bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation‐induced reset of hippocampal theta in the freely performing rat
Authors: Williams J.M. , Givens B.
Published: January 2003

Previous research has suggested that visual and auditory stimuli in a working memory task have the ability to reset hippocampal theta, perhaps allowing an organism to encode the incoming information optimally. The present study examined two possible neural pathways involved in theta resetting. Rats were trained on a visual discrimination task in an operant chamber. At the beginning of a trial, a light appeared over a centrally located lever that the rat was required to press to receive a water reward. There was a 30‐s intertrial interval before the next light stimulus appeared. After learning the task, all rats received surgical implantation of stimulating electrodes in both the fornix and the perforant path and recording electrodes, bilaterally in the hippocampus. After surgery, theta was recorded before and after the light stimulus to determine whether resetting to the visual stimulus occurred. During the intertrial interval, rats received single‐pulse electrical stimulation of either the fornix or perforant path. Theta was recorded both before and after the electrical stimulation to determine whether resetting occurred. In this experiment, hippocampal theta was reset after all three stimulus conditions (light, perforant path, and fornix stimulation), with the greatest degree of reset occurring after the fornix stimulation. The results suggest that activation of the perforant path and fornix may underlie theta reset and provide a mechanism by which the hippocampus may enhance cognitive processing. Hippocampus 2003;13:109–116. © 2003 Wiley‐Liss, Inc.
Long‐term potentiation and long‐term depression induced by local application of ATP to hippocampal CA1 neurons of the Guinea pig
Authors: Yamazaki Yoshihiko , Kaneko Kenya , Fujii Satoshi , Kato Hiroshi , Ito Ken‐Ichi
Published: January 2003

The present study has investigated the role of ATP in the induction of synaptic plasticity, using local application of ATP by picopump administration into the stratum radiatum of guinea pig hippocampal region CA1. Excitatory postsynaptic currents (EPSCs) evoked by stimulation of Schaffer collateral/commissural afferents synapsing on CA1 pyramidal cells of hippocampal slices were monitored in voltage‐clamp mode, using whole‐cell recording. Brief local application of ATP (1 mM) induced an inward current, usually consisting of early‐ and late‐phase components. Because the late‐phase component of an ATP‐induced current was largely inhibited by Ca2+‐free solution, this component is supposed to depend on extracellular Ca2+. After local application of ATP, long‐term synaptic modification of EPSCs was induced: LTP was detected in neurons exhibiting a small late Ca2+ current, while LTD was obtained from recordings showing a large late Ca2+ current in response to ATP application. There was a statistically significant correlation between the magnitude of long‐term plastic changes and the size of Ca2+ currents in response to ATP application. Furthermore, there was significant difference between the average size of the Ca2+ current in the LTP group and the size in the LTD group. These results suggest that a small Ca2+ influx in response to ATP application induces LTP, whereas a large one induces LTD in guinea pig hippocampal CA1 neurons. Hippocampus 2003;13:81–92. © 2003 Wiley‐Liss, Inc.
Tyrosine‐nitration of caspase 3 and cytochrome c does not suppress apoptosis induction in squamous cell carcinoma cells
Authors: Ueta Eisaku , Kamatani Takaaki , Yamamoto Tetsuya , Osaki Tokio
Published: January 2003

The influence of tyrosine nitration of cytochrome c and caspase 3 on apoptosis induction was investigated in an established squamous carcinoma cell line, OSC‐4. The intracellular NO and O levels were increased up to about 110–120% and 140–180% of the control levels, respectively, after the treatment of OSC‐4 cells with 5‐FU (100 μg/ml), PLM (10 μg/ml), CDDP (10 μg/ml), or γ‐rays (20 Gy). The treatment of OSC‐4 cells with ONOO− (1 mM) and the above anticancer agents induced tyrosine nitration of 14, 32 kDa protein among others and nitration of tyrosine residues of cytochrome c and caspase 3 was identified by the Western blotting of immunoprecipitates obtained by antibodies to these proapoptotic proteins. When cytochrome c and procaspase 3 were treated with ONOO−, tyrosine nitration was increased in a ONOO−‐dose dependent manner. Tyrosine nitration of cleaved (17 kDa) caspase 3, however, was not induced by ONOO−. Procaspase 3 in the cytosol of HeLa cells was activated by the addition of ONOO−‐treated as well as ONOO−‐untreated cytochrome c. In addition, cleavage of ICAD and PARP were not suppressed in OSC‐4 cells by pretreatment with ONOO−. Activity of cleaved caspase 3 was not suppressed at low concentrations or by treatment with ONOO− or NO donors, SIN‐1 and SNP. Furthermore, apoptosis of OSC‐4 cells by the anticancer agents was not suppressed by ONOO−. In conclusion, these results suggest that nitration of tyrosine residues of cytochrome c and procaspase 3 is induced by chemoradiotherapy but their nitration does not suppress cancer cell apoptosis. © 2002 Wiley‐Liss, Inc.
Genetic susceptibility to nasopharyngeal carcinoma within the HLA‐A locus in Taiwanese
Authors: Lu Cheng‐Chan , Chen Jung‐Chin , Jin Ying‐Tai , Yang Hsiao‐Bai , Chan Shih‐Huang , Tsai Sen‐Tien
Published: January 2003

NPC is an epithelial tumor that is highly prevalent among the southern Chinese. Numerous studies have indicated that specific HLA haplotypes and genes within the HLA complex are associated with NPC. As a first effort to localize the gene responsible for susceptibility, the HLA‐A, ‐B, and ‐A2 subtypes were examined for their association to NPC. Consistent with previous reports, frequencies of HLA‐A2 [OR = 2.50, pc = 0.020 (study population); OR = 3.73, pc = 0.0030 (≥40 years old)] were significantly higher in patients with NPC than in healthy controls. Two‐locus analysis indicated that A2+B46+ individuals are at greater risk for NPC than A2−B46− individuals in both the population studied and the ≥40‐year‐old group. This, however, may be due to the close linkage of these 2 genes. Moreover, A2+B38+ individuals were at higher risk than A2−B38− individuals in both the population studied and the ≥40‐year‐old group; A2 and B38 are not genetically linked. These findings suggest that B38 or B46 alone cannot confer a high risk of NPC but that, in conjunction with A2, B38 or B46 positivity greatly increases risk. None of 5 A2 subtypes identified from studied populations was significantly associated with NPC. Microsatellite marker D6S211, located 97 kb telomeric to HLA‐A, was analyzed for its association with NPC. Allele 4 of D6S211 was significantly associated with NPC (OR = 3.97, pc = 0.0042). These results strongly support the hypothesis that genes associated with susceptibility to NPC in the HLA region are within the HLA‐A locus. © 2002 Wiley‐Liss, Inc.
Relationship between steroid hormone contraceptives and HPV, cervical intraepithelial neoplasia and cervical carcinoma
Authors: de Villiers Ethel‐Michele
Published: January 2003

Available data demonstrate an increase in the transcription of high‐risk papillomaviruses by the 16α‐hydroxylation of estrogens, which is in line with the epidemiologic data showing an increased cervical carcinogenesis risk for long‐term contraceptive‐using, HPV‐infected women. No evidence exists for an increase in HPV‐negative contraceptive users. © 2002 Wiley‐Liss, Inc.
Impact of comorbidity on lung cancer survival
Authors: Tammemagi C. Martin , Neslund‐Dudas Christine , Simoff Michael , Kvale Paul
Published: January 2003

Lung cancer is associated with smoking and age, both of which are associated with comorbidity. We evaluated the impact of comorbidity on lung cancer survival. Data on 56 comorbidities were abstracted from the records of a cohort of 1,155 patients. Survival effects were evaluated with Cox regression (outcome crude death). The adjustedR2statistic was used to compare the survival variation explained by predictive variables. No comorbidity was observed in 11.7% of patients, while 54.3% had 3 or more (mean 2.97) comorbidities. In multivariate analysis, 19 comorbidities were associated with survival: HIV/AIDS, tuberculosis, previous metastatic cancer, thyroid/glandular diseases, electrolyte imbalance, anemia, other blood diseases, dementia, neurologic disease, congestive heart failure, COPD, asthma, pulmonary fibrosis, liver disease, gastrointestinal bleeding, renal disease, connective tissue disease, osteoporosis and peripheral vascular disease. Only the latter was protective. Some of the hazards of comorbidities were explained by more directly acting comorbidities and/or receipt of treatment. Stage explained 25.4% of the survival variation. In addition to stage, the 19 comorbidities explained 6.1%, treatments 9.2%, age 3.7% and histology 1.3%. Thirteen uncommon comorbidities (prevalence <6%) affected 21.2% of patients and explained 3.5% of the survival variation. Comorbidity count and the Charlson index were significant predictors but explained only 2.5% and 2.0% of the survival variation, respectively. Comorbidity has a major impact on survival in early‐ and late‐stage disease, and even infrequent deleterious comorbidities are important collectively. Comorbidity count and the Charlson index failed to capture much information. Clinical practice and trials need to consider the effect of comorbidity in lung cancer patients. © 2002 Wiley‐Liss, Inc.
Continuous long‐term monitoring of UV radiation in professional mountain guides reveals extremely high exposure
Authors: Moehrle Matthias , Dennenmoser Bernhard , Garbe Claus
Published: January 2003

Ultraviolet radiation (UVR) is estimated to be one of the most important risk factors for nonmelanoma and melanoma skin cancers. High occupational UV exposure is assumed to be associated with skin cancer. Mountain guides receive considerable UV doses due to altitude‐related increase of UVR and reflection from snow‐ and ice‐covered surfaces. The aim of our study was to assess the annual occupational UV exposure of mountain guides. Spore film test chambers containing spores of Bacillus subtilis (VioSpor) were used as UV dosimeters with a spectral sensitivity profile similar to erythema‐weighted data calculated from spectroradiometric measurements. Nine mountain guide instructors carried dosimeters on the sides of their heads on a total of 1,406 working days during one year (July 1999–June 2000). Dosimeters were changed monthly. Measurements of 92 months could be evaluated (4–12 months/mountain guide). The mean individual monthly UV exposure was 107 standard erythema doses (SED) (median 71 SED; range 10–505 SED). The mean annual cumulative UV exposure was 1,097 SED (median 1,273 SED; range 312–1,770 SED) per mountain guide. The mean UV dose per day (4–10 hr) was 6.6 SED (median 5.7 SED; range 0.6–24.2 SED). This is the second study of continuous annual UV dosimetry in a cohort of outdoor workers. Our study showed that it is not sufficient to interpolate annual UV exposure from a few days' measurements. Only long‐term dosimetry can give reliable yearly information of UVR load. Median daily UV exposure exceeded limits for UV radiation (e.g., ACGIH effective dose 30 J/m2 per 8 hr period corresponding to 1.08 SED/day) 6‐fold; maximal exposure exceeded these limits 23‐fold. These extremely high exposure values are suggestive for an increased risk of skin cancer and thorough epidemiologic studies in the collectives of professional and recreational mountaineering are required. © 2002 Wiley‐Liss, Inc.
Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus
Authors: Wu Anna H. , Crabtree Jean E. , Bernstein Leslie , Hawtin Peter , Cockburn Myles , Tseng Chiu‐chen , Forman David
Published: January 2003

Infection with Helicobacter pylori (H. pylori), especially CagA+ strains, has been associated with an increased risk of noncardia gastric adenocarcinoma. The relationship with junctional cancer (adenocarcinomas of the esophagus and gastric cardia combined) has not been adequately investigated, although some studies have reported a reduced risk associated with H. pylori and CagA seroseropositivity. We investigated this question in a subset of cases and controls from a recently completed, large population‐based case‐control study of gastric and esophageal adenocarcinomas in Los Angeles County. Using established antigen‐specific ELISAs, serum IgG antibodies to H. pylori whole‐cell antigens (Helico‐G) and CagA were measured in population controls (n = 356) and patients with incident esophageal adenocarcinoma (n = 80), gastric cardia cancer (n = 87) or distal gastric cancers (noncardia gastric adenocarcinoma) (n = 127). After controlling for demographic characteristics (age, gender, race, birthplace, education), smoking and body mass index, seropositivity for H. pylori was associated with a statistically significant increased risk of distal gastric cancer (adjusted odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.03, 3.32) but the risk of junctional cancer was not increased (adjusted OR = 1.26, 95% CI = 0.82, 1.94). The risk of junctional cancer was not changed when CagA and H. pylori were both considered, but the risk of distal gastric cancer was further increased. Subjects who were seropositive for both CagA and H. pylori compared to those who were seronegative for H. pylori showed a risk of 2.20 (95% CI = 1.13, 4.26) for distal gastric cancer and 0.86 (95% CI = 0.47, 1.59) for junctional cancer. Although tests for interaction between smoking and H. pylori were not statistically significant for junctional or distal gastric cancers, risk for both tumor types tended to be higher among current smokers who were also H. pylori seropositive. In conclusion, we find no evidence that infection with CagA+ strains of H. pylori reduces risk of esophageal and gastric cardia adenocarcinoma in this population. Our findings confirm the positive association between risk of distal gastric cancer and infection with H. pylori infection, especially CagA+ strains. © 2002 Wiley‐Liss, Inc.
A randomised, double‐blind, placebo‐controlled trial of photodynamic therapy using 5‐aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia
Authors: Barnett Adrian A. , Haller J. Christoph , Cairnduff Fiona , Lane Geoffrey , Brown Stanley B. , Roberts David J.H.
Published: January 2003

Photodynamic therapy (PDT) using topical 5‐aminolaevulinic acid (ALA) has been used to treat histologically confirmed cervical intraepithelial neoplasia (CIN‐I and ‐I/II) in a randomised, double‐blind, placebo‐controlled protocol. Fluorescence microscopy revealed that topical application of 3% ALA in Intrasite Gel® to the cervix for 3 hr resulted in the accumulation of protoporphyrin IX in the cervical epithelium. Treatment of CIN with ALA‐PDT was well tolerated, with only 3/12 patients in the PDT arm (0/13 in the placebo arm) reporting any discomfort during illumination. Histologic examination of the treated tissue following loop excision 3 months post‐PDT indicated that 33% of patients had no evidence of CIN, 42% had no change in the grade of their disease, whilst 25% exhibited an apparent progression of disease. In the control group, the respective figures were 31%, 38% and 31%. There was no significant difference in response between the groups receiving ALA‐PDT and those receiving placebo treatment. © 2002 Wiley‐Liss, Inc.
Allelic imbalance at 11p15.5–15.4 correlated with c‐Ha‐ras mutation during radiation‐induced neoplastic transformation of human breast epithelial cells
Authors: Roy Debasish , Calaf Gloria , Hei Tom K.
Published: January 2003

Breast cancer is the most frequent malignancy in women throughout much of the developed world and is associated with a multistage process involving a number of genetic mutations and their corresponding cellular phenotypic alterations. It has already been shown that neoplastic transformation of a spontaneously immortalized human breast epithelial (MCF‐10F) cell line by radiation, in combination with estrogen, represents a successful model in studying the molecular and biological alterations that may contribute to the tumorigenic process. In the present study, the incidence of allelic alterations (microsatellite instability/loss of heterozygosity) on chromosome 11 in different radiation‐induced primary and secondary tumorigenic cell lines, relative to the control MCF‐10F cells was investigated. We identified 3 regions of the chromosome 11 (11p15–p15.5, 11q13 and 11q23) that showed high incidence of LOH among these tumor cell lines and suggested a potential role for these chromosomal regions in breast carcinogenesis. Among them, locus 11p15.5, where c‐Ha‐ras oncogene is located, had incidence of allelic imbalance between 25–40%. Furthermore, direct sequencing analysis of codons 12 and 61 of the c‐Ha‐ras oncogene identified various point mutations. These data highlight the importance of chromosome 11 in radiation induced malignant transformation of human breast epithelial cells and suggest the usefulness of the model in uncovering specific derangements during breast cancer progression. © 2002 Wiley‐Liss, Inc.
Association between a glutathione S‐transferase A1 promoter polymorphism and survival after breast cancer treatment
Authors: Sweeney Carol , Ambrosone Christine B. , Joseph Lija , Stone Angie , Hutchins Laura F. , Kadlubar Fred F. , Coles Brian F.
Published: January 2003

Glutathione S‐transferase (GST) enzymes detoxify chemotherapeutic drugs, and several studies have reported differences in survival for cancer patients who have variant genotypes for GSTP1, GSTM1 or GSTT1 enzymes. A recently described polymorphism alters hepatic expression of GSTA1, a GST with high activity in glutathione conjugation of metabolites of cyclophosphamide (CP). To consider the possible influence of the reduced‐expression GSTA1*B allele on cancer patient survival, we have conducted a pilot study of breast cancer patients treated with CP‐containing combination chemotherapy. GSTA1 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism. Kaplan‐Meier methods and Cox proportional hazards models were used to evaluate survival in relation to genotype. Among 245 subjects, 35% were GSTA1*A/*A, 49% GSTA1*A/*B and 16% GSTA1*B/*B; the genotype distribution did not differ by ethnic group, age or stage at diagnosis. Among patients who had 0 or 1 GSTA1*B allele, the proportion surviving at 5 years was 0.66 (95% CI = 0.59–0.72), whereas for GSTA1*B/*B subjects the proportion was higher, 0.86 (95% CI = 0.67–0.95). Significantly reduced hazard of death was observed for GSTA1*B/*B subjects during the first 5 years after diagnosis, hazard ratio (HR) = 0.3, 95% CI = 0.1–0.8. The association varied with time, with no survival difference observed for subjects who survived beyond 5 years. These results, although based on a small study population, describe an apparent difference in survival after treatment for breast cancer according to GSTA1 genotype. Further studies should consider the possible association between the novel GSTA1*B variant and outcomes of cancer therapy. © 2002 Wiley‐Liss, Inc.
Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation
Authors: Impola Ulla , Toriseva Mervi , Suomela Sari , Jeskanen Leila , Hieta Niina , Jahkola Tiina , Grenman Reidar , Kähäri Veli‐Matti , Saarialho‐Kere Ulpu
Published: January 2003

MMP‐19 (also designated RASI) is a recently discovered member of a large family of zinc‐dependent proteolytic enzymes, most of which have been implicated in cancer growth and metastasis. It differs from the others by its chromosomal location and structure and is expressed by endothelial and vascular smooth muscle cells in vivo. Our aim was to study the putative role of MMP‐19 in skin cancer. We also examined its regulation in keratinocyte cultures using quantitative TaqMan RT‐PCR. Our results show that MMP‐19 can also be detected in stimulated keratinocytes by Northern and Western analyses. In wounds, it was found in keratinocytes outside the migrating area, while in BCC and SCC, it was present in the hyperproliferative (p63‐positive), E‐cadherin‐negative epidermis at the tumor surface but downregulated in invasive cancer islands. Expression was also evident in endothelial cells of neoangiogenic regions and in occasional stromal fibroblasts. Of the 12 tested cytokines/growth factors, only TNF‐α and PMA were able to stimulate the expression of MMP‐19 mRNA in primary keratinocytes. No MMP‐19 mRNA was detected by Northern analysis in cultured HaCaT or A5 cells or in an SCC cell line established from head‐and‐neck cancer. Our data suggest that, unlike most MMPs, MMP‐19 expression in the epidermis is downregulated during transformation and histologic dedifferentiation. © 2002 Wiley‐Liss, Inc.
Association of genomic imbalances with drug resistance and thermoresistance in human gastric carcinoma cells
Authors: Tönnies Holger , Poland Julia , Sinha Pranav , Lage Hermann
Published: January 2003

Therapy resistance is the major obstacle to advances in successful cancer treatment. To characterize chromosomal alterations associated with different types of acquired MDR and thermoresistance, we applied CGH to compare a unique panel of human gastric carcinoma cells consisting of the parental, drug‐sensitive and thermosensitive cancer cell line EPG85‐257P, the atypical MDR variant EPG85‐257RNOV, the classical MDR subline EPG85‐257RDB and their thermoresistant counterparts EPG85‐257P‐TR, EPG85‐257RNOV‐TR and EPG85‐257RDB‐TR. CGH with genomic DNA prepared from these cell lines as probes successfully identified genomic gains and/or losses in chromosomal regions encoding putative genes associated with drug resistance and/or thermoresistance. These genes included various members of the families of ABC transporters and molecular chaperones. The importance of these cell variant‐specific genomic imbalances in the development of MDR and thermoresistance is discussed and remains to be elucidated. © 2002 Wiley‐Liss, Inc.
Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events
Authors: Paschen Annette , Méndez Rosa María , Jimenez Pilar , Sucker Antje , Ruiz‐Cabello Francisco , Song Mingxia , Garrido Federico , Schadendorf Dirk
Published: January 2003

Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN‐γ but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome 15. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies. © 2002 Wiley‐Liss, Inc.
Porous titanium‐nickel for intervertebral fusion in a sheep model: Part 1. Histomorphometric and radiological analysis1
Authors: Assad Michel , Jarzem Peter , Leroux Michel A. , Coillard Christine , Chernyshov Alexandr V. , Charette Sylvie , Rivard Charles‐H.
Published: January 2003

Porous titanium‐nickel (PTN) implants represent an alternative to traditional intervertebral fusion cages. Indeed, PTN materials possess interconnecting pores with cell capillarity properties that may promote bone ingrowth and intervertebral fusion without the need for bone grafting. In this study, a PTN intervertebral fusion device was compared to a conventional TiAlV cage packed with autologous bone in a sheep model. The two devices were implanted at two noncontiguous intervertebral lumbar sites for 3, 6, and 12 months. PTN osseointegration showed a time‐dependent trend increasing from 21.4% to 37.6% (3–12 months), whereas TiAlV cages remained at the same level of bone ingrowth (22.7%–25.4%; 3–12 months). Furthermore, PTN bone apposition (10.9%–24.2%; 3–12 months) was significantly higher than that of TiAlV implants (1.1%–5.1%; 3–12 months; p < 0.001, ANOVA). Radiological fusion scores increased with postsurgery time regardless of material type, but were consistently superior for PTN (12.5–18.5; 3–12 months) than for TiAlV cages (2.0–15.0; 3–12 months; p < 0.001, ANOVA). Implant materials were not significantly different according to the radiological interbody index based on preoperative disc height: Interbody index began at 132.6% (PTN) and 123.5% (TiAlV) immediately after surgery, then declined to 80.8% (PTN) and 91.0% (TiAlV) after 12 months. Nevertheless, ungrafted PTN constituted an excellent substrate for osteogenic cell integration and represents a new osteoconductive biomaterial with improved fusion characteristics in comparison to conventional TiAlV cages. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 64B: 107–120, 2003
Surface composition analysis of failed cementless CoCr‐ and Ti‐base‐alloy total hip implants
Authors: Decking R. , Reuter P. , Hüttner M. , Puhl W. , Claes L. E. , Scharf H. P.
Published: January 2003

The surfaces of retrieved failed cementless total hip implants made of cobalt‐chromium‐molybdenum casting alloy and of wrought titanium 6‐aluminum 4‐vanadium alloy were studied with the use of scanning‐electron microscopy (SEM), energy‐dispersive X‐ray analysis (EDX) and X‐ray photoelectron spectroscopy (XPS). New implants of the same make served as controls. The XPS scans revealed a dense carbon layer on the entire analyzed specimen. The relative composition of the titanium alloy implants showed an overall agreement with the international standards for implants for surgery, and the overall surface composition did not change over the period of the implantation. However, an inhomogeneous distribution of the constituents could be demonstrated in the retrieved as well as in the new MEC‐screw rings made of TiAl6V4 alloy, an implant that has been linked to a high early failure rate. In the CoCr‐alloy components (Lord‐screw rings) a high percentage of aluminum, mainly organized in aluminum inclusions, was found in the retrieved as well as in the new implants. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 64B: 99–106, 2003
Construction of a high efficiency retroviral vector for gene therapy of Hunter's syndrome
Authors: Hong Youngtae , Yu Seung Shin , Kim Jong‐Mook , Lee Karim , Na Young Soon , Whitley Chester B. , Sugimoto Yoshikazu , Kim Sunyoung
Published: January 2003

Background

As an alternative method to the conventional therapies for Hunter's syndrome, which is a lethal lysosomal storage disorder, we have developed gene delivery vehicles using a series of retroviral vectors. The objective of this study was to develop a safe and efficient retroviral vector and to optimize conditions for efficient transduction of human bone marrow CD34+ stem cells using our vector.

Methods

We constructed three types of MLV‐based retroviral vectors expressing iduronate‐2‐sulfatase (IDS) which is deficient in patients suffering from Hunter's syndrome: MIN‐IDS and MIM‐IDS, which express IDS along with bacterial neo and human MDR genes, respectively, and MT‐IDS lacking any selectable marker. Respective producer lines were derived from the packaging line, PG13, and compared for viral titer and levels of gene expression. After comparing, the retroviral vector, MT‐IDS, was used to transduce human bone marrow CD34+ stem cells on fibronectin under various MOIs.

Results

In comparison, MT‐IDS not only produced the highest viral titer (close to 107 cfu/ml), but also showed the highest level of gene expression in various transduction assays and RNA analysis. When 1.5 × 105 human CD34+ bone marrow cells were transduced with MT‐IDS under the most optimal MOIs, about 80% of total colony forming units were shown to contain the IDS cDNA.

Conclusions

Minimum‐sized retroviral vector that contains no selective marker as well as a viral coding sequences could drive a high level of gene expression, be produced efficiently from the producer line, and enter hematopoietic cells at a high frequency. Our data suggest the great potential for using MT‐based vector(s) in a gene therapy trial for Hunter's syndrome utilizing human CD34+ stem cells as target cells. Copyright © 2002 John Wiley & Sons, Ltd.
Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system
Authors: Miyagi Tohru , Koshida Kiyoshi , Hori Osamu , Konaka Hiroyuki , Katoh Hiroaki , Kitagawa Yasuhide , Mizokami Atsushi , Egawa Masayuki , Ogawa Satoshi , Hamada Hirohumi , Namiki Mikio
Published: January 2003

Background

Cytosine deaminase (CD) activates prodrug 5‐FC to 5‐FU and is used for suicide gene therapy (the CD/5‐FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5‐FU into 5‐fluorouridine monophosphate and improves the antitumoral effect of 5‐FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5‐FC cancer suicide gene therapy.

Methods

We investigated a combined suicide gene transduction therapy for human hormone independent prostate cancer cell line DU145 using two separate adenovirus vectors expressing the E. coli CD and E. coli UPRT genes and systemic 5‐FC administration (the CD+UPRT/5‐FC system).

Results

Cells transfected with AdCA‐UPRT showed approximately 57 times lower IC50 to 5‐FU compared with those transfected with AdCA‐LacZ. Furthermore, cells transfected with AdCA‐CD and AdCA‐UPRT proved to be more sensitive to 5‐FC compared with those transfected with AdCA‐CD. Intratumoral injection of AdCA‐CD and AdCA‐UPRT drastically suppressed the growth of tumors which had generated from DU145 cells inoculated into athymic (nude) mice compared with those injected with AdCA‐LacZ or AdCA‐LacZ and AdCA‐CD.

Conclusions

These results suggest that the CD+UPRT/5‐FC system could be a powerful factor in human prostate cancer suicide gene therapy. Copyright © 2002 John Wiley & Sons, Ltd.
Optimisation of dendrimer‐mediated gene transfer by anionic oligomers
Authors: Maksimenko Andrei V. , Mandrouguine Vasilii , Gottikh Marina B. , Bertrand Jean‐Remi , Majoral Jean‐Pierre , Malvy Claude
Published: January 2003

Background

The application of synthetic vectors for gene transfer has potential advantages over virus‐based systems. Their use, however, is limited since they generally lack the efficiency of gene transfer achieved with recombinant viral vectors such as adenovirus. Polyamidoamine (PAMAM) and phosphorus‐containing dendrimers (P‐dendrimers) are specific polymers with a defined spherical structure. They bind to DNA through electrostatic interactions thus forming complexes that efficiently transfect cells in vitro.

Methods and results

The influence of anionic oligomers (oligonucleotides, dextran sulfate) on dendrimer‐mediated polyfection of cultured cells has been studied. Anionic oligomers have been found to increase significantly the capacity of the PAMAM and P‐dendrimers for DNA delivery into cells when they were mixed with plasmid DNA before addition of dendrimers. The efficiency of the DNA/dendrimer penetration depends on the size, structure and charge of anionic oligomers.

Conclusions

Our results represent an important step towards the optimisation of gene transfer mediated by two types of dendrimers. The use of anionic oligomers improves the efficiency of gene expression within cells. As a consequence, a very efficient cell polyfection can be achieved with a lower plasmid quantity for the PAMAM dendrimer greatly increasing the gene expression level for P‐dendrimers. Copyright © 2002 John Wiley & Sons, Ltd.
A review of vaccines for HIV prevention
Authors: Mwau Matilu , McMichael Andrew J.
Published: January 2003

HIV/AIDS has become the most devastating pandemic in recorded history. It has killed 40 million people in the last 20 years and the World Health Organisation estimated that at least 14 000 new infections occurred daily in 2001. There will be up to 100 million new infections in the next 10 years (for current updates, visit http://www.unaids.org/epidemic_update/).

Most HIV infections occur in the developing world, and the adverse social and economic impact of the HIV/AIDS pandemic, particularly in the developing world, is unprecedented.

Highly active antiretroviral therapy (HAART) has had significant effects on HIV/AIDS in the developed world. The drugs have acted to prolong survival, reduce the viral load, and to alleviate suffering. However, the incidence of side effects and resistance is high and the drugs are unaffordable and unavailable in the developing world. HAART regimens are difficult to comply with. Public health efforts to modify the behaviour, attitude and culture that accelerate the spread of HIV/AIDS have had only modest success.

There is urgent need for a prophylactic and/or therapeutic HIV vaccine. This is a review of the obstacles and current trends in HIV vaccine development. Copyright © 2002 John Wiley & Sons, Ltd.
Hot‐electron numerical modelling of short gate length pHEMTs applied to novel field plate structures
Authors: Hussain Shahzad , Cole Eric A. B. , Snowden Christopher M.
Published: January 2003

Hot‐electron numerical simulations were carried out in order to simulate the DC parameters of pseudomorphic high electron mobility transistors (pHEMTs). The hot‐electron effects were studied by simulating several HEMT device structures. Hot‐carrier injection in the substrate and the formation of the peak of electric field in the channel were studied in detail. The inclusion of a field‐plate contact in a multiple recessed pHEMT structure lowered the peak value of the electric field by 24% compared with the conventional pHEMT. These devices were modelled by solving the two‐dimensional Poisson, current continuity and energy transport equations consistently with the time‐independent Schrödinger wave equation. Appropriate Ohmic boundaries are discussed here and implemented in the simulations of pHEMT structures. A new integral approximation is used to calculate electron densities and electron energy densities for degenerate approximations. Copyright © 2002 John Wiley & Sons, Ltd.
Influence of the carrier diffusion process on the transient response of vertical‐cavity surface‐emitting lasers
Authors: Torre M. S. , Ranea‐Sandoval H. F.
Published: January 2003

We investigate the transverse mode dynamics of weakly index‐guided vertical‐cavity surface‐emitting lasers (VCSEL). The turn‐on time of transverse modes are calculated by implementing a model for the VCSEL dynamics including diffusion and transport/capture phenomena. It takes into account the spatial dependence of the two carrier density profiles associated with the confined carriers in the quantum wells, and with the unconfined carriers in the barrier region. Devices of different aperture diameter under different excitation conditions are also studied. The model displays the correct turn‐on time dependence on the injection current density when compared with the experimental data available. We show that the turn‐on time of the modes increases when capture time increases and escape time decreases and also when diffusion increases. Copyright © 2002 John Wiley & Sons, Ltd.
A parallel 3D semiconductor device simulator for gradual heterojunction bipolar transistors
Authors: J. García‐Loureiro Antonio , López‐González J. M. , F. Pena Tomás
Published: January 2003

In this paper, we present a parallel three‐dimensional semiconductor device simulator for gradual heterojunction bipolar transistor. This simulator uses the drift‐diffusion transport model. The Poisson equation and continuity equations were discretized using a finite element method (FEM) on an unstructured tetrahedral mesh. Fermi–Dirac statistics is considered in our model and a compact formulation is used that makes it easy to take into account other effects such as the non‐parabolic nature of the bands or the presence of various subbands in the conduction process. Domain decomposition methods were tested to solve the linear systems. We have applied this simulator to a gradual heterojunction bipolar transistor (HBT), and we present some measures of the parallel execution time for several solvers and some electrical results. This code has been implemented for distributed memory multicomputers, making use of the MPI message passing standard library and a parallel solver library. Copyright © 2002 John Wiley & Sons, Ltd.
An agent‐based framework for parametric studies of numerical modelling problems in computational electromagnetics
Authors: Biniaris C. G. , Kostaridis A. I. , Kaklamani D. I. , Venieris I. S.
Published: January 2003

In this paper, we present the design of a generic agent‐based framework for distributed parametric analysis of numerical modelling problems on a network of workstations and its application in computational electromagnetics (CEM). The entire infrastructure is based on a Master–Worker paradigm that utilizes mobile agents in order to gather information about the hosts of the network, transfer the native code there, handle its execution and collect the results. Such a framework enables scientists and engineers to perform simulations and parametric studies, in order to determine configurations and characteristics of the scenarios being modelled and, thereby, to greatly improve and shorten design processes. A case study in antenna modelling is presented, in order to test the efficiency of the developed framework. Copyright © 2002 John Wiley & Sons, Ltd.
Verification of 1D BJT numerical simulation and its application to mixed‐level device and circuit simulation
Authors: Chang Chia‐Cherng , Dai Jing‐Fu , Tsai Yao‐Tsung
Published: January 2003

In this paper, we study on a 1D BJT model, which saves the memory size and computation time and verify that the characteristic of 1D BJT model is in good agreement with 2D BJT model. We use the equivalent circuit approach to simulate the BJT device. Poisson's equation and continuity equations for electron and hole are formulated into a subcircuit format suitable for general circuit simulator in the equivalent circuit approach. In order to solve the 2D device simulation, the simulation environment needs a powerful solver. So we use the band matrix solver to replace the full matrix solver. But the 2D BJT simulation still needs a large computation time, so we must develop the efficient 1D BJT model. In 1D BJT simulation, we have overcome the base boundary condition and verified that the base boundary conditions in 1D BJT model closely approach to that in 2D BJT model. Finally, we apply it to two applications and study the operation concepts of these applications. Copyright © 2002 John Wiley & Sons, Ltd.
Experimental photodynamic therapy for malignant pleural mesothelioma with pegylated mTHPC
Authors: Krueger Thorsten , Altermatt Hans J. , Mettler Daniel , Scholl Beatrix , Magnusson Lennart , Ris Hans‐Beat
Published: January 2003

Background and Objectives

Experimental assessment of photodynamic therapy (PDT) for malignant pleural mesothelioma using a polyethylene glycol conjugate of meta‐tetrahydroxyphenylchlorin (PEG–mTHPC).

Study Design/Materials and Methods

(a) PDT was tested on H‐meso‐1 xenografts (652 nm laser light; fluence 10 J/cm2; 0.93, 9.3, or 27.8 mg/kg of PEG–mTHPC; drug‐light intervals 3–8 days). (b) Intraoperative PDT with similar treatment conditions was performed in the chest cavity of minipigs (n = 18) following extrapleural pneumonectomy (EPP) using an optical integrating balloon device combined with in situ light dosimetry.

Results

(a) PDT using PEG–mTHPC resulted in larger extent of tumor necrosis than in untreated tumors (P ≤ 0.01) without causing damage to normal tissue. (b) Intraoperative PDT following EPP was well tolerated in 17 of 18 animals. Mean fluence and fluence rates measured at four sites of the chest cavity ranged from 10.2 ± 0.2 to 13.2 ± 2.3 J/cm2 and 5.5 ± 1.2 to 7.9 ± 1.7 mW/cm2 (mean ± SD). Histology 3 months after light delivery revealed no PDT related tissue injury in all but one animal.

Conclusions

PEG–mTHPC mediated PDT showed selective destruction of mesothelioma xenografts without causing damage to intrathoracic organs in pigs at similar treatment conditions. The light delivery system afforded regular light distribution to different parts of the chest cavity. Lasers Surg. Med. 32:61–68,2003. © 2003 Wiley‐Liss, Inc.
MRI thermodosimetry in laser‐induced interstitial thermotherapy
Authors: Prudhomme Michel , Mattéi‐Gazagnes Martine , Fabbro‐Peray Pascale , Puche Pierre , Chabalier Jean‐Paul , Delacrétaz G. , François‐Michel Lopez F.M. , Godlewski Guilhem
Published: January 2003

Background and Objectives

The aim of this study was to establish a correlation between a thermal measurement and a magnetic resonance imaging (MRI) signal during laser‐induced interstitial thermotherapy (LITT) in liver.

Study Design/Materials and Methods

Pig liver was irradiated for 15 minutes with a diode laser at two different powers, 0.5 W (450 J) and 1.5 W (1,350 J). Tissue temperature was monitored every 20 seconds using thermocouples. Thermosensitive MRI sequences (T1‐weighted Turbo‐Flash) were acquired with the same irradiation parameters. Correlation between MRI signals (SI) and temperature measures was defined at two different distances from the fiber (5 and 10 mm).

Results

At 0.5 W, temperatures rose progressively up to a maximum increase of 9.5°C at 5 mm and 4°C at 10 mm after 15 minutes. The corresponding MRI signal decreased progressively to −27.6 SI at 5 mm and −18.5 SI at 10 mm. At 1.5 W, temperatures rose dramatically at 5 mm, reaching a plateau. The temperature elevation measured at the end of the irradiation was of 30°C whereas at 10 mm it was only 14.5°C. The MRI signal varied accordingly, remaining inversely proportional to temperature (−76 SI at 5 mm and −35.5 SI at 10 mm).

Conclusions

An inversely proportional relationship was observed between MRI signal in sequential Turbo‐Flash and temperature. MRI should allow to analyze heat diffusion in the liver, and thus to monitor real‐time LITT treatments. Lasers Surg. Med. 32:54–60,2003. © 2003 Wiley‐Liss, Inc.
Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett's esophagus
Authors: Pfefer T. Joshua , Paithankar Dilip Y. , Poneros John M. , Schomacker Kevin T. , Nishioka Norman S.
Published: January 2003

Background and Objectives

Temporal and spectral fluorescence spectroscopy can identify adenomatous colonic polyps accurately. In this study, these techniques were examined as a potential means of improving the surveillance of high grade dysplasia (HGD) in Barrett's esophagus (BE).

Study Design/Materials and Methods

Using excitation wavelengths of 337 and 400 nm, 148 fluorescence spectra, and 108 transient decay profiles (at 550 ± 20 nm) were obtained endoscopically in 37 patients. Corresponding biopsies were collected and classified as carcinoma, HGD, or low risk tissue (LRT) [non‐dysplastic BE, indefinite for dysplasia (IFD), and low grade dysplasia (LGD)]. Diagnostic algorithms were developed retrospectively using linear discriminant analysis (LDA) to separate LRT from HGD.

Results

LDA produced diagnostic algorithms based solely on spectral data. Moderate levels of sensitivity (Se) and specificity (Sp) were obtained for both 337 nm (Se = 74%, Sp = 67%) and 400 nm (Se = 74%, Sp = 85%) excitation.

Conclusions

In the diagnosis of HGD in BE, steady‐state fluorescence was more effective than time‐resolved data, and excitation at 400 nm excitation was more effective than 337 nm. While fluorescence‐targeted biopsy is approaching clinical usefulness, increased sensitivity to dysplastic changes—possibly through modification of system parameters—is needed to improve accuracy levels. Lasers Surg. Med. 32:10–16,2003. © 2003 Wiley‐Liss, Inc.
Prospective study on the treatment of postburn hyperpigmentation by intense pulsed light
Authors: Ho Wai Sun , Chan Henry H. , Ying Shun Yuen , Chan Pik Chu , Burd Andrew , King Walter WK.
Published: January 2003

Background and Objectives

Postburn hyperpigmentation is a common phenomenon among Asian especially over grafted areas and sometimes over donor sites and healed wounds without skin graft. This condition is difficult to treat and can cause severe psychological distress. Intense pulsed light (IPL) has been used to treat melanocytic lesions with promising result. The role of IPL in treating postburn hyperpigmentation has not been explored. The purpose of this study was to assess the efficacy and complication of IPL in the treatment of postburn hyperpigmentation prospectively.

Study Design/Materials and Methods

Nineteen Chinese patients with postburn hyperpigmentation were treated by IPL. There were 14 females and 5 males. Their age ranged from 8 to 51 years with a mean age of 29.4 ± 11.6 years. The cutoff filters of 550, 570, and 590 nm were used for 3–7 treatments at intervals of 3–4 weeks. Patients were treated with an energy fluence of 28–46 J/cm2, pulse width of 1.7–4 milliseconds, double pulse mode, and a delay of 15–40 milliseconds.

Results

Treatment results and complications were evaluated and scored after each treatment. Over 78% of the patients showed more than 50% clinical clearance and nearly 32% of the patients were able to achieve more than 75% clearing. Although two patients had no clinical response, one patient had 100% clearing. Three patients developed blisters and one patient had erythema that all resolved within 1 week without leaving permanent marks. They have been followed‐up from 11–32 months and there was no recurrence of the hyperpigmentation.

Conclusions

IPL is effective and safe in treating postburn hyperpigmentation in Asian patients. Lasers Surg. Med. 32:42–45,2003. © 2003 Wiley‐Liss, Inc.
Chronic and acute analysis of optic nerve sheath fenestration with the free electron laser in monkeys
Authors: Joos Karen M. , Mawn Louise A. , Shen Jin H. , Casagrande Vivien A.
Published: January 2003

Background and Objectives

The Amide II wavelength (6.45 μm) produced by the free electron laser (FEL) can efficiently create an optic nerve sheath fenestration in rabbits. We wished to determine if it would be equally successful in macaque monkeys and to determine the histopathologic changes between traditional scissors or knife optic nerve sheath fenestration to FEL fenestration.

Study Design/Materials and Methods

Optic nerve sheath fenestration was performed using either the FEL (6.45 μm, 30 Hz, 2–3 mJ, 325‐μm spot size) through a hollow waveguide probe in 12 eyes or with a scissors or a knife in 6 eyes. The monkeys survived 1 month with the fellow optic nerve operated acutely just prior to sacrifice. Optic nerves were evaluated histologically.

Results

Less tissue manipulation was required using the FEL surgical probe. Electroretinograms showed minimal or no change. Tissue responses using either method were similar following chronic or acute incisions. Mild upregulation of vimentin and glial fibrillary acid protein (GFAP) was seen in astrocytes adjacent to the fenestration, but no change in S100β was evident.

Conclusions

The FEL energy at 6.45 μm delivered through a hollow waveguide appears capable of efficiently and safely producing an optic nerve sheath fenestration in monkeys. This innovative surgical technique should be considered for human use. Lasers Surg. Med. 32:32–41,2003. © 2003 Wiley‐Liss, Inc.