bluuebunny/crossref_metadata_2025 huggingface dataset:
ACUTE APOPTOTIC RESPONSE INDUCED BY THE COLON CARCINOGEN AOM IS DEPENDENT ON P53 GENE and NOT THE APC GENE
Authors: Hu Y , Le Leu R , Martin J , Young GP
Published: January 2004

Background/objective  Apoptosis is disordered in tumourigensis, however, the importance of apoptosis in relation to DNA damage created at the time of initiation by genotoxic carcinogens, i.e. the acute apoptotic response to genotoxic carcinogens (AARGC), has hardly been explored. p53 and APC are tumor suppressor genes known to be altered frequently in colon cancer, however, it remains unclear whether AARGC is dependent on the function of p53 or APC. p53 –/–, p53 ± and APCMin/+ mice provide an excellent model to test the biological significance of AARGC in colon in terms of its ability to delete genetically damaged cells that might progress to cancer. Thus, we have tested the hypothesis that p53 and APC play a critical role in AARGC, by studying AARGC in p53+/– , p53 –/– mice and APCMin/+0.

Methods  p53 knockout mice were produced by breeding male p53+/– with female C57BL/J mice or interbreeding p53+/– mice. APCMin/+ mice were produced by breeding male APCMin/+ mice with female C57BL/J mice. Mice geno‐typing were confirmed by PCR. At 10–12 weeks age, 44 mice were given a single subcutaneous azoxymethane (AOM 10 mg/kg) injection to induce AARGC, and killed 6 h later (the time of the maximal response). There were eight p53–/– mice, 11 p53+/– mice, nine p53+/+mice, 12 APCMin/+ mice, and six APC+/+ mice. Three p53–/– mice, four p53+/– mice, seven p53+/+ mice, two APCMin/+, and six APC+/+ mice without AOM injection were used as controls. Apoptosis in colon was measured by classic morphological H & E criteria.

Results  In p53+/+ mice, AOM induced a significant increase in apoptosis (4.70 ± 0.35, SEM, apoptotic cells per crypt column) in the distal colon, located almost exclusively in the proliferative compartment. In comparison to the pattern of apoptosis observed in the p53+/+ mice, the apoptotic response of p53–/– mice was almost nonexistent (0.12 ± 0.06) while in p53+/– mice it was significantly suppressed by approximately 50% (2.26 ± 0.28); P < 0.01. In contrast to the importance of p53 gene on AARGC, absence of the APC gene had no obvious effect on AARGC: APCMin/+ mice (5.07 ± 0.30) and APC+/+ (5.50 ± 0.33); P > 0.05.

Conclusion  p53 function appears to be critically important for carcinogen‐induced apoptosis in colon, while APC homeostasis appears not to be involved in this type of apoptosis. The loss of just one allele of p53, interferes with its function. Further studies are required to determine whether defective AARGC in p53 knockout mice puts them at increased risk of subsequent events in tumorigensis, and whether AARGC can be regulated by known protective agents.
EXPRESSION OF CYCLOOXYGENASE‐2 IN COLONIC MUCOSA IN PATIENTS WITH TUBERCULOUS COLITIS
Authors: Park Young‐Sook , Choi Il‐Ju , Kim Tae‐Hyun , Choo Yeon‐Ho , Lee Jung‐Don , Kim Eun‐Kyung
Published: January 2004

Cyclooxygenase‐2 has shown increased expression on crypt epithelium, inflammatory cells of the lamina propria and myenteric neural cells of active inflammatory bowel disease. In tuberculosis colitis, colonoscopic findings are multiple discrete ulcers on terminal ileum, ic valve and cecum with normal surrounding mucosa which are similar with Crohn's colitis. Pathologically the two disease show similar chronic inflammation and granuloma because typical acid fast bacilli and caseation necrosis are not usually detected by biopsy. We evaluated Cox‐2 expression on mucosal biopsy and surgical specimen of tuberculous colitis comparing with Crohn's colitis and nonspecific infectious colitis using immunohistochemistry. This study included 10 patients with tuberculous colitis which are confirmed by antituberculosis treatment, and 10 patients with active Crohn's colitis and 10 patients with acute infectious colitis. We find high Cox‐2 expression on both crypt epithelium and laminar propria lymphocyte (LPL) in all of tuberculous colitis (10 of 10). There are low and weak expression on epithelium (two of 10) and LPL (nine of 10) of Crohn's colitis and epithelium (one of 10) and LPL (seven of 10) of infectious colitis. Cox‐2 expression on crypt epithelium in patients with tuberculous colitis is significantly higher than Crohn's colits and infectious colitis (P < 0.01). This finding suggests that Cox‐2 expression may help differentiate tuberculous colitis from Crohn's colits before experimental antituberculosis medication.
EXPRESSION OF CYCLOOXYGENASE‐2 PROTEIN IN SERRATED ADENOMAS OF THE LARGE INTESTINE
Authors: Takeuchi M , Kobayashi M , Suzuki Y , Honma T , Azumaya M , Shioji K , Narisawa R , Hayashi S , Ajioka Y , Asakura H
Published: January 2004

Objectives  Recent studies suggest that cyclooxygenase‐2 (COX‐2) protein is involved in colorectal tumorigenesis, but its expression in serrated adenomas (SAs), a newly recognized category of colorectal neoplasia, has not been investigated in detail. The aim of this study was to evaluate the immunohistochemical expression of COX‐2 protein in SAs, especially compared with endoscopic features and with those in tubular adenomas and hyperplastic polyps.

Materials and methods  A total of 79 SAs, 65 tubular adenomas, and 21 hyperplastic polyps, obtained by colonoscopic resection, was provided for the immunohistochemical staining using anti‐COX‐2 polyclonal antibody (PG27, 1:2500). The COX‐2 expression was scored in a semiquantitative evaluation according to the staining intensity and extent of positive neoplastic cells: score 0, no or faint chromagen deposition; 1, weak intensity or moderate intensity < 50%; 2, moderate intensity or strong intensity < 50%; 3, strong intensity.

Results  Colonoscopically, SAs were divided into the following two patterns; cerebriform (n = 44), and hyperplastic (n = 35) pattern. The mean COX‐2 score in SAs with cerebriform pattern was significantly higher than that in SAs with hyperplastic pattern (1.61 vs. 0.97, P < 0.01). In contrast, the mean COX‐2 score in SAs with hyperplastic pattern was significantly higher than that in hyperplastic polyps (0.97 vs. 0.20, P < 0.01). In 26 SAs accompanied with hyperplastic glands, the COX‐2 expression in hyperplastic components was similar to that in traditional hyperplastic polyps, whereas its expression in serrated adenomatous components was similar to that in pure SAs.

Conclusions  The colonoscopic feature of SAs correlated with the immunohistochemical expression of COX‐2 protein. The COX‐2 expression in SAs with cerebriform pattern was similar to that in traditional adenomas. On the other hand, SAs with hyperplastic pattern showed intermediate COX‐2 expression between hyperplastic polyps and tubular adenomas. The expression of COX‐2 protein may be involved in the progression from hyperplastic polyps to SAs with hyperplastic pattern, and to SAs with cerebriform pattern.
EXPRESSION OF THE INTESTINE SPECIFIC TRANSCRIPTION FACTOR CDX2 IN INTESTINAL METAPLASIA OF FURAN‐TREATED RAT LIVER
Authors: Yerkovich ST , De Boer B , Sirica AE , Yeoh GCT , James RJ , Ee HC
Published: January 2004

Objectives  cdx2 is a homeodomain transcription factor exclusively expressed in intestinal epithelium and has been shown to regulate transcription of several intestine specific genes. The aim of this study was to investigate its expression in abnormal gastrointestinal differentiation, such as the development of intestinal metaplasia and subsequent ‘intestinal‐type’ adenocarcinoma in the liver of furan‐treated rats.

Methods  Immunohistochemistry was performed on tissue sections from furan‐treated rat livers and transplanted ‘intestinal‐type’ hepatic adenocarcinoma by using a polyclonal antibody against cdx2.

Results  Strong cdx2 immunoreactivity was seen in intestinal metaplastic foci, in which Alcian blue staining for mucin confirmed the presence of goblet cells. In contrast, regenerating ducts without intestinal features were negative for cdx2 immunoreactivity and Alcian blue staining. Transplanted tumours from furan‐derived hepatic adenocarcinomas were weakly positive for cdx2 and Alcian blue staining demonstrated scanty goblet cells.

Conclusion  The strong association between cdx2 expression and intestinal morphology in furan‐treated rat liver suggests that cdx2 plays an important role in the differentiation towards an intestinal phenotype.
ALTERED BONE METABOLISM IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Onuk M Derya , Yassýkaya Bülent , Akarsu Ersin
Published: January 2004

Patients with inflammatory bowel disease (IBD) are at risk of developing metabolic bone disease. We aimed to compare markers of bone metabolism and bone mineral density in patients with IBD and healthy subjects. Seventeen patients with ulcerative colitis (13 women, four men; median age 33.4; range 15–52), and eight patients with Crohn's disease (five women, three men; median age 30.2; range 21–44), and 20 healthy subjects (12 women, eight men; median age 32.5; range 17–52) were investigated.

The diagnosis of IBD was based on endoscopical, radiological and histological examinations. Markers of bone metabolism (serum calcium, alkaline phosphatase (AP), osteocalcin, phosphate, parathyroid hormone (PTH), 25‐hydroxy‐vitamin D3 (25‐OH‐D3), and urine deoxyprydoline (DPD) were measured. Bone mineral density of lumbar L2–L4 vertebrae in the anterioposterior projection, femoral neck and Ward's triangle were determined by dual X‐ray absorbtiometry (DXA).

While osteocalcine and AP levels (osteoblastic activity parameters) of patients did not differ from those of controls, urine DPD (osteoclastic activity parameter) was higher than that of controls (P < 0.05). Serum PTH and 25‐OH‐D3 levels were also higher in patients (P < 0.05). T scores of bone mineral density were statistically lower in patients than controls (P < 0.001).

Osteopenia was observed in 12 patients with IBD (48%), osteoporosis was in five patients (20%). These were significantly higher than controls (14 and 8%, respectively). There was a high prevalence of reduced bone mineral density in patients with IBD which is independent of site, activity or type of disease.
ANTIBIOTIC PROPHYLAXIS IN ELECTIVE COLORECTAL SURGERY
Authors: Gul Y , Hui Lian L , Jabar MF , Shaker AR , Moissinac K
Published: January 2004

Antibiotic administration in elective colorectal surgery is established in preventing wound infection. However, surgeons may have a tendency to prolong the administration of prophylactic antibiotic therapy in the postoperative period. The aim of this study was to elucidate the pattern of prophylactic antibiotic utilisation in elective colorectal surgery and to determine if evidence based medicine was employed in relation to this practice. A cross sectional study encompassing general surgeons performing elective colorectal surgery was performed. Questionnaires were distributed to 144 surgeons (national, academic and private healthcare). Questions pertaining to the type, timing and duration of antibiotic administration were assessed. The prevalence of wound infection audit rate and the presence of specific guidelines related to antibiotic administration were also determined. The response rate obtained was 67% (n = 96). Although evidence from the current medical literature and recommended national guidelines support the use of single dose prophylactic antibiotics, 72% of the respondents employed more than a single dose. Forty surgeons (42%) claimed that their prescribing practice was supported by the medical literature, 31 respondents (32%) based their practice on hospital guidelines and personal preference was cited as a reason by 21 surgeons (22%). The remaining four respondents (4%) used similar scheduling policy as practiced by their colleagues in relation to antibiotic administration. Twenty‐five percent of respondents audited their wound infection rate for elective colorectal surgery. There was no significant difference in antibiotic dose scheduling between national, private and university academic institutions. χ2 = 0.315 (P = 0.854). The above results suggest that a significant proportion of surgeons administer excessive and unnecessary doses of antibiotics in elective colorectal surgery. Further studies are required to uncover the exact reasons but lack of appropriate guidelines and failure to exercise evidence based medicine are major factors that account for this practice.
ANTI‐HUMAN NEURONAL PROTEIN – A NEW TOOL FOR QUANTIFICATION OF NEURONES IN THE HUMAN ENTERIC NERVOUS SYSTEM
Authors: Murphy EM , Wattchow DA , Costa M , Brookes SJH
Published: January 2004

Understanding how the enteric nervous system controls gastrointestinal function requires an account of the different classes of nerve cells present in the gut wall. Accurately quantifying immunohistochemically identified neurones, would make it possible to characterize changes underlying disorders such as slow transit constipation. Until now, quantification of classes of neurones has relied on antisera to Neuron Specific Enolase (NSE) or Protein Gene Product 9.5 (PGP9.5), however, both stain nerve fibres, making accurate counting of cell bodies unreliable. Anti‐Human Neuronal Protein Antibodies (Hu) were originally isolated from patients with paraneoplastic encephalomyelitis and paraneoplastic neuropathies and have been tested here as a marker for all neurons in the human myenteric plexus.

Specimens of colon were obtained from the uninvolved margins of specimens from 10 patients undergoing elective surgery for carcinoma and were either fixed fresh, or maintained in organ culture for 3 days. Nerve cell bodies were identified using double labelling techniques to compare Hu (mouse monoclonal anti Hu, Chemicon, CA) and NSE antisera for quantification. In both fresh and cultured tissue, neuronal somata were readily identified using the Hu antibody but few axons or varicosities were labelled. In double‐stained preparations, Hu labelling consistently revealed more nerve cell bodies than NSE. In addition, counting was more reliable due to the lack of staining of nerve fibres which obscured some cell bodies in NSE or PGP9.5‐stained preparations.

We used preparations triple labeled with antisera raised against nitric oxide synthase (NOS), choline acetyltransferase (ChAT) and Hu, to determine the size of these major populations. Approximately 47 + 1% (mean + SD, n= 4) of all myenteric nerve cell bodies were immunoreactive for NOS and 52 + 2% were immunoreactive for ChAT. In each preparation, approximately 8 + 2% of NOS cells also contained ChAT. In 5 + 1% of neurons, neither NOS nor ChAT was detectable. Anti‐Hu antiserum makes possible reliable labeling of all enteric neurons in the human colon, allowing accurate quantification of different populations of enteric neurones in normal and diseased tissue.
ERSPC: features and preliminary results of France
Authors: Villers A. , Malavaud B. , Rebillard X. , Bataille V. , Iborra F.
Published: January 2004

The specific details of the French national programme are based on the design of a local mass screening programme. Men in the screening group are repeatedly invited by mail to be screened while no information other that the national available guidelines on the use of prostate‐specific antigen (PSA) is offered to the control group. The protocol includes randomization before information and consent. In addition, knowledge of any pre‐existing PSA test is obtained through the health insurance database. This will allow separate analysis, if necessary, between groups with previous PSA testing (low participation rate expected) and without (higher participation rate expected).
Including the quality‐of‐life effects in the evaluation of prostate cancer screening: expert opinions revisited?
Authors: Essink‐Bot M.L. , Korfage I.J. , De Koning H.J.
Published: January 2004

OBJECTIVE

To apply the general empirical framework for estimating utilities in cost‐utility analysis (CUA) of population‐based prostate cancer screening, including an assessment of empirical health status with a classifying measure (e.g. the EQ‐5D) and linking these descriptions to utility estimates using the standard preference‐based algorithm, combining them with the appropriate duration into quality‐adjusted life years, and sensitivity analysis.

MATERIALS AND METHODS

Empirical studies to describe and value the health status effects of prostate cancer screening have been ongoing within the Rotterdam centre of the European Randomised Study on Screening for Prostate Cancer since 1995. The results of these studies, including the screening, the primary treatment phase and advanced disease, will be used in estimating utilities for cost‐utility analysis.

RESULTS

Estimation of cost‐utility of population‐based prostate cancer screening with the results of the three empirical health status studies yielded partly counterintuitive results, underestimating the unfavourable health status effects that are inevitably associated with prostate cancer screening. This may be caused by other than health effects of the screening itself (‘process effects’) and adaptive changes in perception of their situation in patients after curative primary treatment (‘response shift’), among other elements.

CONCLUSION

These results prompted us to reconsider the suitability of the general framework of CUA for screening programmes. Possible directions for solutions are indicated.
MISCAN: estimating lead‐time and over‐detection by simulation
Authors: Draisma G. , De Koning H.J.
Published: January 2004

OBJECTIVE

To estimate the mean lead‐time and rate of over‐detection associated with screening for prostate cancer with prostate‐specific antigen.

METHODS

Simulation models, fitted to the results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, were used to predict the mean lead‐time and over‐detection rate in population‐based screening programmes.

RESULTS

The mean lead‐time is estimated to be 11–12 years and over‐detection to occur in half the cases found by population screening. The estimates are compared with published estimates.

CONCLUSION

The effect of lead‐time and over‐detection on the balance of positive and negative consequences of screening cannot be neglected.
The Spanish contribution to the European Randomized Study of Screening for Prostate Cancer
Authors: Berenguer A. , Luján M. , Páez A. , Santonja C. , Pascual T.
Published: January 2004

OBJECTIVE

To summarize the experience of the Spanish participation in the European Randomized Study of Screening for Prostate Cancer (ERSPC)

METHODS

In this study men aged 45–70 years were randomized (1 : 1) and allocated to one of two arms: screening, with an indication for transrectal ultrasonography (TRUS) and sextant prostate biopsy when the serum prostate‐specific antigen (PSA) level was > 4 ng/mL (until May 1998) and from then when the PSA was > 2.9 ng/mL; and a control group (no diagnostic tests). The findings from a digital rectal examination were not considered as a criterion for biopsy. When the serum PSA was above the threshold levels, biopsy‐negative men were invited again after a year (‘early recall’). The next (second) screening round was programmed for the rest of participants after a 4‐year interval. Cancer‐specific mortality was recorded and compared in both groups.

RESULTS

In all, 4278 men were recruited (2416 in the screening group and 1862 in the control group). The recruitment phase was closed in June 1999. During the first screening round 40 cancers were detected; the detection rate was then 1.7% and 4.15 biopsies were needed to detect each cancer. The clinical stage was localized in 88.6% and regional or metastatic in 11.4%. Within the first round, 17 more cancers were detected at early recall attendance. During the second screening round 14 cancers were found, giving a detection rate of 1.9%; 17 more cancers were also diagnosed outside the screening programme (contamination), seven in the screening group and 10 in the control group. Until February 2003, 85 participants had died (53 screened and 32 control) but none from prostate cancer.

CONCLUSIONS

Cancer detection rates can be increased with further early recalls; the clinical stage was localized in an important proportion of cancers detected.
Features and preliminary results of prostate cancer screening in Canton Aargau, Switzerland
Authors: Kwiatkowski M. , Huber A. , Stamm B. , Lehmann K. , Wernli M. , Häfeli A. , Recker F.
Published: January 2004

OBJECTIVE

To report the results from Switzerland's participation in the ERSPC from 1998; importantly, epidemiological data showed that Switzerland has one of the highest rates of morbidity and mortality from prostate cancer in the world. The local study protocol was accepted by the ethical committee and after the successful pilot study phase, the centre joined the ERSPC.

SUBJECTS AND METHODS

From September 1998 to June 2003 10 300 men accepted an invitation for the study and were then randomized 1 : 1 into an active screening arm (assessed by testing prostate‐specific antigen, PSA) or a control group (no intervention). The re‐screening interval is 4 years and is ongoing (beginning in September 2002). The study protocol includes offering a prostate biopsy when the total PSA is > 3.0 ng/mL (the main study protocol in agreement with ERSPC requirements) or when the total PSA is 1–3 ng/mL and the free‐to‐total PSA ratio < 20% (side study protocol).

RESULTS

During the first 3 years of screening 3562 men aged 55–70 years were screened; 395 (11.1%) of all participants had a total PSA of > 3 ng/mL and 251 (7.4%) were eligible for the side‐study. In all, 599 (17.2%) of 3562 accepted a prostate biopsy (93% of 646); 120 cases of prostate cancer were detected (3.4% detection rate). The incidence was 2.5% in main study group (positive predictive value, PPV, 24%) and 0.9% in side study group (PPV 13.6%). In radical prostatectomy specimens the cancers were mostly ‘significant’ (92% in main study group and 87% in side‐study group).

CONCLUSIONS

A randomized screening study for prostate cancer is feasible in Switzerland. A longer follow‐up is needed to address within the ERSPC the primary hypothesis (that there will be a reduction in mortality in the active screening arm) and to determine the level of over/under‐diagnosis and over/under‐treatment in the active screening and control arms, respectively.
Population‐based screening for prostate cancer by measuring free and total serum prostate‐specific antigen in Sweden
Authors: Hugosson J. , Aus G. , Bergdahl S. , Fernlund P. , Frösing R. , Lodding P. , Pihl C.‐G. , Lilja H.
Published: January 2004

OBJECTIVES

To report the initial results from Sweden of a large population‐based randomized study of screening using prostate‐specific antigen (PSA) to detect prostate cancer, as the efficacy of such screening to decrease prostate cancer mortality has not yet been proven.

METHODS

From the population registry men aged 50–66 years were randomized to screening (9973) and to future controls (9973). Men randomized to screening were invited to have their serum measured for free PSA (fPSA) and total PSA (tPSA) in serum using the Prostatus® f/tPSA assay (Perkin‐Elmer, Turku, Finland). Men with a tPSA of < 3.0 ng/mL were not further investigated, while those with a tPSA of ≥ 3.0 ng/mL were investigated with a digital rectal examination (DRE), transrectal ultrasonography (TRUS) and sextant biopsies.

RESULTS

Of those invited, 60% accepted PSA testing and 11.3% had a tPSA of ≥ 3.0 ng/mL. Altogether 145 cancers were detected (positive predictive value, PPV, 24%); none were stage M1, two were stage N+ and 10 stage T3–4. Most (59%) cancers were impalpable and 39% were both impalpable and invisible on TRUS. At biopsy, 7% were Gleason score 2–4, 71% 5–6, 19% 7 and 2% Gleason score 8–10. A threshold tPSA of ≥ 4.0 ng/mL would have detected 109 cancers in 366 biopsied men (PPV 30%) while cancer detection would have been 14% higher with a PPV of 36% using a threshold tPSA of ≥ 3.0 ng/mL combined with a f/tPSA threshold of ≤ 18%.

CONCLUSION

PSA screening detects early‐stage low‐grade prostate cancer. Both the sensitivity and specificity can be increased by incorporating f/tPSA with a tPSA threshold of < 4 ng/mL.
Quality assessment for prostate‐specific antigen (PSA) in relation to ERSPC: report of the PSA Committee
Authors: Blijenberg B.G. , Lilja H. , Neels H. , Stenman U.‐H.
Published: January 2004

OBJECTIVE

To assess the application of a quality control scheme for total prostate‐specific antigen (PSA) as used for participants of the European Randomized Study for Screening of Prostate Cancer (ERSPC) during 1996–2002.

METHODS

From 1996, the first complete year being 1997, an external scheme was organized by the Dutch Quality Assessment Foundation especially for the ERSPC. This scheme consists of one control round every 2 months with two different human serum samples and is only meant to compare the recovery of methods. From 1998 an internal scheme was also applied by adding two distinct samples to every round.

RESULTS

Initially there was a wide variation (coefficient of variation of ±15% at threshold PSA of 4.0 ng/mL) among all ERSPC participants who were all using the Tandem assay (Hybritech Inc, USA). After introducing the internal scheme the performance of some intra‐ERSPC group comparisons for PSA and the introduction of the completely automated Beckman‐Access analyser in 2001 there was state‐of‐the‐art precision for PSA of ± 5% in the 2002 surveys.

CONCLUSION

The ERSPC group measurements of PSA have considerably improved since 1996 because of the application of a quality‐assessment scheme and with the introduction of complete automation of the PSA assay. Both findings are in line with earlier developments in clinical chemistry.
Four‐year prostate‐specific antigen progression in the non‐cancer population of the European Randomized Study of Screening for Prostate Cancer
Authors: Páez A. , Luján M. , Raaijmakers R. , Berenguer A. ,   ERSPC
Published: January 2004

OBJECTIVE

To determine the rate of conversion of prostate‐specific antigen (PSA) to values of > 4 ng/mL in a normal male population.

PATIENTS AND METHODS

In men with an initial PSA level of < 4 ng/mL the probability of having a PSA of ≥ 4 ng/mL and its relationship with the age at first PSA test, baseline PSA level and time to the determination was evaluated. Statistical methods were used to correct for the within‐subject variability across many PSA determinations.

RESULTS

In all, 45 433 PSA tests in 21 169 men with an initial PSA of < 4 ng/mL were available. Overall, in 960 men (4.5%) the PSA level changed to ≥ 4 ng/mL. The lowest chance was for men aged < 55 years with an initial PSA of < 1 ng/mL and a new PSA determination during the first 18 months (0.952 conversions per 1000 men) while the highest was for men aged < 55 years with an initial PSA level of > 2.5 ng/mL (395 conversions per 1000 men). There was a significant and independent relationship between conversion and the interval between determinations, with conversion being 3.33 times more frequent during 18–42 months than with the reference category (<18 months) and 5.23 times more frequent during > 42 months. The probability of conversion independently increased by 3 λ for every additional year of age. Every unit of basal PSA multiplied by 6.48 the probability of conversion.

CONCLUSION

The risk for conversion to a PSA of ≥ 4 ng/mL can be anticipated from the patient's age and initial PSA level. Re‐screening before 4 years after the first round can be useless for men with an initial PSA of < 1 ng/mL. Four‐year intervals could be inadequate for men with an initial PSA of > 2.5 ng/mL if conversion to > 4 ng/mL is to be avoided.
Consistency of prostate cancer grading results in screened populations across Europe
Authors: Van der Kwast T.H. , Roobol M.J. , Wildhagen M.F. , Martikainen P.M. , Määtänen L. , Pihl C.‐G. , Santonja C. , Bubendorf L. , Neetens I. , Di Lollo S. , Hoedemaeker R.F.
Published: January 2004

OBJECTIVE

To assess the consistency of grading outcome among seven of eight participating centres of the European Randomised Screening Program of Prostate Cancer (ERSPC), a multicentre randomized trial intended to detect a difference in prostate cancer‐related mortality between screened participants and a control group. Currently, tumour stage and grade in prostatectomy specimens represent the most predictive variables for biological behaviour. In prostate needle biopsies the tumour grade is a strong factor for deciding therapy.

PATIENTS AND METHODS

Within the ERSPC all prostate cancers detected in needle biopsies were graded according to the Gleason score system. Gleason scores were compressed in three categories of ≤ 6, 7 and 8–10. Data for grading outcome were obtained from the databases from seven individual centres; in one centre the slide sets with cancer were separately reviewed.

RESULTS

Combining the data of seven ERSPC centres 66% of cancers detected in the screening arm were Gleason score ≤ 6 and 92% were ≤7. Gleason score 8–10 cancers varied from 2 to 11%. This variation in Gleason scores may be attributed to differences in the population characteristics and biopsy indications.

CONCLUSION

These data indicate that in the seven ERSPC centres most screen‐detected cancers have favourable characteristics on biopsy. Men with these cancers are amenable for treatment with curative intent. The observed differences in Gleason score distribution in different centres may partly be attributed to geographical differences and differences in the age range of the screened populations.
The clinical significance of a small focus of well‐differentiated carcinoma at prostate biopsy
Authors: Hoedemaeker R.F. , Van Der Kwast T.H. , Schröder F.H.
Published: January 2004

OBJECTIVE

To compare a series of 121 sextant needle biopsy sets with their corresponding radical prostatectomy specimens in screened participants in the European Randomized study of Screening for Prostate Cancer (ERSPC), investigating the effect of screening for prostate cancer on disease‐specific mortality and quality of life, as the clinical significance of a small focus of well‐differentiated prostate cancer on biopsy is unclear.

PATIENTS AND METHODS

The expected clinical significance of the discovered tumours was estimated using an arbitrary model combining volume, grade, and stage characteristics.

RESULTS

Of 34 patients who had a small focus (<3 mm on a single biopsy core) of well‐differentiated carcinoma on biopsy, only 18 (53%) were found to have minimal carcinoma (a small focus of well‐differentiated carcinoma) at radical prostatectomy, while 16 (47%) had moderately advanced or advanced carcinoma at radical prostatectomy. The preoperative prediction of minimal carcinoma improved when the amount of cancer in the sextant biopsy set was combined with the preoperative serum prostate specific antigen (PSA) level. Of 12 patients with a small focus of well‐differentiated carcinoma on biopsy and a serum PSA of < 4 ng/mL, 11 had minimal carcinoma at radical prostatectomy, while there was minimal carcinoma in only seven of 22 (32%) patients with a small focus of well‐differentiated carcinoma on biopsy and a serum PSA of ≥ 4 ng/mL.

CONCLUSION

The predictive value of a small focus of well‐differentiated cancer on systematic sextant biopsy for a small well‐differentiated tumour in the prostate is limited. The predictive value improves when serum PSA levels are considered concurrently, but is still considered insufficient to support a base for selecting therapy for the individual patient.
Middlemen*
Authors: Shevchenko Andrei
Published: January 2004

This article provides an equilibrium model of intermediation based on search theory. Intermediaries, like retailers, buy goods from producers and sell them to consumers. The number of intermediaries is endogenously determined by free entry. The size and composition of their inventories is also endogenous. Larger inventories make it more likely that a random customer will find something he likes, but are more costly to store. The distribution of prices is characterized. Conditions are given under which there are too many or too few intermediaries, and under which intermediaries are too big or too small, from an efficiency perspective.
Estimating Labor Demand with Fixed Costs*
Authors: Rota Paola
Published: January 2004

We consider a dynamic model in which firms decide whether or not to vary labor in the presence of fixed costs. By exploiting the first‐order condition for optimality, we derive a semireduced form in which firms' intertemporal employment is defined by a standard marginal productivity condition augmented by a forward‐looking term. We obtain a marginal productivity equilibrium relation that takes into account the future alternatives of adjustment or nonadjustment that firms face. We use the structural parameter from this condition to estimate the fixed cost within a discrete decision process. Fixed costs are about 15 months' labor cost.
Testing for Convergence Clubs in Income Per Capita: A Predictive Density Approach*
Authors: Canova Fabio
Published: January 2004

The article proposes a technique, based on the predictive density of the data, conditional on the parameters of the model, to jointly tests for groups of unknown size in a panel and to estimate the parameters of each group. The procedure is applied to the problem of identifying convergence clubs in scaled income per capita data. The steady‐state distribution of European regional data clusters around four poles of attraction with different economic features. The distribution of income per capita of OECD countries has two poles of attraction and each group clearly identifiable economic characteristics.

We share the uncommonness of being different.

               J. P. Roche
A Unique Informationally Efficient Allocation Mechanism In Economies With Consumption Externalities*
Authors: Tian Guoqiang
Published: January 2004

This article investigates the informational requirements of resource allocation processes in pure exchange economies with consumption externalities. It is shown that the distributive Lindahl mechanism has a minimal informational size of the message space, and thus it is informationally the most efficient allocation process that is informationally decentralized and realizes Pareto‐efficient allocations over the class of economies that include nonmalevolent economies. Furthermore, it is shown that the distributive Lindahl mechanism is the unique informationally efficient decentralized mechanism that realizes Pareto‐efficient and individually rational allocations over a certain class of nonmalevolent economies.
Gradualism In Tax Treaties With Irreversible Foreign Direct Investment*
Authors: Chisik Richard , Davies Ronald B.
Published: January 2004

Bilateral tax treaties govern host country taxation for most of the world's foreign direct investment (FDI). To explain why the tax rates used under these treaties are gradually falling we consider two‐way capital flows with irreversible FDI. The extent of irreversibility determines the magnitude of initial tax reductions. When Pareto‐optimal taxes are not initially self‐enforcing, more modest tax reductions generate an increase in irreversible bilateral FDI so that further tax reductions become self‐enforcing. Depending on the extent of irreversibility and asymmetry, Pareto‐optimal tax rates may be obtainable in the long run.
Barriers to Capital Accumulation and Aggregate Total Factor Productivity*
Authors: Restuccia Diego
Published: January 2004

I develop a growth model where a single good can be produced with a traditional and a modern technology. The traditional technology features low total factor productivity (TFP) and a low share of reproducible capital. In this framework, barriers to capital accumulation affect technology use and therefore aggregate TFP. The theory thus connects recent models of factor accumulation and of TFP. The model is calibrated by interpreting traditional production as agriculture and nonreproducible capital as land. The theory implies that barriers are associated with large agricultural shares, as supported by cross‐country and time‐series evidence. The required TFP differences needed in the model to account for a given income disparity are reduced by 1/2 relative to the standard model that abstracts from technology choice.
Incentive Regulation of Multinational Enterprises*
Authors: Calzolari Giacomo
Published: January 2004

Sectors with a long regulatory tradition have recently experienced intense activity by multinationals whose international operations and relocation threats represent a new cause for concern for regulators. I analyze a multinational serving two countries and being regulated by two national authorities. The firm is shown to favor, or cross‐subsidize, the country with a larger stake in the firm's profit, and the linkage among national regulations may induce unexpected effects on outputs. I also analyze a multinational's lobbying decisions and its effects on national regulations. Finally, a credible threat to “fly” away from tough regulators lets the firm obtain larger profits.
Bioenergetics in the pathogenesis of neurodegeneration
Authors: Beal M. Flint
Published: January 2004

Evidence implicating both mitochondria and bioenergetics as playing a crucial role in necrotic and apoptotic cell death is rapidly accumulating. Mitochondria are essential in controlling specific apoptosis cell death pathways and they are the major source of free radicals in the cell. Direct evidence for a role of mitochondria in neurodegenerative diseases comes from studies in Friedreich's Ataxia. Mutations in frataxin lead to an accumulation of iron within mitochondria. We found a three‐fold increase in a marker of oxidative damage to DNA in the urine of patients with Friedreich's Ataxia. There is evidence for mitochondrial defects in patients with amyotrophic lateral sclerosis (ALS). There are mitochondrial abnormalities in liver biopsies and muscle biopsies from individuals with sporadic ALS. Muscle biopsies have shown reduced complex I activity in patients with sporadic ALS. A study of ALS cybrids showed a significant decrease in complex I activity as well as trends towards reduced complex 3 and 4 activities. We found increased levels of 8‐hydroxy‐2‐deoxyguanosine, a marker of oxidative damage to DNA in the plasma, urine and CSF of sporadic ALS patients and increased numbers of point mutations in mtDNA of ALS spinal cord tissue. There is mitochondrial vacuolization in transgenic mouse models of ALS. We found substantial evidence for mitochondrial dysfunction in Huntington's Disease (HD). In HD postmortem brain tissue, there are significant reductions in complex 2, 3 activity. We also demonstrated increased brain lactate concentrations as well as reduced phosphocreatine to inorganic phosphate ratio in the resting muscle of patients with HD. More recent studies have demonstrated that there is abnormal depolarization of mitochondria of HD lymphoblasts, which directly correlates with CAG repeat length. There are reductions in ATP production in muscle are both presymptomatic and symptomatic HD patients. Transgenic mouse models of HD show significant reductions in N‐acetylaspartate concentrations, which precede the onset of neuronal degeneration. We investigated a number of therapeutic interventions in both transgenic mouse models of ALS and HD. In transgenic ALS mice we found that oral administration of creatine dose‐dependently extends survival and reduces the neuronal degeneration in the spinal cord. We found modest protection with ginkgo biloba and lipoic acid. In the HD mice we found significant improvement with oral administration of creatine in two different transgenic mouse models. Creatine not only extended survival but it also improved motor performance, delayed weight loss and attenuated striatal atrophy. Creatine significantly attenuated reductions in N‐acetylaspartate concentrations as assessed using magnetic resonance spectroscopy. We also found significant neuroprotective effects with dichloroacetate, which stimulates pyruvate dehydrogenase. These findings implicate bioenergetic dysfunction in transgenic mouse models of both ALS and HD, and they suggest several novel therapeutic strategies aimed at energy replenishment.
Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia
Authors: Constant James S , Feng John J , Zabel David D , Yuan Hui , Suh David Y , Scheuenstuhl Heinz , Hunt Thomas K , Hussain M. Zamirul
Published: January 2004

Macrophages respond to various stimuli to produce angiogenic factors but few mechanistic details are known. We examined the effects of hypoxia, lactate and nicotinamide on the expression of vascular endothelial growth factor by cultured macrophages. These agents were chosen because they down‐regulate polyadenosine diphosphoribose levels. Following exposure, conditioned media were analyzed for vascular endothelial growth factor protein. Nicotinamide adenine dinucleotide, polyadenosine diphosphoribose, and vascular endothelial growth factor mRNA were measured in the cellular fraction. Angiogenic capacity of the conditioned media was tested in rabbit corneas and Matrigel implants.

All three agents, hypoxia, lactate and nicotinamide, elicited significantly increased levels of vascular endothelial growth factor mRNA and vascular endothelial growth factor in the conditioned media, and these levels were paralleled by their angiogenic activity. Polyadenosine diphosphoribose in the cellular fraction was correspondingly depressed. Anti‐vascular endothelial growth factor antibody inhibited most of the angiogenic response whereas anti‐basic fibroblast growth factor antibody had little effect. We propose that redox changes associated with the alteration of cellular nicotinamide adenine dinucleotide and polyadenosine diphosphoribose are involved in lactate‐mediated VEGF expression.
Chemokine and chemokine receptor expression in keloid and normal fibroblasts
Authors: Nirodi Chatanya S , Devalaraja Radika , Nanney Lillian B , Arrindell Saundrett , Russell Shirley , Trupin Joel , Richmond Ann
Published: January 2004

Keloids are benign collagenous tumors that occur during dermal wound healing in genetically predisposed individuals. The lesions are characterized by over‐proliferation of fibroblasts, some leukocyte infiltration, and prolonged high rates of collagen synthesis. To determine whether leukocyte chemoattractants or chemokines are participating in this disease process, immunohistochemical staining for the CXC chemokine, MGSA/GROα, and its receptor, CXCR2, was performed on tissue from keloids, hypertrophic scars and normal skin. Immunoreactive MGSA/GROα was not observed in hypertrophic scars or normal dermis, but was present in some myofibroblasts and lymphocytes in nodular areas of the keloid samples. This staining positively correlated with the degree of inflammatory infiltrate in the lesions. Keloids, but not hypertrophic scars or normal dermis, also exhibited intensive immunoreactivity for the CXCR2 receptor in endothelial cells and inflammatory infiltrates with occasional staining of myofibroblasts. In contrast, cultured fibroblasts from either keloids or normal skin did not express detectable amounts of mRNA for MGSA/GRO or CXCR2, although interleukin‐1 strongly induced MGSA/GRO mRNA in both cell types. Interleukin‐1 induction of MGSA/GRO was inhibited by glucocorticoid in normal and keloid fibroblasts, and the effect was more pronounced in keloid fibroblasts. This event was not correlated with inhibition of nuclear activation of NF‐κB, AP‐1 or Sp1, and might therefore be mediated by another mechanism such as decreased mRNA stability or transcriptional repression through the glucocorticoid response element in the MGSA/GRO promoter. Data from in vitro wounding experiments with cultured normal and keloid fibroblasts indicate that there were no significant differences in MGSA/GRO or CXCR2 receptor levels between normal and keloid fibroblasts. We also show that cultured keloid fibroblasts exhibit a delayed wound healing response. We postulate that the inflammatory component is important in development of keloid lesions and chemotactic cytokines may participate in this process.
Outgrowth of chondrocytes from human articular cartilage explants and expression of α‐smooth muscle actin
Authors: Qiu Wei , Murray Martha Meaney , Shortkroff Sonya , Lee Cynthia R , Martin Scott D , Spector Myron
Published: January 2004

The objectives of this study were to investigate the effect of various enzymatic treatments on the outgrowth of chondrocytes from explants of adult human articular cartilage and the expression of a specific contractile protein isoform, α‐smooth muscle actin, known to facilitate wound closure in other connective tissues. Explants of articular cartilage were prepared from specimens obtained from patients undergoing total joint arthroplasty. The time to cell outgrowth in vitro was determined and the expression of α‐smooth muscle actin shown by immunohistochemistry. Treatment of the explants with collagenase for 15 minutes reduced the time to outgrowth from more than 30 days to 3 days. Hyaluronidase, chondroitinase ABC, and trypsin applied for the 15‐minute period had no effect on the time to cell outgrowth when compared with untreated controls. Pretreatment with hyaluronidase prior to collagenase reduced the time to outgrowth. A notable finding of this study was that the majority of chondrocytes in the adult human articular cartilage specimens and virtually all of the outgrowing cells contained α‐smooth muscle actin. We conclude that human articular chondrocytes have the capability to migrate through enzymatically degraded matrix and express a contractile actin isoform. Collagenase treatment reduces the time required for cell outgrowth.
Proteinases, their inhibitors, and cytokine profiles in acute wound fluid
Authors: Baker Elizabeth A , Leaper David J
Published: January 2004

Wound healing is a complex process involving the interactions of many different cell types, matrix components and biological factors, including proteinases and cytokines. This study compared the levels of proteinases (matrix metalloproteinases and plasminogen activators), proteinase inhibitors (tissue inhibitors of metalloproteinases and plasminogen activator inhibitors), inflammatory cytokines and growth factors in acute wound fluid samples collected from the surgical drains of elective breast (n= 24) and colorectal (n= 26) patients on the first postoperative day. Gelatin zymography was used to determine matrix metalloproteinase‐2 and ‐9 levels, quenched fluorescence substrate hydrolysis was applied for total MMP activity and enzyme‐linked immunoassays were used to quantitate other factors.

Colorectal wound fluid samples showed significantly (p < 0.05) greater levels of the matrix metalloproteinases (MMP‐1, 2, 3, and 9), tissue inhibitor of metalloproteinases‐1, urokinase plasminogen activator receptor and the inflammatory cytokines (interleukin‐1β, ‐6, and tumor necrosis factor‐α); e.g., matrix metalloproteinase‐3 colon; median 275 (range 11–2.530) ng/ml; breast; 530–400. However, tissue plasminogen activator and growth factor levels (epidermal growth factor, platelet‐derived growth factor, basic fibroblast growth factor, transforming growth factor‐β1) were significantly greater in breast samples; e.g., epidermal growth factor breast 468 (103–1,444) pg/ml; colon 57(1–573). There was no difference in the levels of urokinase type plasminogen activator, plasminogen activator inhibitor‐1 and ‐2, tissue inhibitor of metalloproteinases –2 or vascular endothelial growth factor. Acute wound fluid from different surgical wounds showed different profiles of proteinases, proteinase inhibitors, and cytokines. This may lead to differences in the rate of tissue remodeling and therefore healing in these two wounds in vivo.