bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Just keep taking the tablets’: adherence to antidepressant treatment in older people in primary care
Authors: Maidment Rachel , Livingston Gill , Katona Cornelius
Published: October 2002

Background

Poor adherence to antidepressant medication may account for a significant proportion of treatment failures. Adherence levels and factors associated with adherence have not previously been studied in older people.

Objectives

To report the prevalence and correlates of adherence to antidepressants in people ≥ 65 years of age in a primary care setting.

Method

Sixty‐seven patients currently being prescribed antidepressants from a single rural general practice were assessed using a range of questionnaires measuring adherence to antidepressants, severity of depression, specific health education about antidepressants, level of side‐effects, insight, positive and negatives beliefs about medication in general and antidepressants in particular, level of intellectual functioning (past and present), a past history of recovery from depression, type of antidepressant, complexity of prescriptions, age and living arrangements.

Results

Forty‐five participants (67.2%) were fully adherent; seven (10.4%) mostly adherent, three (4.5%) adhered sometimes, three rarely and nine (13.4%) never. Backwards linear regression found that adherence increased with information given and cognitive impairment and decreased with concerns about taking antidepressants and severity of side‐effects.

Conclusions

Non‐adherence to antidepressant medication is a significant problem in older patients. Our study probably overestimated adherence as it was self‐report, which usually overestimates adherence and the refusals are more likely to have been people not taking tablets but still found nearly one third of the patients were non‐adherent. An intervention comprising education, eliciting and addressing specific concerns about antidepressant medication and using medication, which minimises side effects, may be helpful. Copyright © 2002 John Wiley & Sons, Ltd.
fMRI study comparing names versus pictures of objects
Authors: Sevostianov Andrei , Horwitz Barry , Nechaev Vladimir , Williams Rihana , Fromm Stephen , Braun Allen R.
Published: October 2002

We performed an fMRI one‐back recognition study aimed at distinguishing the semantic versus perceptual aspects of how objects and their written forms are processed. There were three types of visually presented items: pictures (schematic drawings of objects); words identifying these objects; and a mixed condition in which pictures were interleaved with words. A semantic decision about object identity was required when pictures were interleaved with words. This condition, contrasted with the other two, invoked a larger signal in multiple areas, including frontal cortex, bilateral occipitotemporal cortex, and the right middle temporal gyrus. We propose that the left occipitotemporal and right temporal activations are indicative of the neural substrate mediating picture–word conversions, whereas the frontal activations reflect the coordinating functions of the central executive. Hum. Brain Mapping 16:168–175, 2002. Published 2002 Wiley‐Liss, Inc.
Enzyme‐mediated catalytic asymmetric oxidations
Authors: Colonna Stefano , Sordo Simone Del , Gaggero Nicoletta , Carrea Giacomo , Pasta Piero
Published: October 2002

Enantiomerically pure sulfoxides are excellent chiral auxiliares for asymmetric synthesis and in the preparation of several enantiopure biologically active compounds. We have explored biocatalytic approaches based on the use of heme peroxidases and flavin monooxygenases such as chloroperoxidase and cyclohexanone monooxygenase respectively. By using isolated enzymes or whole‐cell biotransformations, we have prepared alkyl aryl sulfoxides, 1,3‐dithioacetal‐1‐oxides, dialkyl sulfoxides, and thiosulfinates in high enantiomeric excess. An active site model of cyclohexanone monooxygenase has been proposed in order to explain and to predict the absolute configuration of the product. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:467–473, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10074
The impact of second opinion surgical pathology on the practice of head and neck surgery: A decade experience at a large referral hospital
Authors: Westra William H. , Kronz Joseph D. , Eisele David W.
Published: October 2002

Background

A second review of histopathologic diagnoses is a quality assurance practice that helps expose diagnostic errors and guide management of patients being referred from outside hospitals. Identification of anatomic regions and specimen types that are prone to diagnostic error will be helpful in guiding policy decisions regarding mandatory second opinion surgical pathology.

Methods

All available outside pathology reports were retrieved for patients referred to The Johns Hopkins Hospital Department of Otolaryngology–Head and Neck Surgery between January 1, 1990, and January 1, 2000. The outside diagnosis was compared with diagnosis rendered at the referral hospital. A discrepant diagnosis was regarded as any change resulting in a significant modification in therapy or prognosis.

Results

Of the 814 cases reviewed, the second opinion surgical pathology diagnosis resulted in 54 (7%) changed diagnoses. Of the changed diagnosis, 13 (24%) involved a change from a benign to a malignant diagnosis; 8 (15%) involved a change from a malignant to a benign diagnosis; and 33 (61%) involved a change in tumor classification. Follow‐up information supported the second opinion diagnosis in 41 of 43 cases (95%).

Conclusions

In a consequential number of cases, second opinion surgical pathology results in major therapeutic and prognostic modifications for patients sent to large referral hospitals for head and neck oncologic surgery. © 2002 Wiley Periodicals, Inc. Head Neck 24: 684–693, 2002
Cyclooxygenase‐2: A novel molecular target for the prevention and treatment of head and neck cancer
Authors: Lin Derrick T. , Subbaramaiah Kotha , Shah Jatin P. , Dannenberg Andrew J. , Boyle Jay O.
Published: October 2002

Cyclooxygenase‐2 (COX‐2), an enzyme that catalyzes the synthesis of prostaglandins, is overexpressed in a variety of premalignant and malignant conditions, including oral leukoplakia and squamous cell carcinoma of the head and neck. Increased levels of COX‐2 may contribute to carcinogenesis by modulating xenobiotic metabolism, apoptosis, immune surveillance, and angiogenesis. In experimental models, newly developed selective COX‐2 inhibitors suppress the formation of tumors, including tongue cancer. These findings provided a rationale for a number of chemoprevention trials that are underway. Selective COX‐2 inhibitors also suppress the growth and metastases of established tumors and enhance the anticancer activity of both radiotherapy and chemotherapy in experimental animals. In this review, evidence is presented that inhibition of COX‐2 represents a promising strategy to prevent or possibly treat human head and neck cancers. © 2002 Wiley Periodicals, Inc. Head Neck 24: 792–799, 2002
Thyroid calcification and its association with thyroid carcinoma
Authors: Khoo Mark L. C. , Asa Sylvia L. , Witterick Ian J. , Freeman Jeremy L.
Published: October 2002

Aim

Calcification within the thyroid gland may occur in both benign and malignant thyroid disease, and its detection on ultrasonography is frequently dismissed by many clinicians as an incidental finding of little significance. As a tertiary referral center, most of our thyroid patients will have had thyroid ultrasonography before being referred to us, and in our experience, the incidence of malignancy in a thyroid nodule containing calcification seems to be higher than that in the average thyroid nodule. To assess this risk, we conducted this retrospective review.

Materials and Methods

Our analysis included 462 consecutive patients who underwent thyroid surgery at our institution between 1995 and 1999. We reviewed all the patients' charts for data regarding clinical findings, preoperative diagnostic investigations, and histopathologic diagnosis. Of the 462 patients, 361 (78.1%) had thyroid ultrasonography before surgery, and 49 (13.6%) of these ultrasounds showed intrathyroidal calcification.

Results

Of the 49 patients whose ultrasounds showed intrathyroidal calcification, 29 (59.2%) were found on histopathologic examination to have thyroid carcinoma. Twelve of the remaining 20 patients had multinodular goiters. Of the 29 patients with malignancy, seven (24.1%) had preoperative fine‐needle aspirates that were reported as benign. After excluding patients who were initially seen with multinodular disease, in the subset of 37 patients who presented with a solitary thyroid lesion with calcification, 28 (75.7%) were found to have carcinoma.

Conclusions

When calcification is noted within a solitary thyroid nodule, the risk of malignancy is very high. Surgery should be recommended regardless of the result of fine‐needle aspiration cytologic findings. © 2002 Wiley Periodicals, Inc.
Ergonomics interventions for wafer‐handling task in semiconductor manufacturing industry
Authors: Chung Hsiu‐Chen , Wang Mao‐Jiun
Published: October 2002

This article presents the ergonomic interventions in a semiconductor manufacturing company, with a focus on evaluating the effect of pod (wafer container) type and carrying distance on participants' maximal acceptable weight of lift (MAWL), heart rate (HR), wrist posture, and perceived exertion rating. Sixteen field operators participated in this study. The results indicate using the new pod with power grip handles produced greater MAWL than the old pod with pinch grip handles. On the other hand, the new pod also induced greater radial deviations than the old type. Recommendation for improving pod handle design is provided. Further, the increased carrying distance caused a decrease in MAWL and an increase in HR. Thus, using cart for intrabay pod transfer and minimizing manual carrying is also recommended. © 2002 Wiley Periodicals, Inc.
Development of spatial firing in the hippocampus of young rats
Authors: Martin Patrick D. , Berthoz Alain
Published: October 2002

The hippocampal formation participates in learning and memory, particularly that of a spatial nature. In adult rats, individual CA1 pyramidal neurons only fire when the animal visits specific locations in an environment, the “place field” of the neuron. Other structures (postsubiculum, thalamus, cingulum) contain neurons that code for the animal's instantaneous head direction. Previous work has shown that the rat hippocampal formation undergoes anatomical and neurophysiological maturation during the first 2 months of life and that rats <40 days of age are impaired in spatial navigation tasks. Here we show that the locational firing of CA1 pyramidal neurons is both less specific and less stable in animals aged <50 days. However, preliminary results indicate that head directional firing recorded around day 30 is essentially identical to that seen in adult animals. Therefore, the development of reliable, spatially specific place cell activity parallels the developmental time course of spatial navigational ability, but head directional firing appears before full maturation of the hippocampus. Hippocampus 2002;12:465–480. © 2002 Wiley‐Liss, Inc.
Role of medial temporal lobe in extensive retrieval of task‐related knowledge
Authors: Luo Jing , Niki Kazuhisa
Published: October 2002

The role of medial temporal lobe (MTL) in deep semantic processing was examined in a triple semantic judgment task in which subjects were asked to decide which one of the two bottom words was more semantically fit to the top word. By changing the number of bottom words that are semantically related to the top word, we can disassociate effects of reactivating the “old” semantic associations and effects of establishing “new” semantic associations on the MTL. The results of event‐related fMRI analysis indicated that MTL was more activated in the retrieval of old semantic associations than in the establishment of new semantic associations. The function of MTL in this semantic judgment task was explained as subserving the process of extensive retrieval of task‐related knowledge. Hippocampus 2002;12:487–494. © 2002 Wiley‐Liss, Inc.
Semantic knowledge in patient H.M. and other patients with bilateral medial and lateral temporal lobe lesions
Authors: Schmolck Heike , Kensinger Elizabeth A. , Corkin Suzanne , Squire Larry R.
Published: October 2002

We investigated the effects of damage to the medial temporal lobe (MTL) and anterolateral temporal cortex on semantic knowledge. We studied eight male controls, two patients with lesions limited to the hippocampal formation, three postencephalitic patients with extensive MTL lesions and variable damage to the lateral temporal cortex, and patient H.M. (whose lesion is limited mostly to the MTL, but who also has minimal damage to the anterolateral cortex). On 13 tests of semantic memory, patients with lesions limited to the hippocampal formation performed similarly to controls. Postencephalitic patients were mildly to moderately impaired on most tests. Patient H.M.'s performance was impaired on only a few tests and was less severely impaired overall than the three postencephalitic patients. A ranking of test scores showed a direct relationship between impairment and the extent of damage to lateral temporal cortex. These findings, and related findings from other studies, point to the importance of anterolateral temporal cortex for semantic knowledge. Patient H.M. performed uniquely in certain respects. For example, when providing definitions of objects, he made many grammatical errors. In contrast, the other patients with large MTL lesions made no more errors than those made by controls. Considering that H.M.'s lesion, both medially and laterally, is less extensive than the lesions in these other patients, it appears unlikely that his shortcomings in language production are related to his temporal lobe lesion. Hippocampus 2002;12:520–533. Published 2002 Wiley‐Liss, Inc.
Human declarative memory formation: Segregating rhinal and hippocampal contributions
Authors: Fernández Guillén , Klaver Peter , Fell Jürgen , Grunwald Thomas , Elger Christian E.
Published: October 2002

The medial temporal lobe (MTL) is the core structure of the declarative memory system, but which specific operation is performed by anatomically defined MTL substructures? One hypothesis proposes that the hippocampus carries out an exclusively mnemonic operation during declarative memory formation that is insensitive to content, whereas the rhinal cortex carries out an operation supporting memory formation indirectly. To explore the interaction between a salient item feature and memory formation, we contrasted neural correlates of memory formation of high‐ and low‐frequency words. Event‐related potentials (ERPs) were recorded via depth electrodes from within the MTL in nine epilepsy patients while they memorized single words. To assess memory formation, ERPs to words subsequently recalled in a free recall test were contrasted with ERPs to forgotten words. More high‐ than low‐frequency words were remembered. High‐frequency words led to distinct ERP subsequent memory effects in rhinal cortex and hippocampus. Low‐frequency words, however, were only associated with the hippocampal ERP effect. The anatomically restricted interaction between word frequency and memory formation might indicate a semantically affected operation in the parahippocampal region supporting memory formation indirectly. By contrast, the missing interaction in hippocampal recordings might suggest a direct correlate of declarative memory formation that is insensitive to item properties. Hippocampus 2002;12:514–519. © 2002 Wiley‐Liss, Inc.
Survey of the medical financial assistance schemes of the urban poor in Shanghai
Authors: Xiao‐ming Sun , Hong Liang , Yuan Cheng , Wen‐hua Tian
Published: October 2002

After 1990, being a ‘pilot city’ for health care reform, Shanghai constructed modernized medical financial assistance schemes (MFAS), which were progressively applied by the central government rate in the 1990s. As the pioneer of social security reform in China, Shanghai again is the place with most experience of the problems of the transition from ‘Public‐Relief’ to ‘Social‐Assistance’. From the ‘user’ perspective of MFAS, the study reported has attempted to evaluate MFASs. Furthermore, the research seeks to point to future policy and programme options for implementing MFAS and optimizing the allocation of urban health care resources. Copyright © 2002 John Wiley & Sons, Ltd.
Burnout and job satisfaction among student support services personnel
Authors: Brewer Ernest W. , Clippard Laura Faye
Published: October 2002

This study measured burnout and job satisfaction among Student Support Services personnel (SSSP). In
it, the researchers used the Maslach Burnout Inventory (MBI) to measure emotional exhaustion,
depersonalization, and personal accomplishment. Job satisfaction was measured using the Job Satisfaction Scale
(JSS), which examined intrinsic, organizational, and salary and promotion. The study correlated three
components of burnout with the total mean on job satisfaction. Burnout levels were compared to national norms.

Two‐hundred fifty individuals were randomly selected from 1,702 SSSP. This yielded 166 usable surveys,
for a response rate of 66 percent. Results, using the Spearman rho and rank transformation regression analysis,
were significant. Findings disclosed a significant negative relationship between emotional exhaustion and total job
satisfaction, a significant positive relationship between personal accomplishment and total job satisfaction, and
an overall significant relationship between the three components of burnout and total job satisfaction.
Remotely sensed data used for modelling at different hydrological scales
Authors: Droogers Peter , Kite Geoff
Published: October 2002

There is a growing awareness that water will be one of the most critical natural resources and that there is a need for better management of the limited water resources. This paper reports on a study of a water‐scarce river basin in western Turkey. Hydrological analyses, emphasizing water use for irrigation, are performed at three different spatial scales (field scale, irrigation scheme scale and basin scale) using two kind of model: a parametric basin‐scale model and a physically based crop‐scale model. Data accessibility for this basin, especially for areal data, was low. A combined use of public domain data sets and remotely sensed data was used to solve this problem. A public domain digital elevation model was used to generate the streamflow network and the distances and slopes to streams. Land‐cover data and leaf area index data were derived from public domain NOAA–AVHRR images. For one irrigation scheme in the basin, detailed areal water balances were obtained from the simulation model and a comparison was made between a normal and a water‐short year. At the basin scale, observed flows were compared with simulated flows. It is concluded that remotely sensed data and other public domain data can be used with simulation models at different scales to create a powerful tool to evaluate water resources in a basin context. Copyright © 2002 John Wiley & Sons, Ltd.
Prospects for downscaling seasonal precipitation variability using conditioned weather generator parameters
Authors: Wilby R. L. , Conway D. , Jones P. D.
Published: October 2002

This paper explores the use of synoptic‐scale predictor variables to downscale both high‐ and low‐frequency components of daily precipitation at sites across the British Isles. Part I investigates seasonal and inter‐annual variations in three weather generator parameters with respect to concurrent variations in a North Atlantic Oscillation (NAO) index and area‐average sea surface temperature (SST) anomalies. Marked spatial gradients were found in the strength of the associated correlation fields using rainfall data for the period 1961–90. For example, the persistence of winter wet‐spells was most strongly correlated with the NAO index in NW Scotland, and the persistence of autumn dry‐spells with SST anomalies in SE England. At such locations, North Atlantic conditioning accounted for over 40% of the inter‐annual variability of precipitation occurrence. In Part II, three downscaling models were compared using independent daily precipitation data for sites located in the regions of strongest North Atlantic forcing. The parameters of Model M were implicitly conditioned by three regional airflow indices; the parameters of Model X were explicitly conditioned by either the NAO index or SST anomalies and daily vorticity; and the parameters of Model U (a three‐parameter stochastic rainfall model) were unconditional. Overall, the conditional models displayed greater skill for monthly rainfall statistics relative to Model U (the control), but still did not completely remove overdispersion. On comparing Models M and X, it was evident that explicit conditioning did bestow additional advantages for the chosen sites and seasons of greatest forcing. However, further research is required to determine the generality of these results for other regions and periods of the rainfall record. Copyright © 2002 John Wiley & Sons, Ltd.
El Niño–Southern Oscillation and aspects of western South American hydro‐climatology
Authors: Waylen Peter , Poveda Germán
Published: October 2002

The countries of western South America are heavily dependent upon their water resources and are subjected to considerable interannual variability in precipitation and streamflow. Many of these extremes, both high and low, are shown to be associated with the various aspects of atmosphere–ocean behaviour in the eastern and central Pacific, which are collectively termed El Niño–Southern Oscillation (ENSO). ENSO itself constitutes a complex of environmental changes that have differing influences throughout the study area, but which are loosely associated, statistically and physically, with the major regional precipitation‐generating mechanisms. As the result of a non‐linear chaotic system, no two ENSO events are the same, nor are their interactions with other regional climatic factors and the state of the continental hydrologic system, both of which may act to dampen or amplify any changes. However, statistical evidence suggests that probabilistic forecasts are possible based either upon anticipated state of the atmosphere–ocean arbitrarily classified according to somea prioriclassification scheme or upon forecasted sea surface temperatures. Examples of the changing probability distributions of hydro‐climatological variables in the study area suggest that some practical information of value may be extracted. Copyright © 2002 John Wiley & Sons, Ltd.
The Third World Water Forum: to translate visions into concrete actions and commitments
Authors: Oda Hideaki , Toyama Masato
Published: October 2002

Water is vital for the life and health of people and ecosystems and a basic requirement for the development of countries, but many people lack access to adequate and safe water to meet their most basic needs. Water resources, and the related ecosystems, are now under threat from pollution, unsustainable use, climate change, and many other forces.

The World Water Forum series has been likened to a series of stepping stones towards the solution of the world's pressing water problems. Each step constitutes a new phase. The third World Water Forum takes up the World Water Vision created at the second World Water Forum in The Hague in 2000, and sets out to see that vision realized in concrete actions. Copyright © 2002 John Wiley & Sons, Ltd.
Measurement and analysis of evapotranspiration and surface conductance of a wheat canopy
Authors: Shen Yanjun , Kondoh Akihiko , Tang Changyuan , Zhang Yongqiang , Chen Jianyao , Li Weiqiang , Sakura Yasuo , Liu Changming , Tanaka Tadashi , Shimada Jun
Published: October 2002

The characteristics of evapotranspiration and canopy surface conductance of winter wheat have been measured and analysed by using the Bowen ratio–energy balance (BREB) method. In order to understand better the effect of soil water status on evapotranspiration and conductance of wheat, the daily and seasonal variations of leaf stomatal resistance under different soil water conditions have also been monitored and analysed. The experiments have been carried out at Luancheng Experimental Station of Agro‐ecosystem (LESA), Heibei, People's Republic of China. During the growing seasons after turning to green, most of the available energy (Rn − G) of the wheat field is partitioned into latent heat. In the daily course, generally, the Bowen ratio (H/LE) for winter wheat is less than one‐third; sometimes, it can reach a value of around 0·4. The seasonal trend of LE/Rn shows a parabola curve. The ratio of LE/Rn varies from 71 to 93%, with the peak occurring in the blooming stage. G/Rn shows a declining logarithmic trend during the observation period, and reaches its minimum value of around 6–8% after blooming. According to the BREB method, the daily mean evapotranspiration rate from jointing to maturity is 3·9 mm day−1, which is very close to the value 4·1 mm derived from the water balance equation. The daily average value for canopy conductance gc is about 7·8 mm s−1. Seasonal trend of leaf stomatal resistance shows that the stomatal resistance in blooming and milking are lower than that in other growing stages. This is possibly determined by the characteristic of water requirement of winter wheat. The stomatal conductance is strongly dependent on soil water status in natural conditions. When the extractable soil water content (ESW) of the 0–40 cm layer is less than 50%, the leaf stomatal conductance gst is linearly dependent on ESW, whereas there is no relation between ESW and gst when ESW is more than 50%. Therefore, the ESW of 50% can be considered as a threshold value of extractable soil water content for controlling the leaf stomatal conductance, or as an indicator of incipient stomatal closure. The slope of the gst–ESW line varies through the growing stages, with the largest slope occurring in the milking stage. Based on the analysis of gst–ESW relations, we construct a simple but realistic model of stomatal conductance–soil moisture relations. Copyright © 2002 John Wiley & Sons, Ltd.
Different methods for modelling the areal infiltration of a grass field under heavy precipitation
Authors: Merz Bruno , Bárdossy András , Schiffler Gerd R.
Published: October 2002

The areal infiltration behaviour of a grass field is studied using a data set of 78 sprinkler infiltration experiments. The analysis of the experimental data shows a distinct event dependency: once runoff begins, the final infiltration rate increases with increasing rainfall intensity. This behaviour is attributed to the effects of small‐scale variability. Increasing rainfall intensity increases the ponded area and therefore the portion of the plot which infiltrates at maximum rate. To describe the areal infiltration behaviour of the grass field the study uses two different model structures and investigates different approaches for consideration of subgrid variability. It is found that the effective parameter approach is not suited for this purpose. A good representation of the observed behaviour is obtained by using a distribution function approach or a parameterization approach. However, it is not clear how the parameters can be derived for these two approaches without a large measurement campaign. The data analysis and the simulations show the great importance of considering the effects of spatial variability for the infiltration process. This may be significant even at a small scale for a comparatively homogeneous area. The consideration of heterogeneity seems to be more important than the choice of the model type. Furthermore, similar results may be obtained with different modelling approaches. Even the relatively detailed data set does not seem to permit a clear model choice. In view of these results it is questionable to use very complex and detailed simulation models given the approximate nature of the problem. Although the principle processes may be well understood there is a lack of models that represent these processes and, more importantly, there is a lack of techniques to measure and parameterize them. Copyright © 2002 John Wiley & Sons, Ltd.
Bivariate stochastic modelling of ephemeral streamflow
Authors: Cigizoglu H. Kerem , Adamson Peter T. , Metcalfe Andrew V.
Published: October 2002

Streamflow time series in arid and semi‐arid regions can be characterized as a sequence of single discrete flow episodes or clusters of hydrographs separated by periods of zero discharge. Here, two point process models are presented for the joint occurrence of flow events at neighbouring river sites. The first allows for excess clustering by adding autocorrelated errors to an empirically derived seasonally varying probability of an event and is extended to the case of the joint occurrence of flow events in two catchments. The second approach is to explicitly model the occurrences of clusters of events and the bivariate point process of event occurrences within them at both sites. For the two models, the magnitude of event peaks are assumed to be drawn from continuous distributions with seasonally varying parameters. Rises and recessions in discharge are interpolated between the peaks using regression estimates of hydrographs. The models are fitted to mean daily flows at two sites in Namibia and demonstrated to provide realistic simulations of the hydrology. Copyright © 2002 John Wiley & Sons, Ltd.
Urinary level of 1,N6 ‐ethenodeoxyadenosine, a marker of oxidative stress, is associated with salt excretion and ω6‐polyunsaturated fatty acid intake in postmenopausal Japanese women
Authors: Hanaoka Tomoyuki , Nair Jagadeesan , Takahashi Yoshiko , Sasaki Satoshi , Bartsch Helmut , Tsugane Shoichiro
Published: October 2002

Excretion of 1,N6‐ethenodeoxyadenosine (ϵdA), a marker for lipid peroxidation (LPO)‐derived DNA damage was analyzed in urine of nonsmoking postmenopausal women participating in a dietary intervention trial in Northern Japan. Hereby the efficacy of dietary consultation in reducing salt and increasing vitamin C and carotenes during 1 year was estimated. Thirty postmenopausal women, 60–69 years of age, from the intervention group and 30 age‐matched women from the control group were randomly selected. The subjects completed a self‐administered diet history questionnaire and in the pre‐ and post‐intervention period 48 hr urine and fasting blood samples were collected. ϵdA in urine was analyzed by an immuno‐precipitation‐high performance liquid chromatography‐fluorescence detection method. ϵdA excretion (/48 hr) in the 59 postmenopausal Japanese women with complete urine collection ranged from 12–226 pmol at the pre‐intervention. At the pre‐intervention, ϵdA excretion was positively associated with urinary salt excretion (R = 0.33, p = 0.01) and ω‐6 polyunsaturated fatty acid intake (%energy value, R = 0.28, p = 0.03) in the 59 women. The average ϵdA excretion in the intervention group was 61 pmol at pre‐intervention and 44 pmol at post‐intervention (p = 0.14). In the control group, it was 58 pmol at pre‐intervention and 75 pmol at post‐intervention (p = 0.24). During the intervention period, 18/29 (62%) of the subjects in the intervention group exhibited the decreased excretion and 10/26 (38%) in the control group (p = 0.08). Results from this pilot study suggest urinary ϵdA as a potential biomarker of DNA damage possibly derived from salt‐induced inflammation and LPO; further exploration of ϵdA in human biomonitoring studies is warranted. © 2002 Wiley‐Liss, Inc.
Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism
Authors: Feleszko Wojciech , Młynarczuk Izabela , Olszewska Dominika , Jalili Ahmad , Grzela Tomasz , Lasek Witold , Hoser Grażyna , Korczak‐Kowalska Grażyna , Jakóbisiak Marek
Published: October 2002

Lovastatin, a drug successfully used in the clinic to prevent and to treat coronary heart disease, has recently been reported to decrease the incidence of melanoma in lovastatin‐treated patients. Lovastatin has also been proved to potentiate antitumor effects of both cisplatin and TNF‐α in murine melanoma models. Recently, an augmented therapeutic effect of lovastatin and doxorubicin has been reported in 3 tumor models in mice. In our preliminary study lovastatin caused retardation of melanoma growth in mice treated with doxorubicin (Feleszko et al. J Natl Cancer Inst 1998;90:247–8). In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP‐cleavage assay, annexin V assay and TUNEL). The combined antiproliferative activity of lovastatin and doxorubicin was evaluated using the combination index (CI) method of Chou and Talalay, revealing synergistic interactions in melanoma cells exposed to lovastatin and doxorubicin. In B16F10 murine melanoma model in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (5 mg/kg for 14 days) and doxorubicin (4 × 1 mg/kg) as compared with either agent acting alone. Lovastatin treatment resulted also in significant reduction of the number of experimental metastasis in doxorubicin‐treated mice. The results of our studies suggest that lovastatin may enhance the effectiveness of chemotherapeutic agents in the treatment of malignant melanomas. © 2002 Wiley‐Liss, Inc.
Covariates and confounding in epidemiologic studies using metabolic gene polymorphisms
Authors: Taioli Emanuela , Garte Seymour
Published: October 2002

The relationship between exposure and disease when biomarkers are introduced in an epidemiologic study is explored and summarized. In molecular epidemiologic studies, biologic measurements play a major role as markers of exposure, disease or susceptibility to disease and/or exposure. In this scenario, the definition and management of confounding factors may change. Sometimes the presence or activation of the biomarker is partially caused by the relevant environmental exposure, and therefore the 2 variables (exposure and biomarker) should not be always treated as confounders of each other. Models of exposure‐disease association in the presence of biologic markers are presented. The concept of confounders is reviewed in light of the role of biomarkers in the pathway between exposure and disease. © 2002 Wiley‐Liss, Inc.
Distinct in vivo expression patterns of survivin splice variants in renal cell carcinomas
Authors: Mahotka Csaba , Krieg Thomas , Krieg Andreas , Wenzel Michael , Suschek Christoph V. , Heydthausen Manfred , Gabbert Helmut E. , Gerharz Claus D.
Published: October 2002

Survivin, a novel member of the inhibitor of apoptosis protein (IAP) family, reduces the susceptibility of tumor cells to proapoptotic stimuli, thereby promoting tumor cell survival during tumor progression and treatment with anticancer drugs. Recently, we identified 2 novel alternative splice variants of survivin, survivin‐2B and survivin‐ΔEx3, which differ in their antiapoptotic properties. Survivin‐2B has lost its antiapoptotic potential and may act as a naturally occurring antagonist of antiapoptotic survivin and survivin‐ΔEx3. Because the in vivo expression of these splice variants in human cancer has not been analyzed so far, 57 renal cell carcinomas (RCCs) were explored using quantitative reverse transcriptase polymerase chain reaction. We found that all RCCs express survivin‐ΔEx3, survivin‐2B and survivin, the latter being the dominant transcript. When we compared early and intermediate stages with late stages of clear cell RCCs, no significant changes in the expression levels of survivin and survivin‐ΔEx3 became evident. However, a significant decrease was observed for the mRNA ratio between survivin‐2B and survivin in late tumor stages (p = 0.036). Chromophilic/papillary RCCs, which are known to be less aggressive than clear cell RCCs, did not show significantly lower expression levels of antiapoptotic survivin and survivin‐ΔEx3, compared with stage‐adjusted clear cell RCCs. Our study demonstrates for the first time in vivo expression of functionally different survivin variants and suggests a role of these survivin splice variants in the progression and clinical behavior of human RCCs. © 2002 Wiley‐Liss, Inc.
Targeting of the photocytotoxic compound AlPcS4 to hela cells by transferrin conjugated peg‐liposomes
Authors: Gijsens Antoon , Derycke Annelies , Missiaen Ludwig , De Vos Dirk , Huwyler Jörg , Eberle Alex , de Witte Peter
Published: October 2002

Photodynamic therapy has attracted increasing interest over the last few years, whereby the activation of photosensitizers by light causes the production of reactive oxygen species (ROS), such as singlet oxygen, which are cytotoxic. The goal of our study was to enhance the photodynamic activity of the photosensitizer aluminum phthalocyanine tetrasulfonate (AlPcS4) through its specific delivery to tumor cells. Since many tumor cells, among which are HeLa cells, overexpress the transferrin receptor, we synthesized transferrin conjugated PEG‐liposomes that contained AlPcS4 that could be internalized by receptor mediated endocytosis. The antiproliferative activity of the targeted liposomes was evaluated and compared to the native AlPcS4 and the non‐targeted liposome. These findings were supplemented with data on intracellular concentration of the photo‐active compounds. The accumulation together with ROS production after irradiation was visualized by using confocal microscopy to confirm the data found in the antiproliferative and accumulation assay. Tf‐Lip‐AlPcS4 was 10 times more photocytotoxic (IC50, 0.63 μM) than free AlPcS4 at a light dose of 45 kJ/m whereas Lip‐AlPcS4 displayed no photocytotoxicity at all. The high photocytotoxicity of Tf‐Lip‐AlPcS4 was shown to be the result of a high intracellular concentration (136.5 μM) in HeLa cells, which could be lowered dramatically by incubating the conjugate with a competing transferrin concentration. The images of intracellular accumulation and ROS production matched the accumulation and photocytotoxicity profile of the different photo‐active compounds. The photodynamic activity of the Tf‐Lip‐AlPcS4 conjugate on HeLa cells is much more potent than free AlPcS4 as a result of selective transferrin receptor mediated uptake. © 2002 Wiley‐Liss, Inc.
Novel products of the HUD, HUC, NNP‐1 and α‐internexin genes identified by autologous antibody screening of a pediatric neuroblastoma library
Authors: Behrends Uta , Jandl Thomas , Golbeck Anja , Lechner Brigitte , Müller‐Weihrich Stephan , Schmid Irene , Till Holger , Berthold Frank , Voltz Raymond , Mautner Josef M.
Published: October 2002

Autologous serological screening of a cDNA expression library (SEREX) derived from childhood neuroblastoma led to the identification of 10 different antigens, including 6 novel gene products. The novel antigen 018INX was derived from a small open reading frame in a region of α‐internexin mRNA that was previously described as 3′ untranslated region. 018INX thus represents a novel type of tumor antigen. Five novel gene products were derived from NNP‐1 (NNP3) and Hu genes (HuC‐L, HuD3, HuDY, HuD1proc). As indicated by sequence analysis, these antigens were generated by alternative splicing and/or alternative promoter usage or allelic polymorphism. mRNA expression analyses revealed different tissue restrictions of novel compared to known HuD and NNP‐1 transcripts in normal and malignant tissues. The expressions patterns of distinct transcripts indicated potential clinical meanings as diagnostic and/or prognostic tissue markers. When kinetics of serum antibody titres against SEREX‐defined antigens were compared to tumor load over time in our patient with neuroblastoma, we found 100‐fold increases of anti‐Hu and anti‐018INX antibody titres preceding the clinical diagnosis of recurrent tumor growth after 2 years. When sera of pediatric patients with cancer (30) and healthy controls (30) were tested for humoral responses to SEREX‐defined neuroblastoma antigens, we detected antibodies against all known antigens and NNP3 with low frequencies and titres in control sera, while anti‐018INX and anti‐Hu antibodies were found in cancer patients only. Our findings indicate that SEREX‐defined tumor antigens might provide novel tools for understanding and treatment of this aggressive childhood malignancy. © 2002 Wiley‐Liss, Inc.
Recent thymic emigrants and prognosis in T‐ and B‐cell childhood hematopoietic malignancies
Authors: Petridou Eleni , Klimentopoulou Alexandra E. , Moustaki Maria , Kostrikis Leontios G. , Hatzakis Angelos , Trichopoulos Dimitrios ,   Hellenic Pediatric Hematology Oncology Group
Published: October 2002

The concentration of T‐cell receptor rearrangement excision DNA circles (TRECs) in peripheral blood mononuclear cells (PBMCs) is currently known to be a marker of recent thymic emigrants. We evaluated the hypothesis that TREC values would be lower in childhood T‐cell hematopoietic malignancies than in childhood B‐cell acute lymphoblastic leukemia (ALL) or healthy controls because the former category may reflect compromised thymic function. From the Greek national childhood leukemia/lymphoma database we obtained all 30 available T‐cell leukemia/non‐Hodgkin's lymphoma cases, 30 age‐ and sex‐matched childhood B‐cell origin cases of ALL and 60 healthy hospital controls. We compared TREC levels in PBMCs using a real‐time PCR assay. There was highly significant reduction of TREC values in children with T‐cell malignancies (median 3,100 TRECs/106 PBMCs), whereas children with B‐cell origin ALL had slightly but nonsignificantly lower TREC values compared to healthy children (medians 19,300 and 22,500 TRECs/106 PBMCs, respectively). During a median follow‐up period of about 19 months, only 4 children died. All of them had a T‐cell hematopoietic malignancy and relatively low TREC values. The number of TRECs was higher among healthy girls than among healthy boys, and a similar pattern was evident in T‐cell malignancies. It appears that there is a pattern of concordance of high TREC values with better disease prognosis in hematologic childhood malignancies. This applies to specific disease entities with better prognosis (B‐cell origin ALL having higher TREC values than T‐cell leukemia/lymphoma) and to gender, another important predictor of prognosis conditional on disease entity (girls having higher TREC values than boys); however, it may also be true for the survival of individual patients. These preliminary findings can be used as hypothesis‐generating indications that should be confirmed in larger data sets. © 2002 Wiley‐Liss, Inc.
Inhibition of CD40 expression and CD40‐mediated dendritic cell function by tumor‐derived IL‐10
Authors: Shurin Michael R. , Yurkovetsky Zoya R. , Tourkova Irina L. , Balkir Levent , Shurin Galina V.
Published: October 2002

As CD40 plays a key role in both antitumor immunity and DC maturation, we have studied the regulation of its expression during DC hematopoiesis (dendropoiesis) in vitro and in vivo in the tumor microenvironment. Using MC38 colon adenocarcinoma tumor models, we have demonstrated that DCs generated in vitro from bone marrow precursors obtained from tumor‐bearers have significantly lower expression of CD40 molecules compared to DCs generated from tumor‐free mice. Furthermore, CD40 expression on DCs isolated from the spleens of tumor‐bearing mice was also significantly reduced, suggesting that tumor‐derived factors inhibit CD40 expression on DCs during dendropoiesis both in vitro and in vivo. Interestingly, CD40 ligation on DCs generated from tumor‐bearers did not result in inducible expression of IL‐12 protein or IL‐12 p40 mRNA. However, Staphylococcus aureus–induced IL‐12 production by DCs was not altered in tumor‐bearers, confirming that inhibition of IL‐12 production by DCs generated in vitro from tumor‐bearing mice was due to reduced expression of CD40 on DCs. We have also shown that MC38 tumor cells produce IL‐10 and that exogenous IL‐10 causes downregulation of CD40 expression on DCs. In addition, endogenous IL‐10 produced by colon carcinoma cells inhibited CD40‐dependent IL‐12 production by DCs since tumor‐induced inhibition of IL‐12 production was abrogated by neutralizing anti‐IL‐10 antibody. Finally, systemic administration of FLT3L and/or CD40L reversed CD40 and IL‐12 (p40) deficiency of DCs in tumor‐bearing mice in vivo. These findings thus demonstrate that tumor‐derived factors, including IL‐10, inhibit CD40 expression on DCs and DC precursors and suppress their maturation and function. © 2002 Wiley‐Liss, Inc.
Molecular analysis of lipid‐depleting factor in a colon‐26‐inoculated cancer cachexia model
Authors: Inadera Hidekuni , Nagai Shigenori , Dong Hong‐Yan , Matsushima Kouji
Published: October 2002

Cachexia in cancer is characterized by progressive emaciation involving depletion of host adipose tissue stores, the molecular mechanism of which remains largely unknown. In this study, we have attempted to clarify the biologic characteristics of lipid‐depleting factor in a mouse cachexia model. Utilizing differentiated 3T3‐L1 adipocytes, we established an assay method quantifying the lipid‐depleting activity in plasma derived from colon‐26‐inoculated mice and then analyzed the associated molecular mechanism. Injection (s.c.) of a mouse colon adenocarcinoma cell line, colon‐26 clone 20, induced cachexia, as evidenced by progressive weight loss. Addition of clone 20–derived cachexigenic, but not clone 5–derived noncachexigenic, plasma to the culture medium of differentiated 3T3‐L1 adipocytes reduced the TG content in cultured cells. The ability of the introduced plasma to induce TG loss in 3T3‐L1 cells paralleled the body weight changes of tumor‐inoculated host mice. Clone 20 plasma, but not clone 5 plasma or recombinant IL‐6, elicited lipolytic activity, which induced glycerol release from 3T3‐L1 cells. Addition of clone 20 plasma to cultured 3T3‐L1 adipocytes reduced TG synthesis from [14C]‐glucose compared to clone 5 plasma, indicating that the lipid‐depleting activity resulting from addition of clone 20 plasma depended not only on induction of lipolysis but also on inhibition of lipogenesis. Addition of clone 20 plasma to cultured 3T3‐L1 adipocytes reduced the quantity of mature SREBP‐1 in the nucleus of 3T3‐L1 cells without affecting PPAR‐γ and C/EBP‐α. Although TNF‐α induced apoptosis in 3T3‐L1 cells, clone 20 plasma did not. These results suggest that the lipid‐depleting factor in clone 20 plasma is different from either IL‐6 or TNF‐α, and that this factor interfered with not only lipolysis but also lipogenesis through SREBP‐1 of 3T3‐L1 adipocytes. © 2002 Wiley‐Liss, Inc.