n = 1, 3; m = 0, 3] were measured and compared with their solution, nujol mull, and KBr pellet spectra in the spectral region of 300–800 nm. The validity of the DRCD method to obtain reliable CD spectra which reflect a correct absolute configuration at the metal coordination center as well as subtle changes in the stereochemistry of the compound in the solid vs. solution states was proved. DRCD is the only spectroscopic method to examine randomly oriented chiral compounds without the effect of pressure, solvent, or diluting media such as KBr or nujol (which lends the sample irrecoverable and may interact with the sample), and directly relate to the structure that is revealed by X‐ray diffractometry. Chirality 14:750–756, 2002. © 2002 Wiley‐Liss, Inc.
Twenty‐five years of clinical research for patients with limited‐stage small cell lung carcinoma in North America
Authors: Jänne Pasi A. , Freidlin Boris , Saxman Scott , Johnson David H. , Livingston Robert B. , Shepherd Frances A. , Johnson Bruce E.
Published: October 2002

BACKGROUND

To determine the changes in clinical trials and outcomes of patients with limited‐stage small cell lung carcinoma (SCLC) treated on Phase III randomized trials initiated in North America between 1972 and1992.

METHODS

Phase III trials from 1972 to 1992 for patients with limited‐stage SCLC were identified. Patients with limited‐stage SCLC treated during a similar time interval were also evaluated in the Surveillance, Epidemiology, and End Results (SEER) database. Trends were tested in the number of trials, in the number and gender of patients entered on trial, and in survival duration over time.

RESULTS

Thirty trials involving 6564 patients were eligible for analyses. Nineteen trials (61%) involving 3626 patients were initiated within the first half of this time period (1972–1981). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10–16 months) and 17.0 months (range, 11–20 months), respectively (P < 0.001). Of 26 studies available for survival analysis, 5 (19%) showed a statistically significant survival prolongation in the experimental arm compared with the control arm with a median prolongation of 3.4 months (range, 1–5.2 months). All five evaluated some aspect of thoracic radiation therapy. Over a similar time period, there was a 6.4‐month increase in the median survival of limited‐stage SCLC patients listed in the SEER database (P < 0.0001) and a more than doubling of the 5‐year survival from 5.2% to 12.1% (P = 0.0001).

CONCLUSIONS

Analyses of the patients with limited‐stage SCLC treated on Phase III trials in North America initiated between 1972 and 1992 and those listed in the SEER database show significant improvements in median survivals. Furthermore, the 5‐year survival of patients with limited‐stage SCLC listed in the SEER database has more than doubled over the last 25 years. Further research will be needed to determine the relative contribution of improved therapy, supportive care, and stage migration to this prolongation in survival. Cancer 2002;95:1528–38. © 2002 American Cancer Society.

DOI 10.1002/cncr.10841
A high rate of venous thromboembolism in a multi‐institutional Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma
Authors: Desai Apurva A. , Vogelzang Nicholas J. , Rini Brian I. , Ansari Rafat , Krauss Stuart , Stadler Walter M.
Published: October 2002

BACKGROUND

The objective of this study was to determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5‐FU) and daily oral thalidomide in patients with metastatic renal cell carcinoma (RCC).

METHODS

Between June, 2000 and January, 2001, 21 patients with metastatic RCC were enrolled onto this multi‐institutional Phase II study of gemcitabine at 600 mg/m2 per day on Days 1, 8, and 15; 5‐FU at 150 mg/m2 per day by continuous IV infusion through a permanent catheter on Days 1–21; and oral thalidomide on Days 1–28 starting at a dose of 200 mg daily. After the first 2 weeks of therapy, the thalidomide dose was escalated by 100 mg per day every week to a maximum dose of 400 mg per day unless it was precluded by toxicity. Treatment cycles were repeated every 28 days.

RESULTS

A high rate of venous thromboembolism (VTE) was observed. Five patients developed deep vein thrombosis (DVT), three patients developed pulmonary embolization (PE), and one patient suffered a fatal cardiac arrest preceded by hemoptysis, for an overall VTE rate of 43%. Of the 18 assessable patients, there were no complete responses and 2 partial responses (objective response rate, 10%; 95% confidence interval, 1–30%).

CONCLUSIONS

The addition of thalidomide to gemcitabine and 5‐FU did not improve the objective response rate previously observed with gemcitabine and 5‐FU alone and added significant vascular toxicity. The authors recommend against further development or use of this three‐drug regimen. Cancer 2002;95:1629–36. © 2002 American Cancer Society.

DOI 10.1002/cncr.10847
The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma
Authors: Warmann Steven , Hunger Mona , Teichmann Birgit , Flemming Peer , Gratz Klaus Friedrich , Fuchs Jörg
Published: October 2002

BACKGROUND

The P‐glyprotein (P‐gp), which is a membrane channel encoded by the MDR1 gene, represents a possible explanation for multidrug resistance in human hepatoblastoma (HB). P‐gp shows up‐regulation in tumor cells after chemotherapy; however, to date, its exact role in HB has not been described. The authors investigated the role of the MDR1 gene in the clinical course of patients with HB and in an in vivo model of HB. They also studied the effects of the MDR1 antagonizer PSC 833 on chemotherapy in mice xenotransplanted with HB.

METHODS

Resected tumor specimens, including both primary tumors and recurrent tumors, from a child suffering from HB were investigated histologically. Cell suspensions from the originally removed tumor were incorporated subcutaneously into nude mice. Animals were treated with cisplatin (CDDP) plus PSC 833. MDR1 gene expression levels in the different resected tumors from the patient and in the xenotransplants after treatment were determined with polymerase chain reaction analysis.

RESULTS

MDR1 gene expression was increased in the patient's tumors after every course of chemotherapy from 30% to > 190%. In the xenotransplants, MDR1 gene expression was enhanced significantly after chemotherapy (PCDDP = 0.008; PCDDP+PSC = 0.002). Tumor volumes (P < 0.001) and serum α‐fetoprotein levels (P = 0.0002) were significantly lower in the animals that were treated with CDDP + PSC compared with the animals that were treated with CDDP alone.

CONCLUSIONS

The current results suggest that MDR1 gene expression and P‐gp are a potential mechanism of drug resistance in HB. The chemosensitizer PSC 833 significantly improved the effects of chemotherapy in animals xenotransplanted with HB. These data encourage further studies concerning the role of chemosensitizers in overcoming multidrug resistance in patients with HB. Cancer 2002;95:1795–801. © 2002 American Cancer Society.

DOI 10.1002/cncr.10858
Gemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum‐based regimens
Authors: Ricci Sergio , Galli Luca , Chioni Aldo , Iannopollo Mauro , Antonuzzo Andrea , Francesca Francesco , Vocaturo Vittorio , Selli Cesare , Orlandini Cinzia , Conte PierFranco
Published: October 2002

BACKGROUND

The objective of this study was to evaluate the efficacy and toxicity of gemcitabine plus epirubicin in previously untreated patients with advanced urothelial carcinoma who were not eligible for cisplatin‐based regimens.

METHODS

Patients with advanced urothelial carcinoma and at least one of the following characteristics were eligible: impaired renal function (creatinine clearance < 60 mL per minute), an Eastern Cooperative Oncology Group performance status (PS) ≥ 2, and age ≥ 75 years. The treatment included epirubicin 70 mg/m2 as an intravenous bolus on Day 1 and gemcitabine 1000 mg/m2 over 30 minutes on Days 1 and 8 of a 21‐day cycle.

RESULTS

Thirty‐eight patients entered the study, and a total of 152 cycles were administered, with a median of 4 cycles per patient (range, 1–6 cycles per patient). The following Grade 3–4 hematologic toxicities were reported (percent of cycles): neutropenia, 22.4%; anemia, 11.2%; and thrombocytopenia, 6.5%. No cardiac, renal, or hepatic toxicities were observed. Dose intensities of epirubicin and gemcitabine were 19.6 mg/m2 per week (84%) and 532.2 mg/m2 per week (80%), respectively. There were 2 complete responses (5.3%), 13 partial responses (34.2%), 11 patients with stable disease (28.9%), and 12 patients with progressive disease (31.6%), for an overall response rate of 39.5% (95% confidence interval, 25.1–55.1). The median progression free survival (PFS) and overall survival (OS) rates were 4.8 months and 8.0 months, respectively. The 1‐year survival rate was 38%, and the median PFS and OS were 6.4 months and 16.4 months, respectively, in patients with PS 0–1. Thirty patients were symptomatic: Seventeen patients (56.7%) achieved a complete response, and 5 patients (16.7%) achieved a partial symptomatic response.

CONCLUSIONS

At the doses given in this study, gemcitabine and epirubicin had a good tolerability profile with interesting activity in patients with advanced urothelial carcinoma who were not fit for cisplatin‐based regimens. Cancer 2002;95:1444–50. © 2002 American Cancer Society.

DOI 10.1002/cncr.10860
Promoting early detection tests for colorectal carcinoma and adenomatous polyps
Authors: Levin Bernard , Smith Robert A. , Feldman Gabriel E. , Colditz Graham A. , Fletcher Robert H. , Nadel Marion , Rothenberger David A. , Schroy Paul S. , Vernon Sally W. , Wender Richard ,   National Colorectal Cancer Roundtable
Published: October 2002

BACKGROUND

The purpose of the current study was to provide health professionals, professional organizations, policy makers, and the general public with a practical blueprint for increasing the practice of screening for colorectal carcinoma (CRC) and adenomatous polyps over the next decade. The National Colorectal Cancer Roundtable (NCCRT) was founded in 1997 by the American Cancer Society and the Centers for Disease Control and Prevention to provide strategic leadership, advocacy, long‐range planning, and coordination of interventions targeted at reducing the disease burden of CRC through education, early detection, and prevention. The NCCRT and its three workgroups include CRC survivors; recognized experts in primary care, gastroenterology, radiology, colorectal surgery, nursing, public policy, epidemiology, and behavioral science; patient advocates; and representatives of health plans and insurers, government, and other organizations.

METHODS

The NCCRT performed a literature review of published and unpublished data related to CRC screening guidelines, compliance, and barriers to adherence, as well as test effectiveness and cost‐effectiveness. Members of the three NCCRT workgroups developed summary reports regarding professional education, public education and awareness, and health policy. A drafting committee developed the final strategic plan from workgroup reports, which was reviewed by the entire NCCRT membership, amended, and subsequently approved in final form.

RESULTS AND CONCLUSIONS

Although the rationale for population‐wide CRC screening is well established, the majority of adults in the U.S. are not currently being screened for CRC. Thus, the nation foregoes an opportunity to reduce CRC‐related mortality by an estimated ≥ 50%. To increase CRC screening rates, the issues of patient and physician barriers to screening, lack of universal coverage, lack of incentives to motivate adherence, and expanded infrastructure must be addressed. Cancer 2002;95:1618–28. © 2002 American Cancer Society.

DOI 10.1002/cncr.10890
Development of cricket mushroom bodies
Authors: Malaterre Jordane , Strambi Colette , Chiang Ann‐Shyn , Aouane Aicha , Strambi Alain , Cayre Myriam
Published: October 2002

Mushroom bodies are recognized as a multimodal integrator for sensorial stimuli. The present study analyzes cricket mushroom body development from embryogenesis to adulthood. In the house cricket, Kenyon cells were born from a group of neuroblasts located at the apex of mushroom bodies. Our results demonstrate the sequential generation of Kenyon cells: The more external they are, the earlier they were produced. BrdU treatment on day 8 (57% stage) of embryonic life results, at the adult stage, in the labelling of the large Kenyon cells at the periphery of the mushroom body cortex. These cells have specific projections into the posterior calyx, the gamma lobe, and an enlargement at the inner part of the vertical lobe; they represent a part of mushroom bodies of strictly embryonic origin. The small Kenyon cells were formed from day 9 (65% stage) of the embryonic stage onward, and new interneurons are produced throughout the entire life of the insect. They send their projections into the anterior calyx and into the vertical and medial lobes. Mushroom body development of Acheta should be considered as a primitive template, and cross‐taxonomic comparisons of the mushroom body development underscore the precocious origin of the gamma lobe. As a result of continuous neurogenesis, cricket mushroom bodies undergo remodeling throughout life, laying the foundation for future studies of the functional role of this developmental plasticity. J. Comp. Neurol. 452:215–227, 2002. © 2002 Wiley‐Liss, Inc.
Increased brain size and glial cell number in CD81‐null mice
Authors: Geisert Eldon E. , Williams Robert W. , Geisert Grace R. , Fan Liying , Asbury Andrew M. , Maecker Holden T. , Deng Jun , Levy Shoshana
Published: October 2002

A key issue in the development of the central nervous system (CNS) is understanding the molecular mechanisms regulating cell number. The present study examines the role of CD81 (previously known as TAPA, the target of the antiproliferative antibody) in the control of brain size and glial cell number. CD81 is a member of the tetraspanin family of proteins. This group of small membrane proteins is associated with the regulation of cell migration and mitotic activity. Glial cells express CD81, and antibodies directed against this protein suppress the mitotic activity of cultured cells. In this study, we examine the effects of the CD81 −/− mutation on the CNS of mature mice. These mice have extremely large brains, as much as 30% larger than the brains of wild‐type (+/+) littermates. The increase in brain weight is accompanied by an increase in the number astrocytes and microglia, whereas the number of neurons and oligodendrocytes in the CD81 −/− animals appears to be normal. When the CD81 −/− mutation is placed on different genetic backgrounds, there is a remarkable range in the penetrance of the null allele phenotype, demonstrating that the mutation can be affected by modifier loci. This work provides support for the role of CD81 in the regulation of astrocyte and microglial number, perhaps by regulating cell proliferation by a contact inhibition‐dependent mechanism. J. Comp. Neurol. 453:22–32, 2002. © 2002 Wiley‐Liss, Inc.
Quantitative organization of neurotransmitters in the deep cerebellar nuclei of the Lurcher mutant
Authors: Sultan Fahad , König Thomas , Möck Martin , Thier Peter
Published: October 2002

The Lurcher mutant mouse is characterized by a primary selective loss of Purkinje cells, leading to the near total apoptotic death of these neurons. In contrast to the subsequent massive secondary degeneration of the granule cells and the inferior olivary neurons, only mild degeneration occurs in the deep cerebellar nuclei (DCN). However, it is not known to what extent the different populations of DCN neurons—glutamatergic principal projection neurons, γ‐aminobutyric acid (GABA)‐ergic inferior olivary projection neurons, and glycinergic neurons—are affected in their neurotransmitter composition. To answer this question we studied the neurotransmitter contents (glutamate, GABA, and glycine) of DCN neurons and the size of synaptic boutons immunohistochemically on serial semithin sections in both Lurcher and wild‐type mice. Applying the physical dissector counting method, our results confirmed the mild degeneration (a reduction by 20%) of large glutamatergic neurons and a more pronounced degeneration of GABAergic (by 42%) and glycinergic neurons (by 45%). On the other hand, an analysis of neurons colabeled for both GABA and glycine, revealed that this specific colabeling increased in the Lurcher mutant (by 40%). In addition, both the GABA‐immunolabeled (IL) (by 56%) and the glycine‐IL (by 45%) synaptic boutons showed an increase in diameter in the mutant. The density of these boutons showed a decrease of 30% each. In summary, the increase in the number of neurons colabeled for GABA and glycine, together with the increase in the size of the inhibitory synaptic boutons, could help in providing the minimum inhibition needed to maintain a residual “cerebellar” functionality in the Lurcher DCN. J. Comp. Neurol. 452:311–323, 2002. © 2002 Wiley‐Liss, Inc.