bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholinesterase inhibitors for Alzheimer's disease: variations in clinical practice in the north‐west of England
Authors: Purandare Nitin , Swarbrick Caroline , Fischer Alastair , Burns Alistair
Published: August 2006

Background

In the UK, the National Institute for Health and Clinical Excellence (NICE) is currently reviewing cost‐effectiveness of cholinesterase inhibitors (ChEIs) for Alzheimer's disease (AD) in the NHS. The implementation of the original NICE (2001) guidance that made these drugs available in the UK was not examined in this review process, and was the objective of this study.

Method

Ten hospitals in and around Manchester participated in the audit. Case records of all patients who were started on ChEIs between January 2002 and the date of the audit (November 2003 to December 2004) were examined to assess adherence to the NICE (2001) guidance. Information about available resources was gathered from lead clinicians of each hospital.

Results

A total of 1092 case records were examined. The treatment of AD with ChEIs varied considerably with regard to pre‐treatment investigations, waiting period for treatment, scales used to assess efficacy, adherence to the NICE (2001) guidance, and available resources. The actual number of patients with mild to moderate AD receiving ChEIs was much lower than that expected from known prevalence rates. Non‐uniformity of clinical practice and missing data were the main limitations of the audit.

Conclusion

There is a need to harmonise the use and monitoring of ChEIs for AD in the NHS so that the data from routine clinical practice could feed into future clinical and cost‐effectiveness analyses. Copyright © 2006 John Wiley & Sons, Ltd.
Elevation of plasma concentration of adhesion molecules in late‐life depression
Authors: Dimopoulos Nikolaos , Piperi Christina , Salonicioti Aristea , Mitsonis Charalampos , Liappas Ioannis , Lea Robert W. , Kalofoutis Anastasios
Published: August 2006

Objectives

Late‐life depression may be associated with vascular disease. The purpose of the study was to investigate this association by determining the levels of soluble adhesion molecules (sICAM‐1 and sVCAM‐1) which represent markers of ischemia‐induced inflammation in elderly individuals with depression.

Methods

Blood samples were obtained from 33 subjects with depression selected from a community‐dwelling population after screening with the Geriatric Depression Scale, and 33 matched controls. Serum concentrations of sICAM‐1 (ng/mL) and sVCAM‐1 (ng/mL) were measured in both groups.

Results

Depressed patients (Group A) possessed significantly higher sICAM‐1 levels compared to healthy controls (Group B) (674.94 ± 166.90 ng/ml vs 467.05 ± 231.26 ng/ml, respectively, p < 0.01). Similarly the same groups demonstrated elevated sVCAM‐1 levels compared to controls (572.14 ± 182.20 ng/ml vs 449.04 ± 285.27 ng/ml, p < 0.05); a difference that in both cases remained significant after adjustment for potential confounders (gender, smoking, presence of metabolic syndrome).

Conclusion

These findings indicate an association between high serum levels of VCAM‐1, and ICAM‐1 and depression in the elderly and further support the vascular depression hypothesis, which has important implications for the understanding and management of late‐life depression. Copyright © 2006 John Wiley & Sons, Ltd.
Testing effective connectivity changes with structural equation modeling: What does a bad model tell us?
Authors: Protzner Andrea B. , McIntosh Anthony R.
Published: August 2006

Structural equation modeling (SEM) is a statistical method that can assess changes in effective connectivity across tasks or between groups. In its initial application to neuroimaging data, anatomical connectivity provided the constraints to decompose interregional covariances to estimate effective connections. There have been concerns expressed, however, with the validity of interpreting effective connections for a model that does not adequately fit the data. We sought to address this concern by creating two population networks with different patterns of effective connectivity, extracting three samples sizes (N = 100, 60, 20), and then assessing whether the ability to detect effective connectivity differences depended on absolute model fit. Four scenarios were assessed: (1) elimination of a region showing no task differences; (2) elimination of connections with no task differences; (3) elimination of connections that carried task differences, but could be expressed through alternative indirect routes; (4) elimination of connections that carried task differences, and could not be expressed through indirect routes. We were able to detect task differences in all four cases, despite poor absolute model fit. In scenario 3, total effects captured the overall task differences even though the direct effect was no longer present. In scenario 4, task differences that were included in the model remained, but the missing effect was not expressed. In conclusion, it seems that when independent information (e.g., anatomical connectivity) is used to define the causal structure in SEM, inferences about task‐ or group‐dependent changes are valid regardless of absolute model fit. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
The economic value of fatal and non‐fatal occupational risks in Mexico City using actuarial‐ and perceived‐risk estimates
Authors: Hammitt James K. , Ibarrarán María Eugenia
Published: August 2006

Compensating wage differentials are used to estimate marginal rates of substitution between income and both fatal and non‐fatal occupational‐injury risks in the Mexico City metropolitan area. Data are obtained by in‐person survey of almost 600 workers and include workers' perceived risks of fatal and non‐fatal occupational injury supplemented by actuarial‐risk estimates from government statistics. Results using both actuarial‐ and perceived‐risk estimates are reasonably consistent. Estimates of the value per statistical life are between US$235 000 and US$325 000 and estimates of the value per statistical non‐fatal injury are between US$3500 and US$11 000 (2002 US dollars). These values are much smaller than corresponding estimates for higher‐income countries but are compatible with the small number of prior estimates for lower‐income countries. Copyright © 2006 John Wiley & Sons, Ltd.
Behavioral differences between public and private not‐for‐profit hospitals in the Italian national health service
Authors: Barbetta Gian Paolo , Turati Gilberto , Zago Angelo M.
Published: August 2006

In this paper we attempt to identify behavioral differences between public and private not‐for‐profit hospitals, by exploiting the introduction of the DRG‐based payment system in the Italian NHS during the second half of the 1990s. We estimate the technical efficiency of a sample of hospitals for the period 1995–2000 considering an output distance function, and adopting both parametric (COLS and SF) and nonparametric (DEA) approaches. Our results show a convergence of mean efficiency scores between not‐for‐profit and public hospitals, and seem to suggest that differences in economic performances between competing ownership forms are more the result of the institutional settings in which they operate than the effect of the incentive structures embedded in the different proprietary forms. We also observe a decline in technical efficiency, probably due to policies aimed at reducing hospitalization rates. Copyright © 2006 John Wiley & Sons, Ltd.
Progressive segmented health insurance: Colombian health reform and access to health services
Authors: Ruiz Fernando , Amaya Liliana , Venegas Stella
Published: August 2006

Equal access for poor populations to health services is a comprehensive objective for any health reform. The Colombian health reform addressed this issue through a segmented progressive social health insurance approach. The strategy was to assure universal coverage expanding the population covered through payroll linked insurance, and implementing a subsidized insurance program for the poorest populations, those not affiliated through formal employment. A prospective study was performed to follow‐up health service utilization and out‐of‐pocket expenses using a cohort design. It was representative of four Colombian cities (Cendex Health Services Use and Expenditure Study, 2001). A four part econometric model was applied. The model related medical service utilization and medication with different socioeconomic, geographic, and risk associated variables. Results showed that subsidized health insurance improves health service utilization and reduces the financial burden for the poorest, as compared to those non‐insured. Other social health insurance schemes preserved high utilization with variable out‐of‐pocket expenditures. Family and age conditions have significant effect on medical service utilization. Geographic variables play a significant role in hospital inpatient service utilization. Both, geographic and income variables also have significant impact on out‐of‐pocket expenses. Projected utilization rates and a simulation favor a dual policy for two‐stage income segmented insurance to progress towards the universal insurance goal. Copyright © 2006 John Wiley & Sons, Ltd.
A dynamic analysis of GP visiting in Ireland: 1995–2001
Authors: Nolan Anne
Published: August 2006

This paper examines the determinants of GP visiting in Ireland, using panel data from the Living in Ireland Survey from 1995–2001. While cross‐sectional studies provide important information on GP visiting patterns at a certain point in time, with panel data we can also control for unobserved individual heterogeneity, as well as identify whether it is the same individuals who consistently visit their GP year on year, or whether there is more mobility in visiting. We therefore estimate dynamic models of GP utilisation, and attempt to decompose the observed variation in GP visiting into components attributable to observed individual characteristics, unobserved individual heterogeneity and state dependence. Copyright © 2006 John Wiley & Sons, Ltd.
Do personal and societal preferences differ by socio‐demographic group?
Authors: Franks Peter , Lubetkin Erica I. , Melnikow Joy
Published: August 2006

For equity, preferences used in cost‐effectiveness analyses (CEAs) should yield similar values for different groups with similar health states. We used data from the US 2000 Medical Expenditure Panel Survey, including socio‐demographics, EQ‐5D Index and EQ Visual Analog Scale (EQ VAS) scores, to examine whether EQ‐5D Index (representing community preferences) and EQ VAS (representing personal preferences) scores differed systematically by socio‐demographic group. Differences between EQ‐5D Index and EQ VAS scores by socio‐demographic group were small and mostly not statistically significant. These preliminary findings suggest that using the EQ‐5D Index in CEAs may not contribute to socio‐demographic inequities. Copyright © 2006 John Wiley & Sons, Ltd.
Do targets matter? A comparison of English and Welsh National Health priorities
Authors: Hauck Katharina , Street Andrew
Published: August 2006

National priorities and performance management regimes in the National Health Services of England and Wales diverged following devolution, most notably with respect to the use of waiting time targets, which have been progressively strengthened in England but were abandoned in Wales in the immediate post‐devolution period. We analyse routine data collected over a six‐year period from three English and one Welsh hospital trust close to the English–Welsh border to ascertain whether: (a) there is evidence of differential performance over time that relates to the country where the hospital is located; (b) within each hospital, there is evidence that English and Welsh patients faced different waiting times. Over the period the English hospitals recorded increased levels of activity, undertook proportionately more day case activity, and mortality rates fell. Activity levels remained constant in Wales, the proportion of day case activity fell, proportionately more non‐elective patients were admitted, and mortality rates rose. There is partial evidence that English patients faced lower waiting times than their Welsh counterparts and were more likely to be admitted within a target waiting period. The stronger performance management regime operating in England appears to have contributed to higher levels of performance in the English hospitals over the period. Copyright © 2006 John Wiley & Sons, Ltd.
The relationship between reliability and size of willingness‐to‐pay values: a qualitative insight
Authors: Smith Richard D.
Published: August 2006

In a previous paper, the reliability of willingness‐to‐pay (WTP) values was found to be an increasing function of the size of WTP expressed. Here, the results of a qualitative exercise conducted alongside this quantitative study are presented. The results of this exercise suggest that higher WTP values may require more thought from the respondent which, in turn, gives them greater stability. At low levels of WTP, values appear to be taken from a ‘discretionary account’, where expenditure is more volatile. Caveats to this result, and suggestions for future research, are considered in the discussion. Copyright © 2006 John Wiley & Sons, Ltd.
Does a slump really make you thinner? Finnish micro‐level evidence 1978–2002
Authors: Böckerman Petri , Johansson Edvard , Helakorpi Satu , Prättälä Ritva , Vartiainen Erkki , Uutela Antti
Published: August 2006

This paper explores the relationship between height‐adjusted weight and economic conditions in Finland, using individual microdata for the period 1978–2002. If anything, the results reveal that an improvement in regional economic conditions measured by the employment rate produces a decrease in BMI, other things being equal. The Finnish evidence presented does not support the conclusions reported for the USA, according to which temporary economic slowdowns are good for health. In contrast, at least BMI seems to increase during slumps. Copyright © 2006 John Wiley & Sons, Ltd.
The effects of Taiwan's National Health Insurance on access and health status of the elderly
Authors: Chen Likwang , Yip Winnie , Chang Ming‐Cheng , Lin Hui‐Sheng , Lee Shyh‐Dye , Chiu Ya‐Ling , Lin Yu‐Hsuan
Published: August 2006

The primary objective of this paper is to evaluate the impact of Taiwan's National Health Insurance program (NHI), established in 1995, on improving elderly access to care and health status. Further, we estimate the extent to which NHI reduces gaps in access and health across income groups. Using data from a longitudinal survey, we adopt a difference‐in‐difference methodology to estimate the causal effect of Taiwan's NHI. Our results show that Taiwan's NHI has significantly increased utilization of both outpatient and inpatient care among the elderly, and such effects were more salient for people in the low‐ or middle‐income groups. Our findings also reveal that although Taiwan's NHI greatly increased the utilization of both outpatient and inpatient services, this increased utilization of health services did not reduce mortality or lead to better self‐perceived general health status for Taiwanese elderly. Measures more sensitive than mortality and self‐perceived general health may be necessary for discerning the health effects of NHI. Alternatively, the lack of NHI effects on health may reflect other quality and efficiency problems inherent in the system not yet addressed by NHI. Copyright © 2006 John Wiley & Sons, Ltd.
Modelling the chloride signal at Plynlimon, Wales, using a modified dynamic TOPMODEL incorporating conservative chemical mixing (with uncertainty)
Authors: Page T. , Beven K. J. , Freer Jim , Neal Colin
Published: August 2006

The application of a modified version of dynamic TOPMODEL for two subcatchments at Plynlimon, Wales is described. Conservative chemical mixing within mobile and immobile stores has been added to the hydrological model in an attempt to simulate observed stream chloride concentrations. The model was not fully able to simulate the observed behaviour, in particular the short‐ to medium‐term dynamics. One of the primary problems highlighted by the study was the representation of dry deposition and cloud‐droplet‐deposited chloride, which formed a significant part of the long‐term chloride mass budget. Equifinality of parameter sets inhibited the ability to determine the effective catchment mixing volumes and coefficients or the most likely partition between occult mass inputs and chloride mass inputs determined by catchment immobile‐store antecedent conditions. Some success was achieved, in as much as some aspects of the dynamic behaviour of the signal were satisfactorily simulated, although spectral analysis showed that the model could not fully reproduce the 1/f power spectra of observed stream chloride concentrations with its implications of a wide distribution of residence times for water in the catchment. Copyright © 2006 John Wiley & Sons, Ltd.
Determination of Forchheimer equation coefficients a and b
Authors: Sidiropoulou Melina G. , Moutsopoulos Konstadinos N. , Tsihrintzis Vassilios A.
Published: August 2006

This study focuses on the determination of the Forchheimer equation coefficients a and b for non‐Darcian flow in porous media. Original theoretical equations are evaluated and empirical relations are proposed based on an investigation of available data in the literature. The validity of these equations is checked using existing experimental data, and their accuracy versus existing approaches is studied. On the basis of this analysis, some insight into the physical background of the phenomenon is also provided. The dependence of the coefficients a and b on the Reynolds number is also detected, and potential future research areas, e.g. investigation of inertial effects for consolidated porous media, are pointed out. Copyright © 2006 John Wiley & Sons, Ltd.
The River Arno catchment, northern Tuscany: chemistry of waters and sediments from the River Elsa and River Era sub‐basins, and sulphur and oxygen isotopes of aqueous sulphate
Authors: Cortecci Gianni , Dinelli Enrico , Boschetti Tiziano
Published: August 2006

Within the hydrologic balance of the River Arno catchment (northern Tuscany), the Rivers Elsa and Era are important tributaries entering the main river from the left bank in the lower part of the watershed. Waters and bed sediments were sampled in June 2000 during low discharges in the Rivers Elsa and Era, as well as in major tributary streams. Water samples were analysed for major chemistry and sulphur isotope composition of sulphate, and sediment samples were analysed for major composition and selected trace elements of environmental concern (Zn, Cu, Pb, Cr and Ni).

The main results for the waters are: (1) Na and Cl in solution show consistent downstream positive trends in the main rivers, thus supporting progressive contributions of anthropogenic salts; the highest concentration values are observed in tributaries; (2) as shown by sulphur isotopes, sulphate in solution is mainly controlled by dissolution of evaporites (Elsa basin) or oxidation of reduced organic/biogenic sulphur (Era basin), with anthropogenic contributions in most streams not higher than 10% in both the basins. A δ34S signature in the range −2 to +3‰ is estimated for pollutant sulphate in the basins studied. The main results for the sediments are: (1) major chemistry is essentially controlled by the lithotypes drained by the waters; (2) pollution by heavy metals does not reach high levels; (3) compared with local fine‐grained rocks, copper is more frequently anomalous, whereas lead and zinc show only occasional anomalies; (4) local high concentrations of chromium and nickel can be attributed to upstream occurrences of ophiolites. Copyright © 2006 John Wiley & Sons, Ltd.
Parameter identification for leaky aquifers using global optimization methods
Authors: Yeh Hund‐Der , Lin Yu‐Chung , Huang Yen‐Chen
Published: August 2006

In the past, graphical or computer methods were usually employed to determine the aquifer parameters of the observed data obtained from field pumping tests. Since we employed the computer methods to determine the aquifer parameters, an analytical aquifer model was required to estimate the predicted drawdown. Following this, the gradient‐type approach was used to solve the nonlinear least‐squares equations to obtain the aquifer parameters. This paper proposes a novel approach based on a drawdown model and a global optimization method of simulated annealing (SA) or a genetic algorithm (GA) to determine the best‐fit aquifer parameters for leaky aquifer systems. The aquifer parameters obtained from SA and the GA almost agree with those obtained from the extended Kalman filter and gradient‐type method. Moreover, all results indicate that the SA and GA are robust and yield consistent results when dealing with the parameter identification problems. Copyright © 2006 John Wiley & Sons, Ltd.
A recurrent support vector regression model in rainfall forecasting
Authors: Pai Ping‐Feng , Hong Wei‐Chiang
Published: August 2006

To minimize potential loss of life and property caused by rainfall during typhoon seasons, precise rainfall forecasts have been one of the key subjects in hydrological research. However, rainfall forecast is made difficult by some very complicated and unforeseen physical factors associated with rainfall. Recently, support vector regression (SVR) models and recurrent SVR (RSVR) models have been successfully employed to solve time‐series problems in some fields. Nevertheless, the use of RSVR models in rainfall forecasting has not been investigated widely. This study attempts to improve the forecasting accuracy of rainfall by taking advantage of the unique strength of the SVR model, genetic algorithms, and the recurrent network architecture. The performance of genetic algorithms with different mutation rates and crossover rates in SVR parameter selection is examined. Simulation results identify the RSVR with genetic algorithms model as being an effective means of forecasting rainfall amount. Copyright © 2006 John Wiley & Sons, Ltd.
Predicting river water temperatures using stochastic models: case study of the Moisie River (Québec, Canada)
Authors: Ahmadi‐Nedushan Behrouz , St‐Hilaire André , Ouarda Taha B. M. J. , Bilodeau Laurent , Robichaud Élaine , Thiémonge Nathalie , Bobée Bernard
Published: August 2006

Successful applications of stochastic models for simulating and predicting daily stream temperature have been reported in the literature. These stochastic models have been generally tested on small rivers and have used only air temperature as an exogenous variable. This study investigates the stochastic modelling of daily mean stream water temperatures on the Moisie River, a relatively large unregulated river located in Québec, Canada. The objective of the study is to compare different stochastic approaches previously used on small streams to relate mean daily water temperatures to air temperatures and streamflow indices. Various stochastic approaches are used to model the water temperature residuals, representing short‐term variations, which were obtained by subtracting the seasonal components from water temperature time‐series. The first three models, a multiple regression, a second‐order autoregressive model, and a Box and Jenkins model, used only lagged air temperature residuals as exogenous variables. The root‐mean‐square error (RMSE) for these models varied between 0·53 and 1·70 °C and the second‐order autoregressive model provided the best results.

A statistical methodology using best subsets regression is proposed to model the combined effect of discharge and air temperature on stream temperatures. Various streamflow indices were considered as additional independent variables, and models with different number of variables were tested. The results indicated that the best model included relative change in flow as the most important streamflow index. The RMSE for this model was of the order of 0·51 °C, which shows a small improvement over the first three models that did not include streamflow indices. The ridge regression was applied to this model to alleviate the potential statistical inadequacies associated with multicollinearity. The amplitude and sign of the ridge regression coefficients seem to be more in agreement with prior expectations (e.g. positive correlation between water temperature residuals of different lags) and make more physical sense. Copyright © 2006 John Wiley & Sons, Ltd.
Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis
Authors: Ozaki Kazuhide , Nagasaka Takeshi , Notohara Kenji , Kambara Takeshi , Takeda Masanori , Sasamoto Hiromi , Jass Jeremy R. , Tanaka Noriaki , Matsubara Nagahide
Published: August 2006

Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser‐capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O6‐methylguanine‐DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di‐nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer. © 2006 Wiley‐Liss, Inc.
Circulating enterolactone and risk of endometrial cancer
Authors: Zeleniuch‐Jacquotte Anne , Lundin Eva , Micheli Andrea , Koenig Karen L. , Lenner Per , Muti Paola , Shore Roy E. , Johansson Ingegerd , Krogh Vittorio , Lukanova Annekatrin , Stattin Pär , Afanasyeva Yelena , Rinaldi Sabina , Arslan Alan A. , Kaaks Rudolf , Berrino Franco , Hallmans Göran , Toniolo Paolo , Adlercreutz Herman
Published: August 2006

It has been suggested that phytoestrogens protect against hormone‐dependent cancers. Lignans are the main class of phytoestrogens in Western diets. We conducted a prospective study of endometrial cancer and circulating levels of the main human lignan, enterolactone. The design was a case–control study nested within 3 prospective cohort studies, in New York, Sweden and Italy. Serum or plasma samples had been collected at enrollment and stored at −80°C. A total of 153 cases, diagnosed a median of 5.3 years after blood donation, and 271 matched controls were included. No difference in circulating enterolactone was observed between cases (median, 19.2 nmol/L) and controls (18.5 nmol/L). Adjusting for body mass index, the odds ratio for the top tertile of enterolactone, as compared to the lowest was 1.2 (95% CI, 0.7–2.0; p for trend = 0.53). Lack of association was observed in both pre‐ and postmenopausal women. No correlation was observed between enterolactone and circulating estrogens or SHBG in healthy postmenopausal women. These results do not support a protective role of circulating lignans, in the range of levels observed, against endometrial cancer. © 2006 Wiley‐Liss, Inc.
Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing γδ T cell cytotoxicity
Authors: Märten Angela , von Lilienfeld‐Toal Marie , Büchler Markus W. , Schmidt Jan
Published: August 2006

Intestinal cells express MHC related molecules termed MICA/MICB, which are up‐regulated under stress and in many gastrointestinal tumors. These molecules can be recognized by the immunoreceptor NKG2D, which is present on NK and γδ T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells. The immediate effect of soluble MIC (sMIC) on cellular cytotoxicity of γδ T cells is yet not investigated. We determined sMIC levels in sera of patients with pancreatic carcinoma and the expression of MIC on the surface of tumor cells by FACS. The effect of sMIC content in patient serum on cellular cytotoxicity of γδ T and NK cells was investigated by cytotoxicity assays. Subsequently, the effect of IFN‐α treatment on MIC expression, release and cellular cytotoxicity was investigated. Pancreatic carcinoma cells express MIC, and patient sera contain elevated sMIC levels that correlate with tumor stage and differentiation. Furthermore, cellular cytotoxicity of γδ T cells and NK cells against pancreatic carcinoma is impaired by sMIC in patient sera which is prevented by sMIC neutralization. Incubation of pancreatic cancer cells with IFN‐α increases MIC expression without induction of sMIC resulting in enhanced lysis of tumor cells. Our results demonstrate that sMIC impairs NKG2D‐mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of γδ T cells and NK cells. IFN‐α, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up‐regulation of MIC without induction of sMIC release. © 2006 Wiley‐Liss, Inc.
Germline mutations and polymorphic variants in MMR, E‐cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China
Authors: Zhang Yuanying , Liu Xiaorong , Fan Yimei , Ding Jianhua , Xu Ailing , Zhou Xuefu , Hu Xu , Zhu Ming , Zhang Xiaomei , Li Suping , Wu Jianzhong , Cao Haixia , Li Jintian , Wang Yaping
Published: August 2006

Germline mutations in MSH2, MLH1, E‐cadherin and MutY (MYH) genes have been implicated in the occurrence of gastric cancer (GC). Epidemiological investigation was performed by recruiting patients with GC onset during 2002 in Jiangsu province, China. We identified suspected hereditary GC patients based on either the GC family history or GC onset at early ages. We have screened germline variations in 101 suspected hereditary GC patients at the coding sequences of MSH2, MLH1, E‐cadherin and MYH genes with polymerase chain reaction‐denaturing high‐performance liquid chromatography (PCR‐DHPLC) analysis and DNA sequencing. The result showed that about 40% of patients carried germline variations, predominantly with missense mutations. Of the variations detected are 2 base pair substitutions, c.53C > T and c.74G > A, which is predicted to generate missense mutations of p.Pro18Leu and p.Gly25Asp, respectively, and occurred at the same allele of MYH gene. The frequency of variant haplotype T/A in patients was higher than that in the control group (p = 0.021, odds ratio [OR] = 4.43, 95% confidence interval [95% CI] = 1.33–14.72). Difference in the frequency of the silent mutation p.Asn751Asn in E‐cadherin gene was also found between patients and controls (p = 0.009, OR = 2.54, 95% CI = 1.30–4.95). Moreover, 6 types of variations were detected in MSH2 and MLH1 genes in 14 of 101 patients. Most of them occurred at exon7 of MSH2, frequently c.1168C > T, resulting in mutation of p.Leu390Phe. In summary, germline mutation at MSH2, MLH1, E‐cadherin and MYH genes is a frequent event in the familial GC. They may form a genetic basis for the familial GC susceptibility in Chinese population. © 2006 Wiley‐Liss, Inc.
The nuclear DNA repair protein Ku70/80 is a tumor‐associated antigen displaying rapid receptor mediated endocytosis
Authors: Fransson Johan , Borrebaeck Carl A.K.
Published: August 2006

To be of therapeutic relevance, a tumor‐associated antigen should be expressed on the surface of neoplastic cells but not, or to a significantly lower extent, on cells of non‐transformed nature. The Ku heterodimer (Ku70/80) is involved in DNA double strand break recognition and repair and is ubiquitously expressed in the nucleus of all cells. However, its exclusive nuclear localization has been reassessed by studies that demonstrate Ku to be expressed on the surface of tumor cell lines, displaying functions in cell adhesion, migration and invasion. In this study, we add another feature to the pluripotent role of Ku70/80 by showing that, upon binding the novel human recombinant antibody INCA‐X, the Ku70/80 heterodimer is internalized into pancreatic carcinoma cells. The receptor‐mediated endocytosis of Ku70/80 is rapid (t1/2 12 min) and extensive (90% of the receptor pool inside the cell after 100 min) as measured by rotating radioimmunoassay. Ku70/80 was also successfully used as a port of entry for cytotoxic payloads to tumor cells of various origin, as determined by indirect immunotoxin administration of a saporin‐conjugated, secondary anti‐human antibody. Thus, the internalization properties of the Ku70/80 suggest a potential role of this tumor associated antigen in selective drug‐delivery in several human malignancies. © 2006 Wiley‐Liss, Inc.
Functional studies of the chromosome 3p21.3 candidate tumor suppressor gene BLU/ZMYND10 in nasopharyngeal carcinoma
Authors: Yau Wing Lung , Lung Hong Lok , Zabarovsky Eugene R. , Lerman Michael I. , Sham Jonathan Shun‐tong , Chua Daniel Tsin‐tien , Tsao Sai Wah , Stanbridge Eric J. , Lung Maria Li
Published: August 2006

Chromosome 3p plays an important role in tumorigenesis in many cancers, including nasopharyngeal carcinoma (NPC). We have previously shown chromosome 3p can suppress tumor growth in vivo by using the monochromosome transfer approach, which indicated the chromosome 3p21.3 region was critical for tumor suppression. BLU/ZMYND10 is one of the candidate tumor suppressor genes mapping in the 3p21.3 critical region and is a candidate TSG for NPC. By quantitative RT‐PCR, it is frequently downregulated in NPC cell lines (83%) and NPC biopsies (80%). However, no functional studies have yet verified the functional role of BLU/ZMYND10 as a tumor suppressor gene. In the current study, a gene inactivation test (GIT) utilizing a tetracycline regulation system was used to study the functional role of BLU/ZMYND10. When BLU/ZMYND10 is expressed in the absence of doxycycline, the stable transfectants were able to induce tumor suppression in nude mice. In contrast, downregulation of BLU/ZMYND10 in these tumor suppressive clones by doxycycline treatment restored the tumor formation ability. This study provides the first significant evidence to demonstrate BLU/ZMYND10 can functionally suppress tumor formation in vivo and is, therefore, likely to be one of the candidate tumor suppressor genes involved in NPC. Published 2006 Wiley‐Liss, Inc.
Kaposi's sarcoma risk among transplant recipients in the United States (1993–2003)
Authors: Mbulaiteye Sam M. , Engels Eric A.
Published: August 2006

Kaposi's sarcoma (KS) risk is high in immunosuppressed transplant recipients. KS develops in recipients with pre‐existing infection with human herpesvirus 8 (HHV‐8), the causative agent for KS, but it can also occur in recipients infected by donors. The relative importance of these sources of infection in recipients in the United States is unknown. We report recipient and donor characteristics associated with KS among transplant recipients in the United States. KS risk, after solid organ transplantation during 1993–2003, was analyzed using data from the Organ Procurement and Tissue Network. Associations were determined using proportional hazards regression. Sixtyfive KS cases were identified among 234,127 transplants (incidence 8.8 per 100,000 person‐years). Most cases occurred in the first 2 years after transplantation (incidence 12.5 per 100,000 person‐years). KS risk increased steadily with recipient age (ptrend < 0.001) and was associated with the recipient being male (HR 1.8, 95% CI, 1.0–3.2), Hispanic (2.1, 1.1–3.8) and a non‐U.S. citizen (3.9, 1.8–8.6). Mismatch at the HLA‐B locus, but not at HLA‐A or HLA‐DR loci, was associated with heightened risk (HR 3.6, 95%CI 1.1–11 for 1–2 vs. 0 HLA‐B mismatches). KS was unrelated to donor characteristics and was not significantly related to use of specific antirejection medications. Our study found that KS incidence was low among transplant recipients in the United States, but it was associated with recipient age, sex and citizenship, perhaps reflecting pre‐existing HHV‐8 infection. The high KS risk immediately posttransplant and in persons with HLA‐B mismatch highlights the role of immunosuppression and/or immune stimulation in KS pathogenesis. © 2006 Wiley‐Liss, Inc.
Prospective multicenter evaluation of fecal tumor pyruvate kinase type M2 (M2‐PK) as a screening biomarker for colorectal neoplasia
Authors: Shastri Yogesh M. , Naumann Marc , Oremek Gerhard M. , Hanisch Ernst , Rösch Wolfgang , Mössner Joachim , Caspary Wolfgang F. , Stein Jürgen M.
Published: August 2006

Proliferating cells, particularly the tumor cells, express a dimeric isoenzyme of pyruvate kinase, termed M2‐PK. It's a direct target of several oncoproteins; the determination of fecal tumor pyruvate kinase type M2 (M2‐PK) might be another promising tool for colorectal cancer (CRC) screening. In this study, we have evaluated fecal M2‐PK as a screening biomarker for colorectal neoplasia. It was compared against fecal occult blood (FOB) and colonoscopy. Three hundred and seventeen consecutive subjects from 4 different centers were included. Stool specimens were collected before purgation, processed appropriately and were tested for FOB and quantitatively analyzed for M2‐PK. Colonoscopies were performed by experienced endoscopists who were unaware of fecal assay results. At cutoff value of 4 U/ml, fecal M2‐PK assay had a sensitivity, specificity, PPV and NPV of 81.1, 86.7, 71.1 and 61.9% respectively for diagnosing CRC whereas FOBT showed a sensitivity of 36.5%, specificity of 92.2%, PPV of 72.9% and NPV of 71.5% for CRC. Such low specificity of fecal M2‐PK will lead to unacceptably high number of false positives if it is used for mass CRC screening, leading to unindicated colonoscopies with its associated inconveniences, risks and costs. CRC screening test must have high specificity; a high sensitivity is not as vital. To conclude, M2‐PK was found to be a poor screening biomarker for CR neoplasia in a subject population at above average risk based on its prospective comparison with colonoscopy. These marginal performance characteristics do not permit its use as a screening tool for CR neoplasia in present clinical settings. © 2006 Wiley‐Liss, Inc.
Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: Physico‐chemistry and molecular modeling
Authors: Layre Anne‐Magali , Couvreur Patrick , Chacun Hélène , Aymes‐Chodur Caroline , Ghermani Nour‐Eddine , Poupaert Jacques , Richard Joël , Requier Denis , Gref Ruxandra
Published: August 2006

The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino‐occlusive disease. Thus, an intravenous formulation of busulfan‐loaded nanoparticles may be considered as a major progress. This study deals with busulfan entrapment by nanoprecipitation into five different types of poly(alkyl cyanoacrylate) polymers. The polymers leading to the highest busulfan loading efficiencies were poly(isobutyl cyanoacrylate) (PIBCA) and poly(ethyl cyanoacrylate). Molecular modeling along with energy minimization process was employed to identify the nature of the interactions occurring between busulfan and PIBCA. Further, optimization studies enabled to obtain PIBCA nanoparticles displaying busulfan loading ratios equal to 5.9% (w/w) together with nanoparticle yields of 71% (w/w). Since busulfan is a highly reactive molecule, we performed 1H‐NMR spectroscopy experiments showing that chemical integrity of the drug was preserved after loading into nanoparticles. The in vitro release studies under sink conditions, in water, or in rat plasma showed a fast release in the first 10 min followed by a slower one over 6 h. This phenomenon could be explained by the semi‐polar characteristics of busulfan. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Enhancement of the osteogenic efficacy of osteoblast transplantation by the sustained delivery of basic fibroblast growth factor
Authors: Park Min Sun , Kim Sang‐Soo , Cho Seung‐Woo , Choi Cha Yong , Kim Byung‐Soo
Published: August 2006

Previously, the sustained delivery of basic fibroblast growth factor (bFGF) has been demonstrated to promote bone regeneration in bone defects that had not been treated with osteogenic cell transplantation. In this study, we tested the hypothesis that the sustained delivery of bFGF could enhance osteoblast transplantation‐mediated ectopic bone formation. Rat osteoblasts and bFGF were mixed with an injectable fibrin matrix and subcutaneously transplanted to rats (cell + bFGF group). The fibrin matrix played roles in both the cell transplantation matrix and the bFGF sustained delivery matrix. The transplantation of osteoblasts suspended in a fibrin matrix without bFGF served as a control. Twelve weeks after transplantation, histological analyses of retrieved transplants showed that new bone formation was more abundant and mature in the cell + bFGF group than in the control group. The bone formation area and the calcium content in the cell + bFGF group were two‐ and nine‐fold higher, respectively, than those in the control group. Enhanced bone formation by the sustained delivery of bFGF may be attributed to the enhanced osteogenic gene expression of the transplanted cells and neovascularization of the transplants, as both mRNA expression of various osteogenic markers and arteriole density in the cell + bFGF group were significantly higher than those in the control group. This study demonstrates that the sustained delivery of bFGF can potentiate ectopic bone regeneration by osteoblast transplantation. This combination therapy may have effective implications for bone regeneration in large bone defects in which extensive osteogenic cell migration and angiogenesis are required. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Influence of adhesive systems and flowable composite lining on bond strength of class II restorations submitted to thermal and mechanical stresses
Authors: Cavalcanti Andrea Nóbrega , Mitsui Fabio Hiroyuki Ogata , Ambrosano Gláucia Maria Bovi , Marchi Giselle Maria
Published: August 2006

The purpose of this study was to evaluate the effect of adhesive systems and flowable composite lining on bond strength to gingival margins of Class II restorations after thermal/mechanical stresses. Proximal cavities were prepared in 90 bovine incisors. Teeth were assigned into nine groups (n = 10), according to the combination of bonding agent [Single Bond (SB), Optibond Solo Plus (OP), Prime & Bond NT (NT)] and layer (1 mm) of flowable composite Filtek Flow (FF) [absent, one layer, two layers]. Materials were applied according to manufacturers' instructions, and FF layers were photoactivated separately. Restorations were concluded with composite resin and were submitted to thermal (1000×, 5–55°C) and mechanical stresses (100,000×, 80 N). For microtensile evaluation, slabs from the gingival bonded interface were obtained, tested under tension, and their failure mode was observed by scanning electron microscopy. Bond strength data were analyzed using two‐way ANOVA/Tukey's test. No interaction was observed between adhesive systems and FF lining (p = 0.89). Also, no significant difference was found between bond strength values, whether or not FF layers were used (p = 0.33). However, bonding systems demonstrated significant differences (p = 0.01). SB and NT presented means higher than those observed with OP. Fracture modes varied considerably between experimental groups, and a greater frequency of cohesive failures was noted when FF layers were used. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007
Release of gentamicin from bone regenerative materials: An in vitro study
Authors: Teller M. , Gopp U. , Neumann H.‐G. , Kühn K.‐D.
Published: August 2006

Antibiotic loading of bone regenerative materials is a promising way to protect augmentation procedures from infection during the resorption phase of bone substitutes. Especially in the early stage of implantation, it should protect the grafted site against microbiological pathogens. The present study reports the release kinetics of gentamicin after loading from two synthetic bone filling materials. The first, BONITmatrix®, is a biphasic calcium phosphate silica composite obtained by the sol–gel route consisting of 13% silicon dioxide (w/w) and calcium phosphates (hydroxyapatite/β‐tricalcium phosphate 60/40 w/w). The second, Synthacer®, is a sintered hydroxyapatite ceramic. Gentamicin was loaded by dipping and by vacuum coating. Release kinetics of the loaded Gentamicin was investigated by fluorescence polarization immunoassay and by staphylococcus aureus assay. By dipping, loading failed for Synthacer, and it was 12.7 mg gentamicin per gram bone substitute for BONITmatrix. By vacuum coating, loading was 11.3 mg gentamicin per gram bone substitute for Synthacer and 7.4 mg gentamicin per gram bone substitute for BONITmatrix. Distinct release kinetics were measured. For Synthacer, a high initial release was followed by a lower protracted release level up to 28 days. For BONITmatrix release was continuous over the investigated 70‐day period. The present data suggest that the porosity properties at the nano‐ and microscopic levels, or the composition are responsible for antibiotic loading and subsequent release. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Degradation and drug release property of star poly(ϵ‐caprolactone)s with dendritic cores
Authors: Miao Zhi‐Mei , Cheng Si‐Xue , Zhang Xian‐Zheng , Wang Qing‐Rong , Zhuo Ren‐Xi
Published: August 2006

A series of star poly(ϵ‐caprolactone)s (PCL) with dendritic cores, PAMAM‐PCLs, were synthesized through the ring‐opening polymerization of ϵ‐caprolactone (CL) initiated by poly(amidoamine) dendrimer (PAMAM‐OH). By controlling the feed ratio of the macroinitiator PAMAM‐OH to the monomer CL, the star polymers with different branch lengths and properties can be obtained. The successful incorporation of PCL sequences onto the PAMAM‐OH core was verified by FTIR, 1H NMR, and combined size‐exclusion chromatography and multiangle laser light scattering analysis. The in vitro degradation of PAMAM‐PCLs was investigated. The results show the hydrolytic degradation rate increases with increasing content of hydrophilic PAMAM‐OH core. While the enzymatic degradation rate is affected by two competitive factors, the catalytic effect of Pseudomonas cepacia lipase on the degradation of PCL branches and the hydrophilicity that depends on the polymer composition. Using the PAMAM‐PCLs with different molecular weights, the microsphere drug delivery systems with submicron sizes were fabricated using an “ultrasonic assisted precipitation method.” The in vitro drug release from these microspheres was investigated. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006