bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulated Nucleoside Kinases as Tools to Improve the Activation of Therapeutic Nucleoside Analogues
Authors: Monnerjahn Christian , Konrad Manfred
Published: March 2003

The use of nucleoside analogues in anticancer and antiviral treatments is often impaired by the slow intracellular activation of these drugs. This problem can be addressed by the modulation of rate‐limiting enzymes in the activation pathways of the nucleoside analogues. Therapeutic strategies based on the combination of optimized activating enzymes and established nucleoside drugs promise significant improvements to traditional chemotherapy.
Solid‐Phase Synthesis and Biological Activity of a Thioether Analogue of Conotoxin G1
Authors: Bondebjerg Jon , Grunnet Morten , Jespersen Thomas , Meldal Morten
Published: March 2003

A bicyclic thioether analogue of α‐conotoxin G1, a neurotoxin found in the venom of cone snails, was synthesized on solid phase. Two successive intramolecular on‐bead cyclizations between a cysteine residue and a chloroacetylated reduced peptide bond are the key steps in the synthesis. The first reduced peptide bond was introduced by a reductive alkylation with a 9‐fluorenylmethoxycarbonyl protected amino aldehyde, and the second by coupling of a dipeptide building block containing an allyloxycarbonyl protected reduced peptide bond. The desired bicyclic product was obtained as a mixture of two isomers, which were evaluated for their ability to inhibit the muscular nicotinic acetylcholine receptor expressed in Xenopus oocytes. The two isomers were found to have IC50 values (inhibitory activities) of 144 μM and 48 μM, compared to 0.18 μM for native conotoxin G1.
Behavior Of Silica Aerogel Networks as Highly Porous Solid Solvent Media for Lipases in a Model Transesterification Reaction
Authors: El Rassy H. , Perrard A. , Pierre A. C.
Published: March 2003

Highly porous silica aerogels with differing balances of hydrophobic and hydrophilic functionalities were studied as a new immobilization medium for enzymes. Two types of lipases from Candida rugosa and Burkholderia cepacia were homogeneously dispersed in wet gel precursors before gelation. The materials obtained were compared in a simple model reaction: transesterification of vinyl laurate by 1‐octanol. To allow a better comparison of the hydrophobic/hydrophilic action of the solid, very open aerogel networks with traditional organic hydrophobic/hydrophilic liquid solvents, this reaction was studied in mixtures containing different proportions of 2‐methyl‐2‐butanol, isooctane, and water. The results are discussed in relation to the porous and hydrophobic nature of aerogels, characterized by nitrogen adsorption. It was found that silica aerogels can be considered as “solid” solvents for the enzymes, able to provide hydrophobic/hydrophilic characteristics different from those prevailing in the liquid surrounding the aerogels. A simple mechanism of action for these aerogel networks is proposed.
Neuro‐Fuzzy Control of a Continuous Cooled MSMPR Crystallizer
Authors: Bravi M. , Chianese A.
Published: March 2003

This work deals with the design and application of a neuro‐fuzzy controller of the magma density of the fine crystals for the stabilisation of the crystal size distribution (CSD) of the product from an MSMPR (Mixed Suspension, Mixed Product Removal) continuous crystallizer. The cooling crystallization of potassium sulphate from aqueous solutions in a pilot‐scale stirred vessel was investigated. A control strategy, based on the elimination of fines by using a combined sedimentation‐dissolution device, is presented. The control scheme was successfully applied to a pilot‐scale draft‐tube (DT) crystallizer and yielded promising results. The proposed process control system allowed the reduction of the fines fraction by more than 30 %, while maintaining operation stability and short transient responses.
Development of a Continuous Segmented Flow Tubular Reactor and the “Scale‐out” Concept – In Search of Perfect Powders
Authors: Jongen N. , Donnet M. , Bowen P. , Lemaître J. , Hofmann H. , Schenk R. , Hofmann C. , Aoun‐Habbache M. , Guillemet‐Fritsch S. , Sarrias J. , Rousset A. , Viviani M. , Buscaglia M.T. , Buscaglia V. , Nanni P. , Testino A. , Herguijuela J.R.
Published: March 2003

The synthesis of powders with controlled shape and narrow particle size distributions is still a major challenge for many industries. A continuous Segmented Flow Tubular Reactor (SFTR) has been developed to overcome homogeneity and scale‐up problems encountered when using batch reactors. Supersaturation is created by mixing the co‐reactants in a micromixer inducing precipitation; the suspension is then segmented into identical micro‐volumes by a non‐miscible fluid and sent through a tube. These micro‐volumes are more homogeneous when compared to large batch reactors leading to narrower size distributions, better particle morphology, polymorph selectivity and stoichiometry. All these features have been demonstrated on single tube SFTR for different chemical systems. To increase productivity for commercial application the SFTR is being “scaled‐out” by multiplying the number of tubes running in parallel instead of scaling‐up by increasing their size. The versatility of the multi‐tube unit will allow changes in type of precipitate with a minimum of new investment as new chemistry can be researched, developed and optimised in a single tube SFTR and then transferred to the multi‐tube unit for powder production.
Dual‐domain regression analysis for spectral calibration models
Authors: Tan Huwei , Brown Steven D.
Published: March 2003

Taking advantage of the local nature of spectral data in both the time and frequency domains, two novel chemometric algorithms using the wavelet transform, namely dual‐domain partial least squares (DDPLS) and dual‐domain principal component regression (DDPCR), are reported here. The proposed algorithms establish parallel, regular models to describe spectral variation in the time (wavelength) domain. They incorporate these parallel models as a way of emphasizing local features in the frequency domain. Compared with regular PLS or PCR regression models applied to a single domain, these algorithms generate more parsimonious regression models that are also more robust against unexpected variations in the prediction set. Simulation data have been used in this paper to demonstrate this improvement. The new methods have also been successfully applied to NIR spectral data sets to predict moisture, oil, protein and starch content in Cargill corn samples, as well as a set of properties in a series of Amoco hydrocarbon samples. Through their special emphasis on the local nature of spectral signals in the frequency domain, spectral variance can be separately explained over the frequency and time domains with fewer latent variables and with better predictive performance. Copyright © 2003 John Wiley & Sons, Ltd.
Rapid estimation of chemical kinetics by implicit calibration. II
Authors: Taavitsainen Veli‐Matti , Haario Heikki , Laine Marko
Published: March 2003

This study continues the development of a method, implicit calibration, for estimating kinetic parameters from on‐line measurements of batch reactions. The basic idea of implicit calibration is to combine non‐linear parameter estimation with the calibration of measured spectra with concentrations calculated by an assumed kinetic model. A new example is studied, an esterification reaction with a rather complicated kinetic mechanism, where activities, instead of concentrations, and NIR spectra are used as measurements. The emphasis in the study is on estimating the uncertainty of the kinetic parameters. Two approaches, linearization and bootstrap, are applied. In the case studied, the two approaches give closely similar estimates of the uncertainty. As well, a new way is introduced to control the rigidity of the implicit calibration, based on minimizing the lack of fit of the model. It is also shown that ‘mixed implicit calibration’, i.e. implicit calibration combined with a few off‐line calibrated concentrations, greatly enhances the identifiability of the kinetic model. Copyright © 2003 John Wiley & Sons, Ltd.
Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine
Authors: Planck Maria , Ericson Kajsa , Piotrowska Zofia , Halvarsson Britta , Rambech Eva , Nilbert Mef
Published: March 2003

BACKGROUND

Carcinomas of the small intestine are rare, but the risk is greatly increased in patients with hereditary nonpolyposis colorectal cancer (HNPCC) due to an inherited mismatch repair (MMR) gene mutation, most commonly affecting the genes MLH1 or MSH2. Defective MMR is characterized by microsatellite instability (MSI) and loss of MMR protein expression in the tumor tissue. However, a subset of several sporadic tumor types, including about 15% of colon cancers, also evolve through defective MMR.

METHODS

The authors have assessed the frequency of MSI and analyzed the immunohistochemical expression of MLH1 and MSH2 in a population‐based series of 89 adenocarcinomas of the small intestine. To study the contribution of MSI and defective MMR protein expression in young patients, 43 cancers of the small intestine from patients below age 60 years (including 24 tumors from the population‐based series and an additional 19 tumors from young individuals) were also analyzed.

RESULTS

MSI was detected in 16/89 tumors (18%) in the population‐based series, and immunohistochemistry revealed loss of expression for MLH1 in 7/16 MSI tumors and in 2/73 MSS tumors, whereas all tumors showed normal expression for MSH2. Among the young patients, the authors identified MSI in 10/43 tumors (23%), and 6 of these 10 MSI tumors showed immunohistochemical loss of MMR protein expression, which affected MLH1 in 3 cases and MSH2 in 3 cases.

CONCLUSIONS

The frequency of MSI (18%) in adenocarcinomas of the small intestine equals that of colon cancer. However, silencing of MLH1 seems to explain the MSI status in only about half of the MSI tumors. Among patients with cancer of the small intestine before age 60 years, MSI is found in 23% of the cases, with MLH1 and MSH2 being affected at equal frequencies, indicating that HNPCC may underly a subset of such cases. Cancer 2003;97:1551–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11197
Therapy and outcome of small cell carcinoma of the kidney
Authors: Majhail Navneet S. , Elson Paul , Bukowski Ronald M.
Published: March 2003

BACKGROUND

Primary small cell carcinoma originating from the kidneys is an extremely rare neoplasm. The authors described two patients with small cell carcinoma of the kidney and provided a systematic review of the literature to detail the clinical characteristics and therapy of this rare tumor.

METHODS

MEDLINE and CANCERLIT literature search was performed from 1966 to 2002 for articles on small cell carcinoma of the kidney. Twenty‐two patients with small cell carcinoma of the kidney and renal pelvis were reviewed.

RESULTS

The median age at diagnosis was 62 years and there was a female preponderance (male:female ratio, 1:3.4). Abdominal pain (70%) was the most commonly reported symptom. Distant metastases were present in 32% of patients at the time of diagnosis. Surgery and systemic chemotherapy were the primary therapeutic modalities utilized (nephrectomy alone: 9 patients; nephrectomy and chemotherapy: 10 patients; chemotherapy alone: 3 patients). The median survival was 8 months (range, < 1–101 months). The use of platinum‐based chemotherapy was predictive of an improved overall survival (median survival was 20 months in patients receiving a platinum‐containing regimen compared with 8 months in those who did not receive platinum; P = 0.02).

CONCLUSIONS

Small cell carcinoma of the kidney is an extremely rare neoplasm that resembles its counterparts arising from the tracheo‐bronchial and other extrapulmonary sites in its aggressive behavior and high propensity for locoregional and distant dissemination. Clinical presentation is usually late in the course of the disease. The use of platinum‐based chemotherapy has been associated with tumor regression and prolonged survival. Cancer 2003;97:1436–41. © 2003 American Cancer Society.

DOI 10.1002/cncr.11199
Progress in cancer screening practices in the United States
Authors: Swan Judith , Breen Nancy , Coates Ralph J. , Rimer Barbara K. , Lee Nancy C.
Published: March 2003

BACKGROUND

Understanding differences in cancer screening among population groups in 2000 and successes or failures in reducing disparities over time among groups is important for planning a public health strategy to reduce or eliminate health disparities, a major goal of Healthy People 2010 national cancer screening objectives. In 2000, the new cancer control module added to the National Health Interview Survey (NHIS) collected more detailed information on cancer screening compared with previous surveys.

METHODS

Data from the 2000 NHIS and earlier surveys were analyzed to discern patterns and trends in cancer screening practices, including Pap tests, mammography, prostate specific antigen (PSA) screening, and colorectal screening. The data are reported for population subgroups that were defined by a number of demographic and socioeconomic characteristics.

RESULTS

Women who were least likely to have had a mammogram within the last 2 years were those with no usual source of health care (61%), women with no health insurance (67%), and women who immigrated to the United States within the last 10 years (61%). Results for Pap tests within the last 3 years were similar. Among both men and women, those least likely to have had a fecal occult blood test or endoscopy within the recommended screening interval had no usual source of care (14% for men and 18% for women), no health insurance (20% for men and 18% for women), or were recent immigrants (20% for men and 18% for women). An analysis of changes in test use since the 1987 survey indicates that the disparities are widening among groups with no usual source of care.

CONCLUSIONS

No striking improvements have been observed for the groups with greatest need. Although screening use for most groups has increased since 1987, major disparities remain. Some groups, notably individuals with no usual source of care and the uninsured are falling further behind; and, according to the 2000 data, recent immigrants also experience a significant gap in screening utilization. More attention is needed to overcome screening barriers for these groups if the population benefits of cancer screening are to be achieved. Cancer 2003;97:1528–40. Published 2003 by the American Cancer Society.

DOI 10.1002/cncr.11208
Combination of tumor necrosis factor‐α with sulindac augments its apoptotic potential and suppresses tumor growth of human carcinoma cells in nude mice
Authors: Yasui Hiroshi , Adachi Masaaki , Imai Kohzoh
Published: March 2003

BACKGROUND

Resistance to apoptosis may be responsible for a principal mechanism by which cancer cells overcome anticancer therapies. Among antiapoptotic signals, the transcription factor, NF‐κB, plays a pivotal role in the resistance because it is frequently activated in many primary carcinoma cells. However, NF‐κB is also activated by several anticancer therapies, including tumor necrosis factor‐alpha (TNF‐α). The NF‐κB–mediated survival signals are supposed to evade these therapies. Recently, a nonsteroidal antiinflammatory drug, sulindac, and its metabolites have been shown to inhibit the NF‐κB pathway and to enhance TNF‐α–mediated apoptosis in lung carcinoma cell lines. In the current study, the authors investigated whether sulindac can augment TNF‐α–mediated apoptosis in other human carcinoma cells and whether it can be applied for in vivo clinical usage.

METHODS

Human gastric MKN45 and cervical HeLa carcinoma cells were treated with sulindac and/or TNF‐α. Proapoptotic effects of these agents were evaluated by trypan blue exclusion assay, DNA fragmentation, and caspase‐3 activity. The effect of sulindac on NF‐κB activation was evaluated by luciferase reporter and gel‐shift assays. The suppressive effects of these reagents on the subcutaneous tumor growth of MKN45 cells were evaluated by measuring tumor size in nude mice.

RESULTS

Sulindac inhibited TNF‐α–mediated NF‐κB activation and greatly sensitized MKN45 and HeLa cell lines to TNF‐α. Moreover, in vivo tumor growth of MKN45 cells was inhibited most strongly by a combination of TNF‐α with sulindac compared with TNF‐α or sulindac alone.

CONCLUSIONS

The current study data strongly suggest that combination therapy of TNF‐α with sulindac may sensitize tumor cells to TNF‐α and augment its proapoptotic potential. Therefore, in combination with sulindac, TNF‐α may become a potentially useful anticancer agent to suppress tumor growth in a wide range of carcinomas. Cancer 2003;97:1412–20. © 2003 American Cancer Society.

DOI 10.1002/cncr.11210
Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high‐risk myelodysplastic syndromes
Authors: Tsimberidou Apostolia , Estey Elihu , Cortes Jorge , Thomas Deborah , Faderl Stefan , Verstovsek Srdan , Garcia‐Manero Guillermo , Keating Michael , Albitar Maher , O'Brien Susan , Kantarjian Hagop , Giles Francis
Published: March 2003

BACKGROUND

Gemtuzumab is used to treat patients with previously untreated or recurrent acute myelogenous leukemia (AML). The fludarabine and cytarabine (ara‐C) regimen is active in these patients. Resistance to gemtuzumab is associated with blast multidrug resistance (MDR). The objectives of this study were to evaluate the efficacy and toxicity of a combination regimen of gemtuzumab, fludarabine, ara‐C, and the MDR modifier (cyclosporine [CyA]) in patients with previously untreated AML, refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEBT).

METHODS

The MFAC regimen was comprised of gemtuzumab (Mylotarg™) (6 mg/m2 intravenously [i.v.] on Day 1); fludarabine and ara‐C (15 mg/m2 and 0.5 g/m2, respectively, twice daily on Days 2–6); and CSA (6 mg/kg loading dose before gemtuzumab, followed by 16 mg/kg continuous i.v. infusion on Days 1 and 2).

RESULTS

Fifty‐nine evaluable patients were treated: 39 patients (66%) had AML and 20 patients (34%) had RAEB/RAEBT. Their median age was 57 years (range, 27–76 years). The MFAC regimen induced complete remission (CR) in 27 patients (46%) and CR with incomplete platelet recovery (CRp) in 1 patient (2%). The median survival period is 8 months. At 12 months, the survival rate is 38% and the event‐free survival rate in patients with CR/CRp is 27%. Infections complicated 38% of the courses of chemotherapy. Grade 3/4 toxicity included hyperbilirubinemia in 31% and transaminitis in 7% of the patients. Four patients (7%) developed hepatic venoocclusive disease (VOD).

CONCLUSIONS

The MFAC regimen may merit further study in patients with AML if measures to avoid and/or treat VOD can be incorporated into the regimen. Cancer 2003;97:1481–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11239
Morphology and axonal arborization of rat spinal inner lamina II neurons hyperpolarized by μ‐opioid–selective agonists
Authors: Eckert William A. , McNaughton Kirk K. , Light Alan R.
Published: March 2003

The ventral or inner region of spinal substantia gelatinosa (SG; lamina IIi) is a heterogeneous sublamina important for the generation and maintenance of hyperalgesia and neuropathic pain. To test whether IIi neurons can be hyperpolarized by the μ‐opioid agonist [D‐Ala2, N‐Me‐Phe4, Gly5‐ol]‐enkephalin (DAMGO; 500 nM) and to address possible downstream consequences of μ‐opioid–evoked inhibition of IIi neurons, we combined in vitro whole‐cell, tight‐seal recording methods with fluorescent labeling of the intracellular tracer biocytin and confocal microscopy. Twenty‐one of 23 neurons studied had identifiable axons. Nine possessed axons that projected ventrally into laminae III–V; six of these were hyperpolarized by DAMGO. Three of four neurons with identifiable axons that projected to lamina I were hyperpolarized by DAMGO. Most neurons could be classified as either islet cells or stalked cells. Five of nine labeled islet cells and only two of seven stalked cells were hyperpolarized by DAMGO. Three were stellate cells: one resembled a spiny cell and three could not be classified. DAMGO hyperpolarized each of the stellate cells, the spiny cell, and 1 of the unclassified cells. Our data support the hypothesis that part of the action of μ‐opioid agonists involves the inhibition of interneurons that are part of a polysynaptic excitatory pathway from primary afferents to neurons in the deep and/or superficial dorsal horn. J. Comp. Neurol. 458:240–256, 2003. © 2003 Wiley‐Liss, Inc.
Some glial progenitors in the neonatal subventricular zone migrate through the corpus callosum to the contralateral cerebral hemisphere
Authors: Kakita Akiyoshi , Zerlin Marielba , Takahashi Hitoshi , Goldman James E.
Published: March 2003

The great majority of glial cells of the mammalian forebrain are generated in the perinatal period from progenitors in the subventricular zone (SVZ). We investigated the migration of progenitors from the neonatal (postnatal day 0, P0) rat forebrain SVZ by labeling them in vivo with a green fluorescence protein (GFP) retrovirus and monitoring their movements by time‐lapse video microscopy in P3 slices. We identified a small number of progenitors that migrated tangentially within the corpus callosum (CC) and crossed the midline. These cells retained a relatively uniform morphology: the leading process was extended toward the contralateral side but showed no process branching or turning away from the migratory direction. Net migration requires the elongation of the leading process and nuclear translocation, and the migrating cells in the CC showed both modes. We confirmed the presence of unmyelinated axon bundles within the P3 CC, but failed to detect any radially directed glial processes (vimentin‐ or GLAST‐immunolabeled fibers) spanning through the CC. Confocal images showed a close proximity between neurofilament‐immunolabeled axons and the leading process of the GFP‐expressing progenitors in the CC. The destination of the callosal fibers was examined by applying DiI to the right cingulum; the labeled fibers ran throughout the CC and reached the left cingulate and motor areas. The distribution and final fates of the retrovirus‐labeled cells were examined in P28 brains. A small proportion of the labeled cells were found in the contralateral hemisphere, where, as oligodendrocytes and astrocytes, they colonized predominantly the cortex and the underlying white matter of the cingulate and secondary motor areas. The distribution pattern appears to coincide well with the projection direction of the callosal fibers. Thus, glial progenitors migrate across the CC, presumably in conjunction with unmyelinated axons, to colonize the contralateral hemisphere. J. Comp. Neurol. 458:381–388, 2003. © 2003 Wiley‐Liss, Inc.
Chemical coding of the human gastrointestinal nervous system: Cholinergic, VIPergic, and catecholaminergic phenotypes
Authors: Anlauf Martin , Schäfer Martin K.‐H. , Eiden Lee , Weihe Eberhard
Published: March 2003

The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal (GI) tract. For this purpose, antibodies against the vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), dopamine β‐hydroxylase (DBH), serotonin (5‐HT), vasoactive intestinal peptide (VIP), and protein gene product 9.5 (PGP 9.5) were used. For in situ hybridization 35S‐labeled VMAT1, VMAT2, and VAChT riboprobes were used. In all regions of the human GI tract, 50–70% of the neurons were cholinergic, as judged by staining for VAChT. The human gut unlike the rodent gut exhibits a cholinergic innervation, which is characterized by an extensive overlap with VIPergic innervation. Neurons containing VMAT2 constituted 14–20% of all intrinsic neurons in the upper GI tract, and there was an equal number of TH‐positive neurons. In contrast, DBH was absent from intrinsic neurons. Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes. In conclusion, the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species, but also significant differences. VIP is a cholinergic cotransmitter in the intrinsic innervation of the human gut. The substantial overlap between VMAT2 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life. The absence of DBH from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype. J. Comp. Neurol. 459:90–111, 2003. © 2003 Wiley‐Liss, Inc.
Fine‐needle aspiration cytological findings in five cases of epithelial‐myoepithelial carcinoma of salivary glands
Authors: Miliauskas John R. , Orell Svante R.
Published: March 2003

The cytologic features of five cases of epithelial‐myoepithelial carcinoma arising in major salivary glands (four parotid and one submandibular gland) are presented. All cases were initially diagnosed as low‐grade malignancies. The smears were generally cellular, with no specific architectural pattern. Single cells and naked nuclei were prominent in all cases. A biphasic epithelial (small‐cell) and myoepithelial (large/clear‐cell) pattern was identified readily in two cases and with difficulty in one case. The biphasic pattern may be subtle or absent since the clear cells have a fragile cytoplasm and often appear as naked nuclei. The differential diagnosis includes adenoid cystic carcinoma, polymorphous low‐grade adenocarcinoma, and cellular pleomorphic adenoma. Diagn. Cytopathol. 2003;28:163–167. © 2003 Wiley‐Liss, Inc.
Characteristic of Cl− current induced by ATP in bovine aortic endothelial cells
Authors: Wei Wen‐Li , He Hua , Guan Yong‐Yuan
Published: March 2003

Patch‐clamp whole‐cell recording techniques were used to study ATP‐induced Cl‐ current and the effects of Cl‐ channel blockers on NO release in bovine aortic endothelial cells. ATP evoked an outward rectified Cl‐ current with a reversal potential of −29±3 mV. This outward rectified Cl‐ current was dependent on Ca2+ influx, but not Ca2+ release. In Ca2+‐free medium, ATP did not produce the Cl‐ current; however, subsequent addition of Ca2+ to the medium evoked an ATP‐induced outward rectified Cl‐ current. Furosemide, glibenclamide, and DIDS inhibited ATP‐activated Cl‐ current in a concentration‐dependent manner with maximal inhibition of 88±4%, 93±1%, and 79±3%, respectively. The IC50 values of furosemide, glibenclamide, and DIDS were 6.2±2.6, 29.6±12.3, and 21.0±13.4 µM, respectively. These effects of Cl‐ channel blockers matched those on NO release from endothelial cells. Our data suggest that ATP‐induced Ca2+ entry followed by increased [Ca2+]i activates Ca2+‐activated Cl‐ channels which mediate NO release from endothelial cells. Drug Dev. Res. 58:53–56, 2003. © 2003 Wiley‐Liss, Inc.
Effects of taurine and Astragalus membranaceus on ion currents and their expression in cardiomyocytes after CVB3 infection
Authors: Su Yan‐Gang , Yang Ying‐Zhen , Bao Wei‐Sheng , Liu Gong‐Xin , Ge Jun Bo , Chen Haozhu
Published: March 2003

To investigate the effects of taurine and Astragalus membranaceus (AM) on ion currents and their expression in cardiomyocytes after Coxsackie virus B3 (CVB3) infection, hearts were removed from adult or newborn Sprague‐Dawley rats and digested by collagenase. CVB3 was inoculated to the medium and used for recording current of L‐type voltage‐dependent calcium channel (Ica), Na+ current (INa), outward potassium current (Iout), and inward rectifying potassium current (IKI). An in vivo model of viral myocarditis (VMC) was produced by intraperitoneal injection of CVB3 into BALB/c mice and the hearts were used for examining the expression of L‐type voltage‐dependent Ca2+ channel (LVDCC)α1 subunit and the voltage‐gated potassium channel (Kv). Ica and Iout were increased while IKI decreased after inoculation with CVB3 for 2 h. However, INa did not differ between normal and infected cells. The positive hybridization signals of the LVDCCα1 subunit (antigen) and Kv1.2, Kv2.1, and Kv4.2 were much reinforced after CVB3 infection. Taurine and AM could block the enhancement of Ica, Iout, and reduction of IKI after virus infection. Additionally, taurine and AM attenuated the increased expression level of LVDCCα1 subunit as well as Kv mRNA. Taurine and AM may exert their beneficial effect on VMC through modulating the changes in ion currents and expression. Drug Dev. Res. 58:57–60, 2003. © 2003 Wiley‐Liss, Inc.
Arterial baroreflex function and left ventricular hypertrophy
Authors: Miao Chao‐Yu , Su Ding‐Feng
Published: March 2003

It is well known that the arterial baroreflex (ABR) plays a key role in the regulation of heart rate and stabilization of blood pressure. Currently, it appears that ABR dysfunction is involved in the pathophysiology of cardiovascular disease states. Since the mid‐1990s, a number of studies have been carried out in our laboratory to explore the pathological significance of ABR function in cardiovascular damage. This minireview summarizes our research work on the topic of ABR function and left ventricular hypertrophy (LVH). On the basis of discussion concerning the importance of ABR dysfunction in hypertensive LVH and sinoaortic denervation‐induced LVH, we advance a new strategy for reversal of LVH, that is, restoration of impaired ABR function. We tested this hypothesis in animal models with ABR deficiency. It was found that improvement of impaired ABR function with long‐term treatment of ketanserin or candesartan was accompanied by reversal of LVH. The preliminary results indicate that it is feasible to target ABR for treatment of LVH. Drug Dev. Res. 58:61–64, 2003. © 2003 Wiley‐Liss, Inc.
Pharmacological characteristics of the novel antihypertensive drug, iptakalim hydrochloride, and its molecular mechanisms
Authors: Wang Hai
Published: March 2003

The purpose of the present study was to evaluate the pharmacological characteristics of the novel antihypertensive drug iptakalim hydrochloride and to investigate the molecular mechanisms underlying its antihypertensive action. In conscious hypertensive animals, oral administration of iptakalim hydrochloride at doses of 0.75, 1.5, 3.0, and 6.0 mg/kg in spontaneously hypertensive rats, or at doses of 0.125, 0.25, 0.5, and 1.0 mg/kg in renal hypertensive dogs (two‐kidney with one‐clip), decreased the blood pressure in a dose‐dependent manner. In conscious normotensive dogs blood pressure was not changed when iptakalim hydrochloride was given at doses of 0.8–3.2 mg/kg, but was decreased by 20 mmHg at the high dose of 12.8 mg/kg. Repeated administration of iptakalim hydrochloride decreased blood pressure in a dose‐dependent manner and also reversed the hypertensive cardiovascular remodeling. The molecular mechanisms underlying its antihypertensive action include ATP‐sensitive potassium channel activation and endothelin antagonism. Drug. Dev. Res. 58:65–68, 2003. © 2003 Wiley‐Liss, Inc.
Mechanism of the delayed onset of action after intravenous amiodarone for treatment of ventricular arrhythmias
Authors: Shi Guang‐fei , Xu Wei , Huang Shen‐shen , Cao Qiao‐lan
Published: March 2003

The onset of action of intravenous amiodarone (AM) for treatment of ventricular arrhythmias often occurs after at least several hours' delay. To investigate the mechanism of this delayed action, we gave i.v. AM at an initial loading dose of 2.5 mg/kg or 5.0 mg/kg over 10 min, followed immediately by infusion of 7.5 μg/kg.min or 10 μg/kg.min for 20 h in eight dogs. The concentration of AM and its major metabolite, N‐desethylamiodarone (DA), in plasma and myocardial tissue were determined immediately after the loading dose and at 20 h after infusion, respectively, while electrophysiologic parameters were measured at the same times. The concentration of AM and DA in plasma were also determined serially. The results showed that the concentration of AM or DA in plasma or myocardial tissue rose to the peak level within 5–15 min after the loading dose, the sinus cycle length and AV conduction Wenckebach point measured at this time increased significantly relative to baseline (P<0.05), while the ventricular effective refractory period (VERP) and ventricular exciting time (VET) at this time did not increase significantly (P>0.05). The concentration of AM or DA in plasma declined rapidly during the continuous infusion period and remained at a stable low level until infusion stopped. The concentration of AM or DA in the myocardial tissue at 20 h after continuous infusion was lower than immediately after the loading dose. The sinus cycle length and AV conduction Wenckebach point were shortened close to the baseline level, while the VERP and VET were unchanged 20 h after infusion. The delayed onset of action for treatment of ventricular arrhythmias after i.v. administration of AM cannot be explained by higher concentration of AM or its metabolite in myocardial tissue. The specific mechanism(s) of action of i.v. AM in its control of arrhythmias remain to be determined. Drug Dev. Res. 58:145–148, 2003. © 2003 Wiley‐Liss, Inc.
Enduring maternal influences in a precocial rodent
Authors: Hennessy Michael B.
Published: March 2003

The guinea pig is highly developed at birth and requires little active maternal care. Yet the mother and other social figures markedly influence biobehavioral processes of the offspring. Here, responses of guinea pigs and nonhuman primates to maternal and other social separation procedures are compared, and influences of social partners on endocrine responses and behavior in periadolescent guinea pigs are described. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 42: 225–236, 2003.
Does infant memory expression reflect age at encoding or age at retrieval?
Authors: Hartshorn Kristin , Rovee‐Collier Carolyn
Published: March 2003

Do human infants express a memory acquired earlier in ontogeny in a manner appropriate to their age at encoding or their age at the time of retrieval? To answer this, we exploited the fact that retention is highly context dependent at 6 months but not at 8–9 months of age. Six‐month‐olds learned an operant response in one context, and their memory was maintained by monthly reinstatements in the original context. At 8 or 9 months of age, 1 month after the last (or only) reinstatement, infants were tested in either the same or a different context. During testing, infants' retention was no longer context dependent; rather, they responded robustly in both test contexts. These results revealed that infants expressed a memory acquired when they were younger in a manner appropriate to their test age. They were interpreted in terms of changes in the functional significance of context before and after infants self‐locomote. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 42: 283–291, 2003.
Attention during looking and reaching as assessed by heart rate in 7½‐month‐old infants
Authors: O'Sullivan Laura P. , Berthier Neil E.
Published: March 2003

Attention mediates the acquisition and encoding of information about the world and is central to motor action. Heart rate deceleration and behavioral inhibition are sensitive indices of the attentional process, but it is unknown whether these indices are valid in the context of overt action. The current study investigated the relationship between visual attention, action, and heart rate during reaching in 7½‐month‐old infants. We found that infants showed prolonged looking and large heart rate decelerations on reaching and looking trials. We conclude that overt action itself does not prevent the autonomic and behavioral changes that are also seen in attention to simple visual displays and that attention is maintained throughout the act of reaching. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 42: 292–300, 2003.
MRF4 gene expression in Xenopus embryos and aneural myofibers
Authors: Ataian Yeganeh , Owens Jesse , Hinterberger Timothy
Published: March 2003

Vertebrate embryos express the transcription factor MRF4 during skeletal muscle differentiation. Previous studies of MRF4 expression in embryonic Xenopus laevis and its response to muscle denervation in adults have led to the suggestion that its transcription may be activated in myotomes and in multinucleate myofibers through an interaction with the motor nerves. We tested this hypothesis by assaying for MRF4 gene transcripts in early neurula stage embryos, beginning before the appearance of neurons. MRF4 transcripts were detectable by reverse transcriptase‐polymerase chain reaction (RT‐PCR) from at least stage 13–14, well before the differentiation of either nerves or myocytes. We also tested the nerve‐dependence of MRF4 gene expression in multinucleate myofibers by comparing transcript levels between interhyoideus muscles in normal larvae and muscles whose motor innervation had been prevented through surgical removal of the brain before cranial motor axon outgrowth. RT‐PCR demonstrated similar MRF4 transcript levels in the aneural muscles and controls. These results fail to support the hypothesis that MRF4 gene expression is triggered or is significantly up‐regulated in myogenic cells by signals from motor axons. © 2003 Wiley‐Liss, Inc.
Caenorhabditis elegans exoskeleton collagen COL‐19: An adult‐specific marker for collagen modification and assembly, and the analysis of organismal morphology
Authors: Thein Melanie C. , McCormack Gillian , Winter Alan D. , Johnstone Iain L. , Shoemaker Charles B. , Page Antony P.
Published: March 2003

The integral role that collagens play in the morphogenesis of the nematode exoskeleton or cuticle makes them a useful marker in the examination of the collagen synthesizing machinery. In this study, a green fluorescent protein–collagen fusion has been constructed by using the Caenorhabditis elegans adult‐specific, hypodermally synthesized collagen COL‐19. In wild‐type nematodes, this collagen marker localized to the circumferential annular rings and the lateral trilaminar alae of the cuticle. Crosses carried out between a COL‐19::GFP integrated strain and several morphologically mutant strains, including blister, dumpy, long, small, squat, and roller revealed significant COL‐19 disruption that was predominantly strain‐specific and provided a structural basis for the associated phenotypes. Disruption was most notable in the cuticle overlying the lateral seam cell syncytium, and confirmed the presence of two distinct forms of hypodermis, namely the circumferentially contracting lateral seam cells and the laterally contracting ventral–dorsal hypodermis. The effect of a single aberrant collagen being sufficient to mediate widespread collagen disruption was exemplified by the collagen mutant strain dpy‐5 and its disrupted COL‐19::GFP and DPY‐7 collagen expression patterns. Through the disrupted pattern of COL‐19 and DPY‐7 in a thioredoxin mutant, dpy‐11, and through RNA interference of a dual oxidase enzyme and a vesicular transport protein, we also show the efficacy of the COL‐19::GFP strain as a marker for aberrant cuticle collagen synthesis and, thus, for the identification of factors involved in the construction of collagenous extracellular matrices. Developmental Dynamics 226:000–000, 2003. © 2003 Wiley‐Liss, Inc.
Mouse Mix gene is activated early during differentiation of ES and F9 stem cells and induces endoderm in frog embryos
Authors: Mohn Deanna , Chen Siming W. , Dias Dora Campos , Weinstein Daniel C. , Dyer Michael A. , Sahr Kenneth , Ducker Charles E. , Zahradka Elizabeth , Keller Gordon , Zaret Kenneth S. , Gudas Lorraine J. , Baron Margaret H.
Published: March 2003

In frog and zebrafish, the Mix/Bix family of paired type homeodomain proteins play key roles in specification and differentiation of mesendoderm. However, in mouse, only a single Mix gene (mMix) has been identified to date and its function is unknown. We have analyzed the expression of mouse Mix RNA and protein in embryos, embryoid bodies formed from embryonic stem cells and F9 teratocarcinoma cells, as well as several differentiated cell types. Expression in embryoid bodies in culture mirrors that in embryos, where Mix is transcribed transiently in primitive (visceral) endoderm (VE) and in nascent mesoderm. In F9 cells induced by retinoic acid to differentiate to VE, mMix is coordinately expressed with three other endodermal transcription factors, well before AFP, and its protein product is localized to the nucleus. In a subpopulation of nascent mesodermal cells from embryonic stem cell embryoid bodies, mMix is coexpressed with Brachyury. Intriguingly, mMix mRNA is detected in a population (T+Flk1+) of cells which may contain hemangioblasts, before the onset of hematopoiesis and activation of hematopoietic markers. In vitro and in vivo, mMix expression in nascent mesoderm is rapidly down‐regulated and becomes undetectable in differentiated cell types. In the region of the developing gut, mMix expression is confined to the mesoderm of mid‐ and hindgut but is absent from definitive endoderm. Injection of mouse mMix RNA into early frog embryos results in axial truncation of developing tadpoles and, in animal cap assays, mMix alone is sufficient to activate expression of several endodermal (but not mesodermal) markers. Although these observations do not exclude a possible cell‐autonomous function for mMix in mesendodermal progenitor cells, they do suggest an additional, non–cell autonomous role in nascent mesoderm in the formation and/or patterning of adjacent definitive endoderm. Developmental Dynamics 226:000–000, 2003. © 2003 Wiley‐Liss, Inc.
Do eating disorders co‐occur with personality disorders? Comparison groups matter
Authors: Grilo Carlos M. , Sanislow Charles A. , Skodol Andrew E. , Gunderson John G. , Stout Robert L. , Shea M. Tracie , Zanarini Mary C. , Bender Donna S. , Morey Leslie C. , Dyck Ingrid R. , McGlashan Thomas H.
Published: March 2003

Objective

To assess and compare lifetime rates of occurrence of eating disorders (ED) with four Axis II personality disorders (PD) and with major depressive disorder (MDD) without PD. The eating disorders met criteria outlined in the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV).

Method

Six hundred sixty‐eight patients recruited for the Collaborative Longitudinal Personality Disorders Study (CLPS) were reliably assessed with the Structured Clinical Interview for DSM‐IV Axis I Disorders and the Diagnostic Interview for DSM‐IV Personality Disorders. The distribution of ED diagnoses was compared among four PD study groups (schizotypal, borderline, avoidant, obsessive‐compulsive) and a fifth study group with MDD without any PD.

Results

The distribution of lifetime diagnoses of anorexia nervosa (N = 40), bulimia nervosa (N = 56), and eating disorder not otherwise specified (N = 118) did not differ significantly across the five study groups, between the MDD group versus all PD groups, and among the four PD study groups.

Conclusions

ED diagnoses did not differentially co‐occur significantly across common Axis I and II disorders. The pattern of ED lifetime co‐occurrence rates demonstrates the powerful influence of base rates and highlights that declarations of comorbidity demand significant variations from base‐rate patterns. © 2003 by Wiley Periodicals, Inc. Int J Eat Disord 33: 155–164, 2003.
Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse
Authors: Ardouin Laurence , Bracke Madelon , Mathiot Anne , Pagakis Stamatis N. , Norton Trisha , Hogg Nancy , Tybulewicz Victor L. J.
Published: March 2003

Activation of T lineage cells through the TCR by peptide–MHC complexes on APC is critically dependent on rearrangement of the actin cytoskeleton. Vav1 is a guanine nucleotide exchange factor for members of the Rho/Rac family of GTPases which is activated following TCR stimulation, suggesting that it may transduce TCR signals to the activation of some or all actin‐controlled processes. Weshow that Vav1‐deficient double‐positive thymocytes are less efficient at forming conjugates with APC presenting agonist peptide than wild‐type cells are. Furthermore we demonstrate that Vav1 is required for TCR‐induced activation of the integrin LFA‐1, which is likely to explain the defect in conjugate formation. However, once Vav1‐deficient cells form a conjugate, the assembly of proteins into an immunological synapse at the conjugate interface is normal. In contrast, thymocyte polarization is defective in the absence of Vav1, as judged by the relocalization of the microtubule‐organizing center. These data demonstrate that Vav1 transduces signals to only a subset of cytoskeleton‐dependent events at the immunological synapse.
Bis(sulfonyl)methyl Insertion into Alkenyl versus Phenyl Carbon−Hydrogen Bonds in the Reaction of Bis(sulfonyl)iodonium Ylides with Highly Phenylated Ethylenes
Authors: Adam Waldemar , Gogonas Efstathios P. , Hadjiarapoglou Lazaros P.
Published: March 2003

The reaction of bis(sulfonyl)iodonium ylides α−γ with triphenylethylene (2a) and tetraphenylethylene (2b) affords insertion products into the alkenyl and phenyl carbon−hydrogen bonds of the substrate. A mechanistically perplexing feature is the diversity displayed in the reactivity pattern of the bis(sulfonyl)iodonium ylides in their reaction with the phenylated alkenes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Snm as a Photolabile Protecting Group for the Cysteinyl Radical − Direct Evidence from Time‐Resolved IR and UV/Vis Spectroscopies
Authors: Kolano Christoph , Sander Wolfram
Published: March 2003

The cysteinyl radical and the methyl(phenyl)thiocarbamic acid radical have been generated by laser flash photolysis (266 nm) of BOC−Cys(Snm)−OH in acetonitrile and characterized both by time‐resolved (IR and UV/Vis) and standard spectroscopic methods (UV, IR, and NMR). The mode of action of the Snm unit [methyl(phenyl)thiocarbamic acid] is similar to the so‐called “caging” technique. Cleavage of the disulfide bridge by irradiation is possible in acceptable quantum yields. Time‐resolved IR (TR‐IR) spectroscopic experiments using the step‐scan FTIR technique allowed the detection of the methyl(phenyl)thiocarbamic acid radical (νC=O = 1607.7 and 1579.3 cm−1), which has a lifetime of about 3 µs. Because of the weak absorptions in the IR spectrum and the tendency for fast recombination to BOC‐protected cystine, the cysteinyl radical cannot be monitored by TR‐IR spectroscopy. Time‐resolved UV/Vis spectroscopy revealed the formation of both of these radicals and permitted the determination of the decay rates of the methyl(phenyl)thiocarbamic acid radical in the presence of several quenchers. NMR spectroscopic studies of the photolysis of BOC−Cys(Snm)−OH allowed us to identify N‐methylaniline, carbonyl sulfide, and BOC‐protected cystine as the major products. This study clearly demonstrates that the thiol protection group Snm is a suitable photolabile protecting group. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)