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PubMed2006

Multiple inflammatory markers in patients with significant coronary artery disease.

BACKGROUND: Several inflammatory biomarkers are linked to cardiovascular risk. In order to investigate their coexistence and relative responses, several established and two novel markers (lactoferrin and the terminal complement complex), representing infection and central components of inflammation, were measured simultaneously in patients undergoing first-time coronary angiography. METHODS AND RESULTS: Blood samples from patients with (n=131) or without (n=103) significant coronary artery stenosis were analyzed for plasma markers representing endothelium, platelets, neutrophils, monocytes, and complement, C-reactive protein, and antibodies against the infectious agents Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus. In multivariate logistic regression analysis, hypercholesterolemia (p<0.001), increased concentrations of the neutrophil activation marker lactoferrin (p<0.001) and the monocyte activation marker neopterin (p=0.012), lower concentrations of the terminal complement complex (p<0.001), and antibodies against C. pneumoniae (p=0.023) were variables linked to coronary artery stenosis. In univariate analysis additional relationships were found to current smoking (p<0.001), increased plasma concentrations of vascular cell adhesion molecule-1 (p=0.015), E-selectin (p<0.01), myeloperoxidase (p=0.051) and endothelin-1 (p=0.053), as well as diabetes (p=0.039). CONCLUSIONS: Activation of multiple inflammatory pathways and C. pneumoniae infection may influence the inflammatory response in atherosclerosis. These pilot data provide an indication of the relative usefulness of various inflammatory biomarkers, indicating that the novel markers lactoferrin and the terminal complement complex warrant further investigation.

Analysis of Variance↗

PubMed2003

Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata.

X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2.

Adult↗

PubMed2003

The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer.

BACKGROUND: In recent studies serum levels of human glandular kallikrein 2 (hK2) demonstrated significant differences in pathologically organ-confined versus non-organ-confined prostate cancer (PCa). In this study we investigated whether hK2 adds independent information when considered together with traditionally used parameters to predict organ confined (pT2a/b) PCa. METHODS: Serum levels of hK2, total and free prostate-specific antigens (PSA) were obtained one day before radical prostatectomy in 245 consecutive men. These were included with clinical stage and biopsy Gleason grade into univariate analysis and multivariate logistic regression models. RESULTS: pT2a/b PCa was found in n = 148 patients. In univariate analysis all preoperative parameters demonstrated significant association with the presence of pT2a/b PCa. Using multivariate logistic regression model hK2 (P = 0.022), clinical stage (P < 0.0001), and Gleason grade (P < 0.0001) were independent predictors of pT2a/b PCa whereas PSA (P = 0.3) was not. In bootstrap corrected logistic regression based nomograms the addition of hK2 density marginally enhanced predictive accuracy when PSA, PSA density, clinical stage, and Gleason grade were considered (AUC = 0.879 without hK2 density and 0.883 with hK2 density). CONCLUSIONS: hK2 and hK2 density could independently predict pT2a/b PCa. However, improvement in predictive accuracy was marginal when nomograms based on traditional variables were complemented with this serum marker.

Area Under Curve↗

PubMed1992

Prostate-specific antigen: establishment of the reference range for the clinically normal prostate gland and the effect of digital rectal examination, ejaculation, and time on serum concentrations.

This study investigated the serum prostate-specific antigen concentration in 100 healthy men (mean age, 26.3 years; range, 20-29 years) with a clinically normal prostate gland. The effect of digital rectal examination and ejaculation on the serum concentration, and the variability of the serum concentration over 1-week and 1-month periods were examined. In the 100 subjects, the serum prostate-specific antigen concentration ranged from less than 0.1-2.6 ng/ml. The mean, median, and mode were 0.68 ng/ml, 0.6 ng/ml, and 0.4 ng/ml, respectively. The 97.5th percentile value was 2.1 ng/ml. The mean and median changes in the serum concentration after digital rectal examination were -0.013 +/- 0.11 ng/ml and 0.0 ng/ml, respectively (P = 0.59 compared with control group). The mean change after ejaculation was 0.05 +/- 0.12 ng/ml, and the median change was 0.0 ng/ml (P = 0.14 compared with control group). Diurnal variation showed minimal change in 16 patients over a 1-week period. The mean change (p.m. value-a.m. value) was 0.003 ng/ml (range, -0.2-0.06 ng/ml). In addition, the serum concentration showed minimal intrapatient variability in 20 patients throughout a 1-month period; the average coefficient of variation (standard deviation/mean) in these subjects was 16.5% (range, 6.4-45.2%). These results indicate that the range in the serum concentration of prostate-specific antigen for healthy men with a clinically normal prostate gland is significantly lower (0.0-2.6 ng/ml) than the currently employed range (0.0-4.0 ng/ml; Tandem-R PSA assay); in addition, digital rectal examination and ejaculation have no significant effect on the serum concentration. Finally, the time of day has little effect, and the variability in the serum concentration of prostate-specific antigen over a 1-week and 1-month interval is minimal.

Adult↗

PubMed2001

Identification of syt-ssx fusion transcripts in both epithelial and spindle cell components of biphasic synovial sarcoma in small tissue samples isolated by membrane-based laser microdissection.

In order to confirm the presence of SYT-SSX fusion gene in epithelial and spindle cell components of synovial sarcoma, we performed a nested reverse transcriptase-polymerase chain reaction (RT-PCR) using microbeam microdissection of membrane-mounted native tissue (MOMeNT) technique applied on formalin-fixed, paraffin-embedded tumor specimens from two biphasic synovial sarcomas and a control tissue of adamantinoma. Small targeted portions of either an epithelial or spindle cell component of the tumor tissue were microdissected together with the supporter membrane, by using an ultraviolet (337-nm) pulsed laser microbeam coupled into a robot-stage microscope with infinity optics. The SYT-SSX fusion transcript was detected in epithelial and spindle cell components of both biphasic synovial sarcomas, but not in the control tissue. Southern blot analysis also confirmed that the detected messages were derived from the SYT-SSX fusion gene. In conclusion, the microbeam MOMeNT is a useful method for isolating selected small portions from tissue sections. The SYT-SSX fusion gene is present in both cellular components of biphasic synovial sarcoma and is involved in oncogenesis of the synovial sarcoma rather than in morphologic epithelial differentiation. Therefore, in spite of the variable proportions of each component, our results confirm that the synovial sarcoma is of monoclonal origin.

Adult↗

PubMed1995

Plasma tetranectin and colorectal cancer.

The prognostic significance of plasma tetranectin (PL-TN) in colorectal cancer was retrospectively examined in 504 patients (80 Dukes' A, 174 Dukes' B, 98 Dukes' C and 152 Dukes' D). Follow-up time was 7-12 years. No significant prognostic variable was found for Dukes' A patients by Cox multivariate analysis. In stage B, PL-TN was the second strongest prognostic variable [relative hazard (RH) = 3.3 for patients with PL-TN < or = 7.5 mg/l]. The other prognostic variables were perineural invasion (RH = 3.7), tumour distance < or = 10 cm from the anal verge (RH = 3.0), postoperative radiotherapy (RH = 2.9) and a high carcinoembryonic antigen (CEA) score (RH = 1.8). In Dukes' C, only CEA score and gender were of prognostic significance. For Dukes' D, PL-TN was the only prognostic variable (RH = 1.7). Testing all patients in one multivariate analysis, Dukes' staging was the strongest and PL-TN the second strongest prognostic variable. The shortened survival for patients with low PL-TN levels is illustrated with lifetables.

Aged↗

PubMed2002

Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging.

PURPOSE: To test whether elevated homocysteine levels are associated with an increased risk of decline in physical function in older persons. METHODS: We performed a prospective cohort study of 499 highly functioning men and women aged 70 to 79 years who were enrolled in the MacArthur Studies of Successful Aging. We measured total homocysteine levels and performance-based physical function at baseline; physical function measures were repeated an average of 28 months later. A summary measure of physical performance from tests of balance, gait, lower body strength and coordination, and manual dexterity was developed, and a change score was calculated as the difference in scores from 1988 to 1991. RESULTS: The mean (+/-SD) homocysteine level was 11.6 +/- 4.3 micromol/L. With each SD increase in homocysteine, there was an increased risk of being in the worst quartile of decline in physical function (odds ratio = 1.5; 95% confidence interval: 1.2 to 1.9) in analyses that adjusted for age, sex, baseline physical performance, smoking status, vitamin B(12) levels, and incident stroke. Similar results were seen when change in physical performance was treated as a continuous variable. CONCLUSION: Older persons with elevated plasma homocysteine levels are at an increased risk of decline in physical function.

Aged↗

PubMed1989

The role of clinical investigations in biological markers research.

As the agenda of the occupational and environmental health community proceeds from the study of the effects of high doses of toxins causing grossly altered disease patterns to examination of the impact of lower doses on prevalent disorders, new scientific approaches have become necessary. The emerging concept of molecular epidemiology, substituting biologically determined markers of dose and early effect for traditional measures of exposure and morbidity, offers a heuristically appealing direction for the field. However, the transition to this evolving approach has been slow and its potential has yet to be validated. In this essay, some of the limitations of this approach are discussed and theoretical modifications developed. The central proposition is that existing modalities of clinical research, widely employed in subspecialty medicine research but heretofore unexploited in the study of environmental diseases, offer great promise. By incorporating clinical investigations centrally, some historically rate-limiting problems such as variability of host responses, multiplicity of environmental risks, and differences between human and animal responses could be transformed from major impediments at present to realistic objects for future study.

Animals↗

PubMed1992

Methodological issues in epidemiologic studies using biologic markers.

Biologic markers are becoming prominent features of many classical epidemiologic studies. Their existence has also modified the character of some epidemiologic research such that the term "transitional epidemiologic studies" may be warranted. In the latter type of study, collaboration between laboratory and epidemiologic investigators is integral to the research. In this paper, goals, characteristics, and examples of transitional epidemiologic research are presented. Pertinent features are highlighted, including sources of misclassification and confounding, and elements of study design useful in reducing these potential biases. Sample size issues, transformation of variables, and sources of variability acquire enhanced importance. The study examples presented are intended to illustrate the altered substrate for these methodological features in studies using biologic markers.

Analysis of Variance↗

PubMed1990

A study of factor XIIIa and MAC 387 immunolabeling in normal and pathological skin.

Immunolabeling with two new antibodies, Factor XIIIa and MAC 387, has been studied in routinely processed biopsy specimens of normal skin, subcutaneous tissues, lymph nodes, and a variety of pathological conditions. These presumptive cell markers of the monocyte-macrophage lineage appear to label totally different and possibly mutually exclusive subsets of cells. In normal skin, Factor XIIIa labeled fixed dermal connective tissue cells, emphasizing their dendritic morphological appearance. Factor XIIIa expression in fibroproliferative conditions and spindle cell tumors varied: in particular, scars, keloids, and dermatofibrosarcomas do not label, whereas histiocytomas, fibrous papule of the nose, and atypical fibroxanthomas were well labeled. In inflammatory conditions, increased numbers of Factor XIIIa cells were found, but most macrophages and epithelioid and multinucleate cells did not label. In contrast, normal dermal connective tissue cells did not label with MAC 387, nor did the constituent cells of various fibroproliferative disorders. In inflammatory conditions, variable numbers of MAC 387-positive cells were observed, corresponding to histiocytes and macrophages, but labeling of epithelioid cells and multinucleate foreign body giant cells was variable. Histiocytosis X cells do not express either label. The theoretical and practical implications of these results are explored.

Antibodies, Monoclonal↗

PubMed2003

Use of DNA and peptide nucleic acid molecular beacons for detection and quantification of rRNA in solution and in whole cells.

DNA and peptide nucleic acid (PNA) molecular beacons were successfully used to detect rRNA in solution. In addition, PNA molecular beacon hybridizations were found to be useful for the quantification of rRNA: hybridization signals increased in a linear fashion with the 16S rRNA concentrations used in this experiment (between 0.39 and 25 nM) in the presence of 50 nM PNA MB. DNA and PNA molecular beacons were successfully used to detect whole cells in fluorescence in situ hybridization (FISH) experiments without a wash step. The FISH results with the PNA molecular beacons were superior to those with the DNA molecular beacons: the hybridization kinetics were much faster, the signal-to-noise ratio was much higher, and the specificity was much better for the PNA molecular beacons. Finally, it was demonstrated that the combination of the use of PNA molecular beacons in FISH and flow cytometry makes it possible to rapidly collect quantitative FISH data. Thus, PNA molecular beacons might provide a solution for limitations of traditional FISH methods, such as variable target site accessibility, poor sensitivity for target cells with low rRNA content, background fluorescence, and applications of FISH in microfluidic devices.

Base Sequence↗

PubMed1997

Vitamin A levels and human immunodeficiency virus load in injection drug users.

Although low plasma vitamin A levels are associated with increased mortality and higher vertical transmission during human immunodeficiency virus (HIV) infection, it is unknown whether plasma low vitamin A levels are a marker for circulating HIV load. We conducted a cross-sectional study within a prospective cohort study of injection drug users in order to evaluate the relationship between plasma vitamin A levels and HIV viral load. Plasma vitamin A level was measured by high-performance liquid chromatography. Infectious viral load was measured by quantitative microculture of serial fivefold dilutions of 10(6) peripheral blood mononuclear cells. A total of 284 HIV-infected adults (79 women, 205 men) were studied. Plasma vitamin A levels consistent with deficiency were found in 28.9% of adults. A total of 38.0% of women and 25.3% of men had vitamin A deficiency (P < 0.04). The median infectious viral load for the entire study population was 8 infectious units per million cells. No significant relationship between plasma vitamin A levels and infectious viral load was observed in these injection drug users. This study suggests that there is no correlation between HIV viral load and plasma vitamin A levels in injection drug users, and these variables may represent independent risk factors during HIV infection. HIV-infected adult women appear to be at higher risk of developing vitamin A deficiency.

Adult↗

PubMed2000

Wechsler subscale IQ and subtest profile in early treated phenylketonuria.

AIM: Mildly depressed IQ is common in treated phenylketonuria. This study explored whether a particular intellectual ability profile typifies early and continuously treated phenylketonuria and whether component skills comprising the IQ relate to socioeconomic and treatment factors. METHODS: IQ scores were collected retrospectively from variants of the "Wechsler intelligence scale for children" performed at age 8 on 57 children with early treated, classic phenylketonuria. The mental ability pattern underlying IQ was investigated by analysing subscale and subtest scores and dietary factors, such as historical phenylalanine blood concentrations. RESULTS: The children's mean full scale IQ of 91.11 was significantly below the healthy population norm. There was a significant discrepancy between their mean verbal IQ (94.65) and mean performance IQ (89.42), suggestive of a spatial deficit, but the data did not support a biochemical or sociological explanation. Individual Wechsler subtests had no distinctive pattern. Phenylalanine control at age 2 was predictive of overall IQ. At this age, children with annual median phenylalanine < 360 micromol/litre (recommended UK upper limit) had a mean IQ 10 points higher than those above. CONCLUSIONS: Early and continuous treatment of phenylketonuria does not necessarily lead to normalisation of overall IQ. Verbal intelligence in the primary school years appears to normalise if blood phenylalanine is maintained below 360 micromol/litre in infancy, but spatial intelligence may remain poor. However, the discrepancy in skill development is not the result of social status or treatment variables. Perhaps weak spatial intelligence is an ancillary effect of a protective rearing style occasioned by the dietary treatment regimen.

Biomarkers↗

PubMed2000

Reliability of immunohistochemical demonstration of oestrogen receptors in routine practice: interlaboratory variance in the sensitivity of detection and evaluation of scoring systems.

AIMS: To investigate interlaboratory variance in the immunohistochemical (IHC) detection of oestrogen receptors so as to determine the rate of false negatives, which could adversely influence the decision to give adjuvant tamoxifen treatment. METHODS: To ensure that similar results are obtained by different institutions, 200 laboratories from 26 countries have joined the UK national external quality assessment scheme for immunocytochemistry (NEQAS-ICC). Histological sections from breast cancers having low, medium, and high levels of oestrogen receptor expression were sent to each of the laboratories for immunohistochemical staining. The results obtained were evaluated for the sensitivity of detection, first by estimating threshold values of 1% and 10% of stained tumour cells, and second by the Quick score method, by a panel of four assessors judging individual sections independently on a single blind basis. The results were also evaluated using participants' own threshold values. RESULTS: Over 80% of laboratories were able to demonstrate oestrogen receptor positivity on the medium and high expressing tumours, but only 37% of laboratories scored adequately on the low expressing tumour. Approximately one third of laboratories failed to register any positive staining in this tumour, while one third showed only minimal positivity. CONCLUSIONS: There is considerable interlaboratory variability, especially in relation to the detection of breast cancers with low oestrogen receptor positivity, with a false negative rate of between 30% and 60%. This variability appears to be caused by minor differences in methodology that may be rectified by fine adjustment of overall technique.

Biomarkers, Tumor↗

PubMed2005

Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements.

Biologic monitoring (i.e., biomonitoring) is used to assess human exposures to environmental and workplace chemicals. Urinary biomonitoring data typically are adjusted to a constant creatinine concentration to correct for variable dilutions among spot samples. Traditionally, this approach has been used in population groups without much diversity. The inclusion of multiple demographic groups in studies using biomonitoring for exposure assessment has increased the variability in the urinary creatinine levels in these study populations. Our objectives were to document the normal range of urinary creatinine concentrations among various demographic groups, evaluate the impact that variations in creatinine concentrations can have on classifying exposure status of individuals in epidemiologic studies, and recommend an approach using multiple regression to adjust for variations in creatinine in multivariate analyses. We performed a weighted multivariate analysis of urinary creatinine concentrations in 22,245 participants of the Third National Health and Nutrition Examination Survey (1988-1994) and established reference ranges (10th-90th percentiles) for each demographic and age category. Significant predictors of urinary creatinine concentration included age group, sex, race/ethnicity, body mass index, and fat-free mass. Time of day that urine samples were collected made a small but statistically significant difference in creatinine concentrations. For an individual, the creatinine-adjusted concentration of an analyte should be compared with a "reference" range derived from persons in a similar demographic group (e.g., children with children, adults with adults). For multiple regression analysis of population groups, we recommend that the analyte concentration (unadjusted for creatinine) should be included in the analysis with urinary creatinine added as a separate independent variable. This approach allows the urinary analyte concentration to be appropriately adjusted for urinary creatinine and the statistical significance of other variables in the model to be independent of effects of creatinine concentration.

Adolescent↗

PubMed2003

The application of clinical proteomics to cancer and other diseases.

The term "clinical proteomics" refers to the application of available proteomics technologies to current areas of clinical investigation. The ability to simultaneously and comprehensively examine changes in large numbers of proteins in the context of disease or other changes in physiological conditions holds great promise as a tool to unlock the solutions to difficult clinical research questions. Proteomics is a rapidly growing field that combines high throughput analytical methodologies such as two-dimensional gel electrophoresis and SELDI mass spectrometry methods with complex bioinformatics to study systems biology--the system of interest is defined by the investigator. Even with all its potential, however, studies must be carefully designed in order to differentiate true clinical differences in protein expression from differences originating from variation in sample collection, variation in experimental condition, and normal biological variability. Proteomic analyses are already widely in use for clinical studies ranging from cancer to other diseases such as cardiovascular disease, organ transplant, and pharmacodynamic studies.

Biomarkers↗

PubMed2002

Postmortem cytokine levels and the cause of death.

We investigated the usefulness of cytokine measurement in the field of forensic medicine. In this study, the levels of Interleukin (IL)-1beta, IL-6, IL-8, IL-10 in serum collected within 2 days after death were used to estimate the cause of death. In seventy-one victims, mean age 55.5 +/- 17.7 (S.D.) years, the cases were classified as traumatic death (24 cases, trauma group), unnatural deaths by other than traumatic causes (31 cases, unnatural death group), and deaths due to natural causes (16 cases, natural death group). The Kruskal-Wallis test showed that IL-6 and IL-8 were good indices of trauma. According to the Scheffé test, IL-6 and IL-8 levels of the traumatic death group were significantly higher than those of the unnatural death group (p < 0.05), but there was no significant difference in IL-6 levels between the traumatic death and natural death groups. Further, IL-6 levels showed considerable variability even among similar cases. However, IL-8 measurement of postmortem samples is useful to evaluate non-quantitative damage received before death.

Adolescent↗

PubMedDate not supplied

Microalbuminuria in essential hypertension.

The prevalence of microalbuminuria in patients with essential hypertension ranges between 10 and 25%. The level of albuminuria is highly correlated with arterial pressure and more closely ambulatory arterial pressure. The interaction between albuminuria and arterial pressure is enhanced by overweight and smoking. The renal mechanisms of microalbuminuria are not well elucidated; however, an increase in filtration fraction suggestive of intraglomerular hypertension was observed in patients with hyperfiltration. The significance of microalbuminuria as a marker of cardiovascular risk or hypertensive renal damage needs to be confirmed through long-term follow-up studies. Antihypertensive treatment has variable influence on albuminuria; and angiotensin-converting enzyme inhibitors and to a lesser extent other agents, tend to partially correct this abnormality.

Albuminuria↗