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The aim of this study was to investigate cycle dependent changes of serum CA 125 and CA 15-3 concentrations during spontaneous ovulatory cycles. Twenty apparently healthy women with spontaneous menstrual cycles attending our infertility clinic were included. Of these women, 18 had occluded tubes as a result of sterilization. Ovulation was confirmed by luteinizing hormone test and ultrasonography and, to exclude endometriosis, a laparoscopy was performed. Serum samples for CA 125, CA 15-3, 17 beta-oestradiol and progesterone determinations were taken every second day starting on the 2nd day of the cycle until the 7th day of the next cycle. After correction for inter-individual variation in serum concentrations, highest CA 125 concentrations were found during the menstruation. During the follicular and peri-ovulatory phase CA 125 serum concentrations were lowest. For CA 15-3, serum concentrations were not statistically different throughout the cycle. CA 125 and oestradiol concentrations were negatively correlated, CA 15-3 and oestradiol concentrations were positively correlated. Absolute serum concentrations of both CA 125 and CA 15-3 vary among females. Within the female, fluctuations of CA 125 are phase related. In the population studied most of the patients had tubal obstruction and high CA 125 serum concentrations during menstruation, which revokes the theory that the menstrual rise of CA 125 is due only to retrograde menstruation. [ABSTRACT FROM AUTHOR]

Background: Decreased amyloid beta (1-42) (Abeta42) and increased (phosphorylated) tau in cerebrospinal fluid (CSF) are considered to be a reflection of plaques, tangles, and neuronal degeneration in Alzheimer's disease (AD). Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) reflects neuronal loss in this area., Objective: To compare diagnostic accuracy of CSF biomarkers and MTA in AD versus controls., Methods: Abeta42, tau and tau phosphorylated at threonine 181 (Ptau-181) were measured in CSF from 61 AD patients and 32 controls by sandwich enzyme-linked immunosorbent assay. A CSF biomarker profile for AD was constructed. MTA was rated visually on MRI., Results: When AD patients and controls were evaluated separately, no correlations were present between the CSF markers and MTA score. Both MTA and CSF biomarker profile were independently associated with the diagnosis AD (MTA: OR (95% CI)=28 (3-239); CSF biomarker profile: OR (95% CI)=57 (13-262)). Among individuals younger than 65 years old and without MTA 60% suffered AD, and the finding of an abnormal CSF biomarker profile was limited to AD patients only., Conclusions: MTA and CSF biomarkers seem to be of incremental value for the diagnosis AD. CSF analysis is most sensitive in the absence of MTA, and especially among early-onset AD patients.

In order to better understand the large variation in cerebrospinal fluid (CSF) tau and amyloid-beta(1-42) (Abeta42) in frontotemporal lobar degeneration (FTLD), relations between these biomarkers and clinical parameters, neuroimaging characteristics, and apolipoprotein E (ApoE) genotype were studied in 31 patients with FTLD, including 16 patients with the frontal variant and 15 with the temporal variant. CSF tau was highest in FTLD with predominant temporal involvement. In the frontal subgroup, CSF tau level was influenced by the number of ApoE epsilon3 alleles. In the temporal subgroup, CSF tau level was dependent on a combination of CSF Abeta42, age, disease duration, and disease severity. No relation with degree of atrophy or asymmetry on neuroimaging could be established. CSF Abeta42 variability remained unexplained. Future research could study the role of ApoE genotype and Abeta42 in FTLD, as well as establish measures for disease intensity.

Background: The apolipoprotein E (ApoE) e4 polymorphism is linked to increased mortality rates, Alzheimer's disease, and cardiovascular disease in older people, but previous studies have largely failed to detect an effect on self-reported mobility disability. We hypothesized that poor performance on mobility-related tests may provide a better measure of effects, and we aimed to estimate the extent to which the ApoE e4 allele increases risks of poor performance on measured mobility and self-reported mobility disability compared to e3/3, in a medium-sized population cohort., Methods: Data were from 1262 people at baseline older than 65 years from the Longitudinal Aging Study Amsterdam (LASA), followed up for 6 years. Age- and sex-adjusted logistic regression models were used to explore associations., Results: At baseline, those individuals with an e4 allele had an odds ratio of 2.26 (95% confidence interval, 1.31-3.90) for poor performance on gait speed testing (<0.4 m/s) and 1.94 (95% confidence interval, 1.19-3.16) for five chair stands (> or =20 s), compared to those with e3/3 status. At follow-up, associations between e4 status and incident poor performance on the chair stand test was significant. Associations with self-reported inability or need for help walking for 5 minutes or for climbing 15 steps were nonsignificant throughout., Conclusions: The ApoE e4 polymorphism is associated with a substantial excess of mobility limitation. The impact is detectable by performance testing, but not by self-reports. Poor results on mobility performance tests may provide a phenotype of ageing.

Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.

Various C-terminally truncated amyloid beta peptides (Abeta) are linked to Alzheimer's disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Abeta38, Abeta40, and Abeta42 were measured by enzyme-linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Abeta42 levels was decreased in patients with AD, whereas CSF Abeta38 and Abeta40 levels were similar in patients with AD and control subjects. All three Abeta peptides were interrelated, particularly CSF Abeta38 and Abeta40. Diagnostic accuracy of CSF Abeta42 concentrations was not improved by applying the ratios of CSF Abeta42 to Abeta38 or Abeta40.

The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer's disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Abeta42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Abeta32 or high CSF tau (intermediate-risk) and 20% a normal CSF Abeta42 and tau (low-risk). Both high-and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS),which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Abeta42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.

During cardiopulmonary bypass (CPB), the brain and the kidneys may be damaged because of microemboli, ischemia, and inflammation. The latter has been reduced by the use of heparin coated circuits. We questioned whether heparin coated circuits could also reduce cerebral and renal damage and whether inflammatory markers correlate with damage to the brain and the kidneys. Fifty-one patients scheduled for coronary artery bypass grafting were perfused with either a heparin coated or an uncoated circuit. To compare the effect of a heparin coated circuit with an uncoated circuit upon cerebral and renal function in relation to inflammation, we assessed markers of cerebral (S100beta) and renal (N-acetyl-beta-D-glucosaminidase [NAG], creatinine, and urea) function, inflammation, and oxygen metabolism. S100beta levels and NAG levels increased during CPB in both groups as compared with baseline levels (p < 0.01), without differences between the groups. After 15 minutes on CPB, C4b/c levels were significantly higher in the coated group compared with the uncoated group (p < 0.02). C4b/c correlated with S100beta (p < 0.01). Total body oxygen delivery (DO2) and consumption (VO2) decreased significantly in both groups during CPB (p < 0.01), but recovery was better in the coated group. After protamine infusion, total body oxygen delivery and consumption correlated negatively with S100beta levels (both p < 0.05) and with NAG levels (both p < 0.01). This study suggests that, if adequate tissue perfusion is not maintained, the use of a heparin coated circuit gives no additional benefit beyond that of the uncoated circuit. The inverse relationship of both cerebral and renal markers with DO2 and VO2 suggests that increased levels of S100beta and NAG during CPB may primarily be caused by an oxygen deficit and secondary to the inflammatory response.

Background: Reported concentrations of amyloid beta (1-42) (A beta 42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of A beta 42 and tau in CSF., Methods: Stability of samples stored at -80 degrees C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. A beta 42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and -80 degrees C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative A beta 42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h., Results: A beta 42 and tau concentrations were stable in CSF when stored for a long period at -80 degrees C. CSF A beta 42 decreased by 20% during the first 2 days at 4, 18, and 37 degrees C compared with -80 degrees C. CSF tau decreased after storage for 12 days at 37 degrees C. After three freeze/thaw cycles, CSF A beta 42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations., Conclusions: Repeated freeze/thaw cycles and storage at 4, 18, and 37 degrees C influence the quantitative result of the A beta 42 test. Preferably, samples should be stored at -80 degrees C immediately after collection.

Background: Whereas a number of studies suggest that the ApoE polymorphism is not associated with disease susceptibility in multiple sclerosis (MS), results with regard to disease severity, however, are conflicting. Some studies suggest an unfavourable role of the epsilon4 allele. This study was performed to assess the association of the ApoE polymorphism with both disease susceptibility and disease course in a large group of MS patients using clinical and MRI measures. In addition the data were combined with available data from the literature., Methods: In a group of 408 patients with clinically definite MS, genotype distribution was compared with that of 144 healthy controls. Combined analysis of published data on the association of ApoE polymorphism with MS was performed. Demographic and clinical findings were recorded and related to the ApoE genotype. In a subgroup, longitudinal MRI findings were available and related to the ApoE genotype., Results: No significant differences were found in the distribution of genotypes between MS patients and controls. Combined analysis of published data showed a slightly increased susceptibility for MS in epsilon2-carriers. Disease characteristics (including age at onset and onset type), disease severity (progression index, time to reach EDSS 6) and MRI findings (lesion volumes and atrophy measures) were not associated with carriership o epsilon2 or epsilon4., Conclusions: In this cohort no association of the ApoE genotype with disease susceptibility nor clinical and MRI measures could be identified. However, combined analysis of published data could not definitely exclude the possibility of a minor role for epsilon2-carriership in MS.

Objective: To determine the diagnostic value of CSF amyloid beta(1-42) (Abeta42), CSF total tau, and CSF tau phosphorylated at threonine-181 (Ptau-181) in early-onset Alzheimer disease (EAD) vs frontotemporal lobar degeneration (FTLD)., Methods: Levels of Abeta42, total tau, and Ptau-181 in CSF were measured using commercially available ELISA in 47 EAD patients, 28 FTLD patients, and 21 nondemented control subjects., Results: CSF Abeta42 was significantly lower and CSF total tau and CSF Ptau-181 significantly higher in EAD patients than FTLD patients and control subjects. There was an increase in diagnostic accuracy for CSF Ptau-181 vs CSF total tau (p = 0.067). Combining low CSF Abeta42 and high CSF Ptau-181 allowed EAD patients to be distinguished from FTLD patients with a sensitivity of 72% and a specificity of 93%. Logistic regression analysis with CSF Abeta42 and CSF Ptau-181 as independent continuous variables resulted in correct classification of 46 of 47 (98%) EAD patients and 23 of 28 (82%) FTLD patients. The diagnostic accuracy for EAD was independent of gender, disease duration, and disease severity., Conclusion: The combination of CSF Abeta42 and CSF Ptau-181 may help in differentiating EAD from FTLD.

Background: In this study the clinical and technical performance of the CA125- detecting Bayer ACS:OV immunoluminometric serum assay was compared with three other well-established CA125-detecting assays., Methods: A total of 1112 serum samples was included in this evaluation: 462 from apparently healthy women, 153 from patients with benign ovarian disease, 163 from patients with malignant ovarian disease, 10 from patients with borderline ovarian malignancies and 78 samples from 12 ovarian cancer patients during monitoring of disease. Serum samples from women with malignant endometrial (n = 68) and colon (n = 32) diseases were also included. Moreover, serum samples from women with benign uterine disease and endometriosis (n = 136) plus 10 serum samples from men (n = 7) and women (n = 3) with human anti-mouse antibodies (HAMA) after immunoscintigraphy were included. All samples were tested in duplicate with the Bayer ACS:OV, the Centocor CA125 II, the Abbott IMx CA125 and the Roche (formerly Boehringer Mannheim) Enzymun-Test CA125 II assays., Results: The clinical performance of the Bayer ACS:OV assay, assessed in various patient groups, was similar to that of the two other automated assays. In serum from patients with benign diseases the highest values were found in patients with benign ovarian tumours. In the ovarian cancer patients followed during the course of disease we found similar marker patterns with all four assays. In contrast to the Roche Enzymun-CA125 II assay and to a lesser extent the Centocor CA125 II assay, the Bayer ACS:OV assay was less sensitive to interference from HAMA., Conclusion: The Bayer ACS:OV assay is a precise and reliable test for the quantification of CA125 in serum.

Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

The aim of the present study was to evaluate the clinical performance of the CA 15-3 assay on Elecsys systems in an international multicenter study (11 centers). A total of 1326 single samples (272 apparently healthy individuals, 34 pregnant women, 308 benign diseases, 273 cancers other than breast, 439 breast cancer) and 538 serial samples of 98 breast cancer patients during follow-up were analyzed. 95% of values in healthy individuals were below 25 kU/L, and 88% in benign breast diseases, respectively. In malignant breast disease at primary diagnosis the value distribution of Elecsys CA 15-3, sensitivity at 95% specificity, as well as the areas under the curve in ROC analysis were clearly correlated to tumor stages: UICC I to IV 88 to 25% of values < 25 kU/L, sensitivity 7 to 78%, areas under the curve 0.53 to 0.94. During follow-up, sensitivity/specificity for detection of recurrences were 90%/71%. In metastatic disease clinical progression/response to therapy were indicated in 91%/78% of patients at a specificity of 92%/78%. The findings indicate that the Elecsys CA 15-3 assay is very suitable in routine work for detection of recurrences as well as for therapy control in metastatic breast cancer.

Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity. Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Background/aims: Loss of heterozygosity (LOH) on chromosome 13q has been reported to occur frequently in human ovarian cancer, and indications have been found that chromosome 13 may also play a specific role in the inherited form of ovarian cancer. The aim of this study was to define regions on chromosome 13 that may harbour additional tumour suppressor genes involved in the tumorigenesis of BRCA1 related ovarian and fallopian tube cancer., Materials/methods: DNA extracted from paraffin wax blocks of 36 BRCA1 associated ovarian and fallopian tube carcinomas was analysed by LOH polymerase chain reaction using seven highly polymorphic microsatellite markers spanning chromosome 13q., Results: High LOH frequencies were found on loci 13q11, 13q14, 13q21, 13q22-31, 13q32, and 13q32-4, suggesting the presence of putative tumour suppressor genes on the long arm of chromosome 13 that may play a role in the pathogenesis of BRCA1 related ovarian and fallopian tube cancer. LOH patterns appeared to be independent of the type of BRCA1 mutation, stage, and grade. Although in some cases there were indications for loss of larger parts of chromosome 13, in most cases losses were fairly randomly distributed over chromosome 13 with retained parts in between lost parts. Microsatellite instability was found in six cases., Conclusion: Several loci on chromosome 13q show high frequencies of LOH in BRCA1 related ovarian and fallopian tube cancer, and may therefore harbour putative tumour suppressor genes involved in the carcinogenesis of this particular type of hereditary cancer.

The aim of this study was to examine whether the presence of apolipoprotein E epsilon4 (ApoE epsilon4) is associated with a lower bone mineral density (BMD), lower quantitative ultrasound (QUS) measurements, higher bone turnover and fracture risk, and whether these relations are modified by gender and age. A total of 1406 elderly men and women (> or =65 years) of the Longitudinal Aging Study Amsterdam (LASA) participated in this study. In all participants, QUS measurements were assessed, as well as serum osteocalcin (OC) and urine deoxypyridinolin (DPD/Cr urine). Follow-up of fractures was done each three months. In a subsample ( n = 604), total body bone mineral content (BMC) and BMD of the hip and lumbar spine were measured. In addition, prevalent vertebral deformities were identified on radiographs. In women, the presence of ApoE epsilon4 was associated with significantly lower femoral neck BMD (g/cm(2); mean +/- SEM; epsilon4+, 0.64 +/- 0.01 vs. epsilon4-, 0.67 +/- 0.01; p = 0.04), lower trochanter BMD (g/cm(2); mean +/- SEM; epsilon4+, 0.58 +/- 0.01 vs. epsilon4-, 0.61 +/- 0.01; p = 0.01) and lower total body BMC (g; mean +/- SEM; epsilon4+, 1787 +/- 40.0 vs. epsilon4-, 1863 +/- 23.8; p = 0.04). Women with ApoE epsilon4 also had a higher risk of severe vertebral deformities (OR=2.78; 95%CI: 1.21-6.34). In men, the associations between ApoE status and both hip BMD and QUS depended on age. Only among the younger men (65-69 years) was the presence of ApoE epsilon4 associated with lower BMD values. Bone markers and fractures were not associated with ApoE epsilon4 in either women, or men. In conclusion, this large community-based study confirms the importance of ApoE epsilon4 as a possible genetic risk factor related to BMD and vertebral deformities and demonstrates that its effect is gender related, and depends on age in men only.

Nitric oxide (NO) may play a role in the pathophysiology of Alzheimer's disease (AD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is involved in regulation of NO production. Recently it has been reported that dimethylarginine dimethylaminohydrolase, an enzyme that hydrolyses ADMA into citrulline and dimethylamine, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in AD. We hypothesized that this could lead to altered CSF concentrations of ADMA in AD. Measurement of ADMA and dimethylamine in CSF revealed no significant differences between AD patients (n = 20) and age-matched control subjects (n = 20). Our results suggest that in early stages of AD overall regulation of NO production by ADMA is not aberrant.

Objective: The purpose of this study was to assess the differential diagnostic potential of a combination of CA 125, CA 15-3, and CA 72-4 antigens in the definition of malignant disease, especially ovarian carcinoma in patients with a pelvic mass., Study Design: A total of 412 patients were evaluated in a multicenter, retrospective study., Results: Two hundred twenty-six malignant, 171 benign pelvic tumors (of which 129 were benign ovarian tumors), and 15 borderline tumors were evaluated. One hundred thirty-three patients had ovarian carcinoma. In 76 cases (55%), the International Federation of Gynecology and Obstetrics stage was III or IV. Borderline tumors (n = 15) were excluded from the statistical calculations. CA 125 antigen was the most sensitive marker for ovarian carcinoma (81%). The highest specificity and positive predictive value was obtained with CA 15-3 antigen (95% and 92%, respectively). Considering a concomitant elevation of all 3 markers as positive, a positive predictive value of 97% was found. However, only 28% of the patients in the total group and 41% of the patients with ovarian carcinoma had a concomitant elevation of all 3 markers. The combination of all 3 markers with levels below the cut-off resulted in a (false-positive) positive predictive value for malignancy between 12% and 36%. With the use of logistic regression analysis, we found a correct prediction in 73% of the cases. CA 15-3 antigen makes the most significant (P <.0001) contribution to the logistic model in the prediction of malignancy in the total group, with all pelvic masses with an odds ratio of 3.86., Conclusion: The combination of a simultaneous elevated level of CA 125, CA 15-3, and CA 72-4 antigens was predictive for malignant disease in almost all cases. However, such concomitant elevation was found in few of the malignant masses. Logistic regression analysis revealed that CA 15-3 antigen makes the most significant contribution to a model for the prediction of malignancy in the total group. The logistic model gave a correct prediction in 73% to 83%. The present tumor marker panel seems inferior to combinations with other test modalities, which include ultrasonography and/or physical examination and/or menopausal status or age.

Objective: To investigate to what extent subjective memory complaints and APOE-epsilon4 allele carriage predict future cognitive decline in cognitively intact elderly persons, by evaluating both their separate and combined effects., Methods: We selected 1,168 subjects from the population-based Longitudinal Aging Study Amsterdam who were 62 to 85 years of age and had no obvious cognitive impairment at baseline (Mini-Mental State Examination [MMSE] score, > or =27). Memory complaints and APOE phenotypes were assessed at baseline. MMSE, the Auditory Verbal Learning Test (memory: immediate recall and delayed recall), and the Alphabet Coding Task-15 (information processing speed) were used to study cognitive decline. Follow-up data were collected after 3 and 6 years. Data were analyzed with generalized estimating equations, adjusted for age, sex, education, and depression., Results: Baseline memory complaints were reported by 25.5% of the cognitively intact elderly persons. Overall, 25.3% of the subjects were carriers of at least one APOE-epsilon4 allele. Memory complaints were associated with a greater rate of decline in all cognitive measures, except immediate recall. In addition, APOE-epsilon4 allele carriers had a greater rate of cognitive decline shown by MMSE scores and slower information processing speeds after 6 years. The effects of both memory complaints and APOE-epsilon4 allele carriage were additive: subjects with both factors had a two times higher cognitive decline than did subjects without both factors., Conclusions: Both memory complaints and APOE-epsilon4 allele carriage predict cognitive decline at an early stage. This finding highlights the importance of subjective memory complaints, which are important even at an early stage when objective tests are still unable to detect cognitive deficits and are especially important for elderly carriers of the APOE-epsilon4 allele because they have an additional risk.

Objective: To evaluate the value of maternal serum CA125 and CA15-3 concentrations for discriminating pathological from normal pregnancies., Methods: Serum samples from 120 women, in whom pregnancy outcome was pathological, i.e. spontaneous abortion, fetal death, intrauterine growth retardation, chromosomal and structural abnormalities, and (pre)eclampsia, were assessed for CA125 and CA15-3 and compared with levels found in 350 women with a normal pregnancy outcome matched for age and duration of pregnancy., Results: Maternal CA125 serum values were significantly higher in the first and the third trimester of pregnancy (median 23.0 and 21.0 U/ml; p < 0.00001 and p < 0.001, respectively), compared to those in the second trimester (median 14.0 U/ml), but not significantly different from those obtained in pathological pregnancies. Maternal serum CA15-3 values were significantly higher during the third trimester (median 26.0 U/ml) compared to the first and second trimester of pregnancy (median 14.0 and 15.0 U/ml; p < 0.0001); CA15-3 serum levels in normal and pathological pregnancies showed no significant difference., Conclusion: Maternal serum levels of CA125 are higher during the first and third trimester of pregnancy. CA15-3 maternal serum levels are higher during the third trimester compared to the first and second trimester. Maternal CA125 and CA15-3 serum levels showed no relation with a pathological outcome of pregnancy., (Copyright 2001 S. Karger AG, Basel)

Unlabelled: A phase I therapy study was conducted to determine the safety, maximum tolerated dose (MTD), pharmacokinetics, dosimetry, immunogenicity, and therapeutic potential of 186Re-labeled anti-CD44v6 chimeric monoclonal antibody (cMAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC). The potential of a diagnostic study with 99mTc-cMAb U36 to predict the biodistribution of 186Re-cMAb U36 was evaluated., Methods: Thirteen patients with recurrent or metastatic HNSCC were given 750 MBq 99mTc-cMAb U36 (2 mg) followed 1 wk later by a single dose of 186Re-cMAb U36 (12 or 52 mg) in radiation dose-escalating steps of 0.4, 1.0, and 1.5 GBq/m2. After each administration, planar and SPECT images were obtained, and the pharmacokinetics and development of human antimurine as well as anti-cMAb responses were determined. Radiation absorbed doses to tumor, red marrow, and organs were calculated., Results: Administration was well tolerated, and excellent targeting of tumor lesions was seen in all patients. Dose-limiting myelotoxicity (thrombocytopenia being most prominent) was the only toxicity observed, resulting in grade 4 myelotoxicity in 2 patients treated with 1.5 GBq/m2. The MTD was established at 1.0 GBq/m2, at which a transient grade 3 thrombocytopenia was seen in 1 patient. One patient showed stable disease for 6 mo after treatment at the MTD. The 2 patients with dose-limiting myelotoxicity showed a marked reduction in tumor size. The reduction was of short duration and, therefore, not considered an objective response. Tumor absorbed doses at MTD ranged from 3.0 to 18.1 Gy. Red marrow doses ranged from 20 to 112 cGy (mean, 51 +/- 16 cGy/GBq) and correlated with platelet nadir (r = 0.8; P < 0.01). Pharmacokinetics varied between patients treated at the same dose level and were accurately predicted by the diagnostic procedure. Five patients experienced a human anti-cMAb response, 1 of which was a human antimouse antibody response., Conclusion: This study shows that 186Re-cMAb U36 can be safely administered, with dose-limiting myelotoxicity at 41 mCi/m2. The use of cMAb U36 instead of its murine counterpart did not decrease the induction of human antibody responses. The availability of a 99mTc-labeled diagnostic study that can predict the pharmacokinetics of 186Re-cMAb U36 offers the possibility of using such a study for selection of a safe radioimmunotherapy dose.

Objective: To analyse whether pregnancies resulting in a small for gestational age neonate are preceded by a prostacyclin deficiency or an imbalance between thromboxane and prostacyclin., Study Design: At five fixed time points during pregnancy, 24-h urine samples were collected for the measurement of thromboxane and prostacyclin metabolites thromboxane-B(2) (TXB(2)) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In order to study trend differences between pregnancies with appropriate (AGA; n=26) and small for gestational age neonates (SGA; n=17), trend analysis with simple contrasts were accomplished for TXB(2), 6-keto-PGF(1alpha) and the TXB(2)/6-keto-PGF(1alpha) ratio., Results: Trend analysis showed higher TXB(2) levels and higher TXB(2)/6-keto-PGF(1alpha) ratios in patients with SGA versus AGA newborns. No statistically significant difference in 6-keto-PGF(1alpha) excretion between patients with SGA and AGA newborns was detected., Conclusion: The birth of an SGA neonate is not preceded by prostacyclin deficiency. With ongoing pregnancy an imbalance between thromboxane and prostacyclin becomes more obvious in pregnancies with SGA newborns.

The objective of this study was to investigate whether the association between Apolipoprotein E4 (ApoE4) and memory decline is modified by baseline general cognitive impairment and age in a population-based elderly sample. Subjects were participants in the Longitudinal Aging Study Amsterdam (LASA). The study sample consisted of 1,243 subjects, 62-85 years old, with a Mini-Mental State Examination (MMSE) score between 21-30 and known ApoE phenotypes. Memory performance was measured with a short version of the Auditory Verbal Learning Test (AVLT) at baseline and repeated after three years (N = 854). Memory decline was defined as a decrease of at least one standard deviation from the mean change score on immediate recall, delayed recall and retention. ApoE4 was associated with memory decline in cognitively impaired subjects (MMSE 21-26), but not in cognitively normal subjects (MMSE 27-30). In particular cognitively impaired E4 carriers older than 75 years were at high risk of memory decline. Contrary to AD studies, our study suggests that the risk of ApoE4 on memory decline does not decrease with ageing.

Antibodies (Abs) to MUC1 occur naturally in both healthy subjects and cancer patients and can be induced by MUC1 peptide vaccination. We compared the specificity of natural and induced MUC1 Abs with the objective of defining an effective MUC1 vaccine for active immunotherapy of adenocarcinoma patients. Serum samples, selected out of a screened population of 492 subjects for their high levels of IgG and/or IgM MUC1 Abs, were obtained from 55 control subjects and from 26 breast cancer patients before primary treatment, as well as from 19 breast cancer patients immunized with MUC1 peptides coupled to keyhole limpet hemocyanin (KLH) and mixed with QS-21. The samples were tested with enzyme-linked immunoassays for reactivity with (1) overlapping hepta- and 20-mer peptides spanning the MUC1 tandem repeat sequence; (2) two modified 60-mer peptides with substitutions in the PDTR (PDTA) or in the STAPPA (STAAAA) sequence of each tandem repeat; and (3) four 60-mer glycopeptides with each 1, 2, 3 and 5 mol N-acetylgalactosamine (GalNAc) per repeat. More than one minimal epitopic sequence could be defined, indicating that Abs directed to more than one region of the MUC1 peptide core can coexist in one and the same subject. The most frequent minimal epitopic sequence of natural MUC1 IgG and IgM Abs was RPAPGS, followed by PPAHGVT and PDTRP. MUC1 peptide vaccination induced high titers of IgM and IgG Abs predominantly directed, respectively, to the PDTRPAP and the STAPPAHGV sequences of the tandem repeat. Natural MUC1 Abs from breast cancer patients reacted more strongly with the N-acetylgalactosamine (GalNAc) peptides than with the naked 60-mer peptide, while reactivity with the GalNAc-peptides was significantly reduced (2-tailed p < 0.0001) in the MUC1 IgG and IgM Abs induced by MUC1 peptide vaccination. Whereas in cancer patients glycans appear to participate in epitope conformation, the epitope(s) recognized by MUC1 Abs induced by peptide vaccination are already masked by minimal glycosylation. Therefore, our results indicate that a MUC1 glycopeptide would be a better vaccine than a naked peptide., (Copyright 2000 Wiley-Liss, Inc.)

Blood pressure varies during the menstrual cycle, but the reason for this is unclear. Administration of (synthetic) sex hormones can influence the level of vasoactive substances such as endothelin (ET). However, it is not known whether short-term variations in sex hormone levels in physiological situations affect ET levels. We assessed the effects of the menstrual cycle on plasma ET-1 in 8 healthy premenopausal women not using oral contraceptives (OCs) and 8 premenopausal women using OCs. ET-1 levels were measured in all subjects on days 1 to 3 (menstrual phase), 9 to 12 (follicular phase), and 20 to 23 (luteal phase) of the menstrual cycle. ET-1 levels remained constant in OC users (2.4 +/- 0.4, 2.6 +/- 0.4, and 2.4 +/- 0.4 pg/mL on days 1 to 3, 9 to 12, and 20 to 23 of the pill cycle). In contrast, ET-1 levels in non-OC users decreased in all women during the follicular and luteal phase of the menstrual cycle compared with the menstrual (low-estrogenic) phase (3.6 +/- 0.5, 2.8 +/- 0.5, and 2.9 +/- 0.3 pg/mL for the menstrual, follicular, and luteal phase, respectively, P < .01 for menstrual vfollicular and P < .01 for menstrual v luteal). The differences between OC users and nonusers were significant in the menstrual phase of the cycle (P < .01). We conclude that ET levels fluctuate during the menstrual cycle. Previously reported effects of the menstrual cycle on blood pressure may be partly explained by the effects of sex hormones on the level of vasoactive mediators. This fluctuation is not present in OC users. Studies on hemodynamic parameters in premenopausal women should account for hormonal variations in the various phases of the menstrual cycle.

Objective: To investigate whether the association between APOE-epsilon4 and memory decline is modified by baseline cognition and age in a population-based elderly sample., Methods: The study sample consisted of 1,243 subjects, 62 to 85 years old, with a Mini-Mental State Examination (MMSE) score between 21 and 30 and known APOE phenotypes. Memory performance was measured with an abbreviated Auditory Verbal Learning Test (AVLT) at baseline and repeated after 3 years (n = 854). Memory decline was defined as a decrease of at least 1 SD from the mean change score on immediate recall (IR), delayed recall (DR), and retention, based on the AVLT., Results: Multivariate logistic regression analyses showed that APOE-epsilon4 is associated with memory decline in cognitively impaired subjects (MMSE score, 21 to 26) (OR for decline on IR adjusted for age, sex, education, and baseline recall score, 3.8; 95% CI, 1.4 to 10.0; adjusted OR for decline on DR, 2.9; 95% CI, 1.2 to 7.0; adjusted OR for decline on retention, 3.3; 95% CI, 1.1 to 10. 1), but not in cognitively normal subjects (MMSE score, 27 to 30) (adjusted OR for decline on IR, 1.1; 95% CI, 0.6 to 2.0; adjusted OR for decline on DR, 1.0; 95% CI, 0.6 to 1.8; adjusted OR for decline on retention, 1.5; 95% CI, 0.7 to 3.0). In particular, cognitively impaired epsilon4 carriers older than 75 years were at high risk of memory decline (adjusted OR for decline on IR, 4.5; 95% CI, 1.4 to 13.8; adjusted OR for decline on DR, 3.6; 95% CI, 1.2 to 10.8; adjusted OR for decline on retention, 6.6; 95% CI, 1.5 to 29.7)., Conclusions: APOE-epsilon4 was associated with memory decline in subjects with cognitive impairment, but not in normally functioning subjects. Contrary to AD studies, our study suggests that the risk of APOE-epsilon4 on memory decline does not decrease at higher ages.

Purpose: Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine substrate for the immunotherapy of patients with adenocarcinoma. The present study analyzes the incidence of naturally occurring MUC1 antibodies in early breast cancer patients and relates the presence of these antibodies in pretreatment serum to outcome of disease., Materials and Methods: We measured immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat peptide conjugated to bovine serum albumin, in pretreatment serum samples obtained from 154 breast cancer patients (52 with stage I disease and 102 with stage II) and 302 controls. The median disease-specific survival time of breast cancer patients was 74 months (range, 15 to 118 months). A positive test result was defined as MUC1 IgG or IgM antibody levels equal to or greater than the corresponding rounded-up median results obtained in the total breast cancer population., Results: A positive test result for both MUC1 IgG and IgM antibodies in pretreatment serum was associated with a significant benefit in disease-specific survival in stage I and II (P =.0116) breast cancer patients. Positive IgG and IgM MUC1 antibody levels had significant additional prognostic value to stage (P =.0437) in multivariate analysis. Disease-free survival probability did not differ significantly. However, stage II patients who tested positive for MUC1 IgG and IgM antibody and who relapsed had predominantly local recurrences or contralateral disease, as opposed to recurrences at distant sites in the patients with a negative humoral response (P =.026)., Conclusion: Early breast cancer patients with a natural humoral response to MUC1 have a higher probability of freedom from distant failure and a better disease-specific survival. MUC1 antibodies may control hematogenic tumor dissemination and outgrowth by aiding the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant setting may favorably influence the outcome of disease.

Background: Beta human chorionic gonadotropin (beta-hCG) is expressed in human fetal tissue and cancer cells of various histologic types. It is degraded to the beta-core fragment (beta cf-hCG) which is concentrated in urine, and is known as urinary gonadotropin peptide (UGP). The objective of this study was to assess 1) the value of urinary gonadotropin peptide (UGP) as a single test and the combination of UGP with CA 125 as a diagnostic test in predicting the benign or malignant origin of gynecologic disease, 2) the influence of surgical removal of the tumor on the levels of UGP and CA 125, 3) the influence of the urinary concentration on the UGP levels in relation to the test results. PATIENTS, MATERIALS, METHODS AND STATISTICS: Serum and urine were collected from 31 gynecological patients with malignant and non-malignant disease, preoperatively, and 1 week and 6 weeks after surgery. Optimal cut-off levels were determined by Receiver Operating Characteristic-curves (ROC). Sensitivity (SENS), specificity (SPEC), positive (PPV) and negative predictive value (NPV) and overall test accuracy (ACC) for their ability to discriminate benign from malignant masses were calculated. Logistic regression analysis was performed to calculate the contribution of CA 125, UGP and UGP/creatinine (UGP/creat) to a model predicting malignancy., Results: The optimal cut-off level for UGP was found 1 fmol/l, for UGP/creat 1.33 fmol/mg creatinine and for CA 125 100 kU/L. The distribution of the urinary creatinine values varied considerably (median = 8.3 mmol/l, range 0.6-25.8 mmol/l). The correlation coefficient (r) between log UGP and log CA 125 was 0.44 (p = 0.001) and between log UGP/creat and log CA 125 0.53 (p < 0.0001)., Conclusions: UGP may be used as a tumor maker in gynecological disease. However, CA 125 as single test discriminates malignant from benign disease better than UGP or UGP/creat. In a logistic model the combination of CA 125 with UGP and UGP/creat predicts the benign or malignant character in 89% of the study population. Significant changes in UGP and UGP/creat levels were seen after removal of benign tumors, however, this was not found in ovarian cancer patients. Correction of the UGP values for the urinary concentration improved the results slightly.

Since the OC 125 monoclonal antibody (Mab) was generated, other Mabs to the CA 125 glycoprotein have been produced and classified into two families associated with two major epitope regions on the CA 125 molecule. New generation assays, combining Mabs to two distinct regions of the molecule, compare favorably with that of the original assays as demonstrated by ROC curves. The original CA 125 assay suffered from interference of HAMA, an important drawback considering the increasing use of murine antibodies for immunodiagnosis and treatment of ovarian cancer. This problem has been solved for the majority of currently available tests. The sensitivity of the assays for early ovarian cancer remains low, precluding its indiscriminate use for screening and diagnosis of ovarian cancer. Its use in screening for early cancer, combined with ultrasonography, is limited to high risk populations, such as women from families with mutations in the BRCA1 or 2 gene. Although CA 125 assessment may play a limited role in the (early) detection of ovarian cancer, its role in the follow-up during and after therapy is well established. The major contribution of CA 125 is in the monitoring of tumor response to chemotherapy, where it is valuable in detecting those patients with an inadequate response to the chosen treatment. The role of CA 125 in early detection of recurrences remains to be established and is currently the subject of two large clinical trials., (Copyright 1999 Academic Press.)

Objective: To compare the performance of four serum assays for the quantification of MUC1 in breast cancer patients., Study Design: A total of 282 serum samples were evaluated with two automated (Boehringer Mannheim Enzymun-Test CA 15-3 and Chiron ACS BR) and two manual assays (Centocor CA 15-3 radioimmunoassay [RIA] and Biomira Truquant BR RIA). Sera were obtained from healthy controls (n=50), patients with benign (n=25) and malignant breast disease (n=77) and patients with other malignancies (n=69). In addition, sera from pregnant women (n=56) and patients with liver cirrhosis (n=5) were included., Results: Intraassay coefficients of variation (C.V.s) were highest for the manual Centocor CA 15-3 assay (7.4% for values below 50 kU/l and 8.1% for values above 180 kU/l). Interassay C.Vs were highest for the manual Truquant BR assay (11.7% for the lower concentration values and 18.6% for the higher concentration values). False positive rates ranged between 0% for the Centocor CA 15-3 RIA and 14% for the ACS BR assay (cut-off: 30 kU/l). In monitoring breast cancer patients all four assays show similar patterns, although absolute MUC1 values found may differ up to 50%., Conclusion: For monitoring purposes all assays perform equally well, however, automated assays show lower inter- and intraassay variability, especially in the higher value range. Therefore we recommend the use of the same, automated, assay for quantification of MUC1 during the follow-up of breast cancer patients.

Objective: The objective of this study was to evaluate the extent to which endothelin and the eicosanoids prostacyclin and thromboxane A2 are involved in the pathophysiology of gestational hypertension and preeclampsia., Study Design: In a longitudinal design, venous blood samples and 24-hour urine specimens were collected from 396 women in each trimester of pregnancy. After delivery of all patients, venous plasma endothelin was assessed in 20 subjects with identified preeclampsia, 48 subjects with gestational hypertension, and 59 normotensive subjects. Urinary excretions of the thromboxane A2 and of the prostacyclin metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were assessed in 16 subjects with preeclampsia, 35 subjects with gestational hypertension, and 31 normotensive subjects., Results: Endothelin levels showed a second-trimester drop in all groups. In all 3 gestational trimesters a high correlation was found between the excretion of thromboxane B2 and that of 6-keto-prostaglandin F1 alpha (P <.001). The overall thromboxane B2 and 6-keto-prostaglandin F1 alpha urinary excretions increased throughout pregnancy and the overall thromboxane B2 /6-keto-prostaglandin F1 alpha ratio decreased. No significant differences in endothelin, thromboxane B2, and 6-keto-prostaglandin F1 alpha excretion levels or in thromboxane B2 /6-keto-prostaglandin F1 alpha ratios were found between women with preeclampsia, gestational hypertension, and normotension. Only in a small group of patients with severe preeclampsia (n = 2) and severe gestational hypertension (n = 2) were increased second-trimester endothelin values and increased thromboxane B2 /6-keto-prostaglandin F1 alpha ratios found., Conclusion: In this longitudinal study we found no evidence for prostacyclin deficiency or increased endothelin levels in preeclampsia. Only women with severe preeclampsia and severe gestational hypertension expressed increased endothelin levels and thromboxane dominance over prostacyclin.

Objective: To study plasma concentrations of endothelin (ET), lipidhydroperoxides (LOOH), glutathione peroxidase (GSHpx) and fibronectin in relation to abnormal umbilical artery velocimetry., Study Design: Plasma concentrations of ET, LOOH, GSHpx and fibronectin were measured in fetal and maternal venous blood in: (i) a control group (n=10); (ii) in pregnancies complicated by intrauterine growth retardation (IUGR) (n=6) or preeclampsia (n=5) with positive end diastolic flow; and in (iii) pregnancies complicated by absent or reversed end diastolic (ARED) flow in the umbilical artery (n=18). All children were delivered by primary caesarean section., Results: The significantly highest maternal and fetal ET concentrations were found in plasma collected in pregnancies complicated by ARED flow in the umbilical artery. Maternal fibronectin levels were significantly raised in the ARED flow group. Maternal plasma ET levels were lowest in pregnancies complicated by IUGR. The maternal and fetal plasma concentrations of LOOH and GSHpx did not differ significantly between the groups., Conclusion: Abnormal Doppler velocimetry, especially ARED flow is associated with elevated maternal and fetal plasma levels of ET. The exact mechanism causing the placental vasoconstriction is unknown yet, but oxidative stress seems not to be involved.

Seven CA 125 immunoassays were compared for their clinical performance. CA 125 concentrations were determined in 289 serum samples obtained from women with benign pelvic tumors (samples from 98 patients) and patients with various cancers (samples from 111 patients). In the range of 0-1000 kilounits/L, all assays tested were linearly correlated, with correlation coefficients ranging from 0.89 to 0.99. In relation to the original Centocor CA 125 assay, there was an overall tendency to measure higher absolute values in the lower CA 125 value range. This was not seen in relation to the Centocor CA 125 II assay. ROC curves (benign vs pretreatment ovarian cancer patients) were nearly identical for all assays, and the areas under the ROC curves were not markedly different. We conclude that the CA 125 assays tested are strongly related to each other and are clinically reliable for the quantification of serum CA 125 and that none of the assays offers higher diagnostic accuracy or better discrimination between patient groups, especially not in the lower ranges.

We studied thirteen male-to-female (M-->F) and ten female-to-male (F-->M) transsexuals who, for four months, received cross-sex treatment with, respectively, ethinylestradiol and cyproterone acetate, and with testosterone esters. We assessed the effects of treatment on plasma levels of tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), vWF-propeptide (vWF:AgII) and big-endothelin-1 (big-ET-1), four proteins that are markers of endothelial cell functioning. We also measured urokinase-type PA (uPA) and plasminogen activator inhibitor-type 1 (PAI-1), which may not be endothelium-derived but share major clearance pathways with tPA. In M-->F transsexuals, mean plasma levels of tPA (minus 4.4 ng/ml), big-ET-1 (minus 0.8 pg/ml), uPA (minus 0.5 ng/ml) and PAI-1 (minus 26 ng/ml) decreased (all Ps < or =0.02). The level of vWF increased (plus 24%; P = 0.005), while vWF: AgII did not change (P = 0.49). In F-->M transsexuals, levels of big-ET-1 increased (plus 0.4 pg/ml; P = 0.02), while tPA, uPA and PAI-1 did not change (all Ps >0.25). In this group vWF decreased (minus 14%; P = 0.06), but vWF:AgII did not change (P = 0.38). Estrogens and androgens have clear effects on plasma levels of endothelial marker proteins. The mechanisms behind these effects are complex and appear to involve both altered secretion (big-ET-1) and processing and/or clearance (vWF and possibly tPA). Therefore, effects of hormones on the levels of endothelial marker proteins do not necessarily reflect changes in endothelial cell functioning, at least with regard to changes in vWF level associated with the oral administration of high doses of ethinylestradiol and cyproterone acetate to healthy men and the parenteral administration of testosterone to healthy women.