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PubMed2005

Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects.

AIMS: Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. METHODS: These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (-), improvement/increase (+) or no change (=) relative to placebo. RESULTS: 56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration. CONCLUSIONS: SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review.

Biomarkers↗
PubMed2006

[Establishment of method for cytochrome P450 of earthworms (Eisenia fetida) as a biomarker].

Earthworm (Eisenia fetida) was chosen as test soil fauna to establish the method for determination of cytochrome P450 content. By means of thoroughly washing with salt solution, changing centrifugal acceleration and dissolving microsomal membranes of earthworms with sodium cholate, the determination of cytochrome P450 was performed. Base on the method, dynamic relationships of dose-response for cytochrome P450 contents in earthworm and phenanthrene concentrations were conducted by contact filter paper and soil contaminated with phenanthrene. Results indicate that cytochrome P450 are covered up by interferential material in earthworm, which makes the classic peak lag and appear at 455 - 457nm in the CO difference spectrum with a spectrophotometer. Through increasing centrifugal acceleration and adding reagent of solubilization, the interference is removed mostly and the classic peak of P450 returns to appear at 450nm +/- 1nm. The exposure tests of phenanthrene with contact filter paper (10(-6), 10(-5), 10(-4), 10(-3) and 10(-2) mg x mL(-1)) and soil (1, 2, 4 and 8 mg x kg(-1)) reveal that the dose-response relationships exist between the pollutant and cytochrome P450. Soil tests of different exposure durations (1, 3, 7, 14 and 28d) show the effects of different phenanthrene concentration on earthworm cytochrome P450 contents are to activate (7d) and to inhibit (14d and 28d), and the content of P450 is 0.99 - 1.41 and 0.77 - 0.88 (p < 0.05) times of control respectively. From this study, cytochrome P450 content of earthworm has the merit of simpleness, speediness and economy for determination, and it could be used as a sensitive biomarker for monitoring the exposure of sublethal pollution in terrestrial ecosystem.

Animals↗
PubMed2006

Bench to bedside: evidence for brain injury after concussion--looking beyond the computed tomography scan.

The emergency management of cerebral concussion typically centers on the decision to perform a head computed tomography (CT) scan, which only rarely detects hemorrhagic lesions requiring neurosurgery. The absence of hemorrhage on CT scan often is equated with a lack of brain injury. However, observational studies revealing poor long-term cognitive outcome after concussion suggest that brain injury may be present despite a normal CT scan. To explore this idea further, the authors reviewed the evidence for objective neurologic injury in humans after concussion, with particular emphasis on those with a normal brain CT. This evidence comes from studies involving brain tissue pathology, CT scanning, magnetic resonance image (MRI) scanning, serum biomarkers, formal cognitive and balance tests, functional MRI, positron emission tomography, and single-photon emission computed tomography scanning. Each section is accompanied by technical information to help the reader understand what these tests are, not to endorse their use clinically. The authors discuss the strengths and weaknesses of the evidence in each case. These reports make a compelling case for the existence of concussion as a clinically relevant disease with demonstrable neurologic pathology. Areas for future emergency medicine research are suggested.

Axons↗
PubMed2006

Prevalence of SIL and SCCA in human immunodeficiency virus-seropositive women at anonymous clinic in Chonburi Hospital.

UNLABELLED: The series of 231 HIV-infected women were recruited in Chonburi Hospital, Thailand. Demographic, gynecologic factors were interviewed Pap smear was performed and classified based on the Bethasda system (1991) by a cytotechnologist. All abnormal Pap smear slides were reviewed by a cytopathologist. The prevalence of LSIL, HSIL and SCCA were 2.2%, 8.3% and 2.2%, respectively. There was statistically significant association between the duration of HIV infection and occurrence of SIL and SCCA. (p = 0.007) CONCLUSION: The present study showed a high prevalence of SIL and SCCA in-HIV-infected women at Chonburi Hospital.

Adult↗
PubMed2003

Do tissue damage biomarkers used to assess machine-perfused NHBD kidneys predict long-term renal function post-transplant?

BACKGROUND: Renal transplantation in many units is limited by the availability of donor organs. Kidneys obtained from non-heart-beating donors (NHBD) represent an important resource, with the potential to substantially increase the available donor organ pool. Such kidneys are associated with increased warm ischaemic tissue injury which may be assessed by hypothermic machine perfusion. Within our transplant centre, a key component of such damage assessment and viability screening involves the quantification of the tissue damage biomarkers glutathione S-transferase in kidney perfusates. METHODS: Since 1998, 126 NHBD kidneys were machine-perfused prior to implantation, resulting in 74 transplants. Kidney perfusate samples were assayed for glutathione S-transferase in "real time", and alanine aminopeptidase and fatty acid binding protein in "retrospect". RESULTS: The pre-transplant concentration of these tissue injury biomarkers determined pre-transplant did not correlate with subsequent longer-term renal function, as assessed by measurement of serum creatinine (tGST: Spearman correlation r=-0.02; Ala-AP: r=0.02; H-FABP: r=-0.05) and creatinine clearance (tGST: r=0.08; Ala-AP: r=-0.02; H-FABP: r=0.14) for those kidneys that had passed their viability tests. CONCLUSIONS: Thus whilst these biomarkers may represent reliable pre-transplant indicators of immediate kidney viability and short-term kidney function, they do not predict the efficacy of renal function in the longer term.

Biomarkers↗
PubMed2004

The in vivo use of the stable isotope-labelled biomarkers lactose-[15N]ureide and [2H4]tyrosine to assess the effects of pro- and prebiotics on the intestinal flora of healthy human volunteers.

Amongst the various claimed beneficial effects of pro- and prebiotics for the human host, it has been hypothesised that functional foods are able to suppress the generation and accumulation of toxic fermentation metabolites (NH3, p-cresol). Direct evidence supporting this hypothesis is lacking mainly because of the unavailability of reliable biomarkers. Preliminary data indicate that lactose-[15N]ureide and [2H4]tyrosine may be potential biomarker candidates. The aim of the present study was to evaluate the effect of pro- and prebiotics on the colonic fate of these biomarkers in a randomised, placebo-controlled, cross-over study with nineteen healthy volunteers. At the start of the study and at the end of each 2-week study period, during which they were administered either a probiotic (n 10; 6.5 x 10(9) Lactobacillus casei Shirota cells twice daily) or a prebiotic (n 9; lactulose 10 g twice daily), the volunteers consumed a test meal containing the two biomarkers. Urine was collected during 48 h. Results were expressed as percentage of the administered dose. As compared with the placebo, the decrease in the percentage dose of p-[2H4]cresol in the 24-48 h urine fraction was significantly higher after probiotic intake (P=0.042). Similar changes were observed for the 15N tracer (P=0.016). After prebiotic intake, a significantly higher decrease in the percentage dose of p-[2H4]cresol (P=0.005) and 15N tracer (P=0.029) was found in the 0-24 h urine collection. The present results demonstrate that suppression of the generation and accumulation of potentially toxic fermentation metabolites by pro- and prebiotics can reliably be monitored in vivo by the use of stable isotope-labelled biomarkers.

Adult↗
PubMed2002

Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients.

BACKGROUND: The low specificity of the prostate-specific antigen (PSA) test makes it a poor biomarker for early detection of prostate cancer (PCA). Because single biomarkers most likely will not be found that are expressed by all genetic forms of PCA, we evaluated and developed a proteomic approach for the simultaneous detection and analysis of multiple proteins for the differentiation of PCA from noncancer patients. METHODS: Serum samples from 386 men [197 with PCA, 92 with benign prostatic hyperplasia (BPH), and 96 healthy individuals], randomly divided into training (n = 326) and test (n = 60) sets, were analyzed by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. The 124 peaks detected by computer analyses were analyzed in the training set by a boosting tree algorithm to develop a classifier for separating PCA from the noncancer groups. The classifier was then challenged with the test set (30 PCA samples, 15 BPH samples, 15 samples from healthy men) to determine the validity and accuracy of the classification system. RESULTS: Two classifiers were developed. The AdaBoost classifier completely separated the PCA from the noncancer samples, achieving 100% sensitivity and specificity. The second classifier, the Boosted Decision Stump Feature Selection classifier, was easier to interpret and used only 21 (compared with 74) peaks and a combination of 21 (vs 500) base classifiers to achieve a sensitivity and specificity of 97% for the test set. CONCLUSIONS: The high sensitivity and specificity achieved in this study provides support of the potential for SELDI, coupled with a bioinformatics learning algorithm, to improve the early detection/diagnosis of PCA.

Algorithms↗
PubMed2003

A medium-term rat liver bioassay for rapid in vivo detection of carcinogenic potential of chemicals.

A reliable medium-term bioassay system for rapid detection of carcinogenic potential of chemicals in the human environment has been developed. The 8-week-protocol consists of 2 stages; male F344 rats are given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg) for initiation of liver carcinogenesis, followed by a 6-week test chemical treatment starting 2 weeks thereafter. Test chemicals are usually given in the diet or the drinking water and in the 2nd week of test chemical treatment, all rats are subjected to two-thirds partial hepatectomy in order to induce regenerative cell replication. The end-point marker is the glutathione S-transferase placental form (GST-P)-positive hepatic focus, the numbers and sizes of which are analyzed using an image-analyzer and expressed as values per unit liver section (1 cm2). When the yield of GST-P-positive foci is significantly enhanced (P<0.05) over the control value, a chemical is judged to possess carcinogenic or promotion potential for the liver. Among 313 chemicals already tested in this system in our laboratory, 30/31 (97%) mutagenic hepatocarcinogens and 29/33 (88%) non-mutagenic hepatocarcinogens gave positive results. Ten out of 43 (23%) agents known to be carcinogenic in organs other than the liver were also positive. It is particularly important that only one of 48 non-carcinogens gave a very weak positive result, so that the system has a very low false-positivity rate. It is now well documented that the assay system is highly effective for detecting hepatocarcinogens, bridging the gap between traditional long-term carcinogenicity tests and short-term screening assays. At the Fourth International Conference on Harmonization, our medium-term liver bioassay based on an initiation and promotion protocol was recommended in the guidelines as an acceptable alternative to the long-term rodent carcinogenicity test.

Administration, Oral↗
PubMed1998

Colonic epithelial cell proliferation in hereditary non-polyposis colorectal cancer.

BACKGROUND: Despite the recent discovery of four genes responsible for up to 90% of all cases of hereditary non-polyposis colorectal cancer (HNPCC), there will still be families in whom predictive testing is not possible. A phenotypic biomarker would therefore be useful. An upwards shift of the proliferative compartment in colonic crypts is reported to be one of the earliest changes in premalignant mucosa. AIMS: To assess the role of crypt cell proliferation as a phenotypic biomarker in HNPCC. PATIENTS: Thirty five patients at 50% risk of carrying the HNPCC gene (21 of whom subsequently underwent predictive testing and hence gene carrier status was known) and 18 controls. METHODS: Crypt cell proliferation was measured at five sites in the colon using two different techniques. Labelling index was determined using the monoclonal antibody MIB1 and whole crypt mitotic index was measured using the microdissection and crypt squash technique. The distribution of proliferating cells within the crypts was also assessed. RESULTS: There were no significant differences in the total labelling index or mean number of mitoses per crypt, nor in the distribution of proliferating cells within the crypt, between the study and control groups at any site. When the 21 patients in whom gene carrier status was known were analysed separately there were no significant differences in the measured indices of proliferation between the HNPCC gene carriers and non-gene carriers. CONCLUSION: Crypt cell proliferation is not a discriminative marker of gene carriage in HNPCC.

Adolescent↗
PubMed1997

Development of broad spectrum antibodies to heat shock protein 70s as biomarkers for detection of multiple stress by pollutants and environmental factors.

To test the hypothesis that broad spectrum antibodies may be developed as biomarkers useful in detecting the consequence of combined environmental stresses in a wide variety of tissues and organisms, a stretch of 16 amino acids, TVPAYFNDSQRQATKDA, a well-conserved portion of heat shock 70 proteins, was identified, against which specific antibodies could be designed. This stretch of peptide was synthetically prepared and used as a hapten for antibody preparation by coupling to keyhole lympet hemocyanin, injecting into a rabbit, collecting its blood, and purifying an IgG-rich fraction. The resulting polyclonal antibody was found to react with many heatshock protein (HSP) 70s in every species tested so far, including two species of fish and one amphibian, two arthropod, and one plant species. To relate the reactivity of this antibody preparation to heat shock proteins known to be induced by environmental stress, a Western blot assay method was used to study several organisms under unstressed or stressed conditions. Invariably, heat treatment caused a rise in the titer or HSP70 and/or glucose-regulated proteins. In addition, in some species chemical stresses were also found to be manifested in the form of an increased titer of these proteins.

Amino Acid Sequence↗
PubMed2005

The use of probrain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions resulting from heart failure.

PURPOSE OF REVIEW: Natriuretic peptides are secreted by the myocardium in response to mechanical stretch and have been proposed as a possible test for assisting the diagnosis of heart failure. This article reviews the rationale for measuring N terminal probrain natriuretic peptide in pleural fluid to identify heart failure as the cause of a pleural effusion. RECENT FINDINGS: Rapid and accurate testing of natriuretic peptides as biomarkers for heart failure is now a clinical reality. In patients presenting with dyspnea, heart failure is usually absent at blood brain natriuretic peptide levels less than 100 pg/mL, possible from 100 to 500 pg/mL, and probable at levels greater than 500 pg/mL. In evaluating natriuretic peptide assays, one needs to consider carefully laboratory and biologic variation, including gender, sex, obesity, renal function, and the assay used. Potential future applications of natriuretic peptide testing include the differential diagnosis of pleural effusion. A recent study has shown good diagnostic characteristics in cardiac pleural effusions, with likelihood ratios of 13 and a diagnostic accuracy of more than 90% for pleural fluid N terminal probrain natriuretic peptide levels > or =1500 pg/mL. Specifically, N terminal probrain natriuretic peptide pleural levels correctly categorized most cardiac effusions misclassified as exudates by standard criteria, and discriminated between cardiac and hepatic transudates. SUMMARY: Pleural fluid N terminal probrain natriuretic peptide may help accurately differentiate cardiac from noncardiac conditions in patients presenting with pleural effusion.

Heart Failure↗
PubMed2006

Potential use of glycogen level as biomarker of chemical stress in Biomphalaria glabrata.

Biomphalaria glabrata, a freshwater gastropod mollusc, was tested as biondicator organism to assess cadmium, lead and arsenic exposure using acute laboratory bioassays. Modifications of glycogen levels were measured in different anatomical regions of B. glabrata in order to test the usefulness of this parameter as a general biomarker of chemical stress. The snails were exposed 96 h to different concentrations of the following contaminants: 0.1 and 0.05 mg Cd/L; 0.5, 0.1 and 0.05 mg Pb/L; 0.5, 0.1 and 0.05 mg As/L. Significant decreases in the polysaccharide content were observed in gonadal region for all treated animals. Arsenic and lead at 0.1 and 0.5 mg/L level of exposure were also able to decrease the levels of glycogen in the pulmonary and digestive gland region. Glycogen content in the cephalopedal region of treated animals presented a significant decrease (p<0.05) when compared with control organisms only for arsenic at the highest level of exposure. To establish possible correlations between glycogen and contaminants accumulated by snails, analyses of the elements bioaccumulated in the different anatomical regions of B. glabrata were also performed. Cadmium and lead followed a similar pattern of bioaccumulation with highest values in the digestive gland region. Arsenic bioaccumulation, however, was highest in the gonadal region.

Animals↗
PubMed2003

Are coagulation times biomarkers? Data from a phase I study of the oral thrombin inhibitor LB-30057 (CI-1028).

Ecarin clotting time and activated partial thromboplastin time are coagulation tests that meet the definition of a biomarker. Prolongation of these coagulation times closely correlated with blood concentrations of the oral thrombin inhibitor LB-30057 (CI-1028) during a phase 1 study. But this simply reflects their functioning as enzyme inhibition assays of drug concentration. Directly adding the drug to blood results in the same concentration-response relationship. Changes in coagulation tests only demonstrate that ex vivo clot formation has been altered, not that an in vivo process has been affected. To be most informative in drug development, biomarker assays should measure in vivo drug effects, not drug concentrations.

Administration, Oral↗
PubMed2006

The applicability of acetylcholinesterase and glutathione S-transferase in Daphnia magna toxicity test.

The most commonly used toxicity test worldwide is the acute Daphnia magna test. The relevance of acetylcholinesterase (AChE) and glutathione S-transferase (GST) activity in D. magna exposed to chromium, cadmium, and diazinon was evaluated in connection with this standard test. We found no link between enzyme activities and immobility. Concentrations of Cr(6+) up to 280 microg/L had no effect on AChE and GST activities, while 20% immobility was observed. At concentrations of 20-25 microg/L of Cd(2+) AChE activity was increased by about 50%. The effect of diazinon on both enzymes was insignificant up to concentrations that caused 27% immobility. Consequently, while the use of AChE and GST activities is recommended when the mode of action of chemicals is studied, the value of these biomarkers in routine acute toxicity tests is limited because the relationship between enzyme activities and immobility of D. magna exposed to different chemicals is unclear.

Acetylcholinesterase↗
PubMed2004

Splice variants as cancer biomarkers.

Inherited and acquired changes in pre-mRNA splicing have been documented to play a significant role in human disease development and many cancer-associated genes are regulated by alternative splicing. Loss of fidelity, variation of the splicing process, even controlled switching to specific splicing alternatives may occur during tumor progression and could play a major role in carcinogenesis. Splice variants that are found predominantly in tumors have clear diagnostic value and may provide potential drug targets. Moreover, understanding the process of aberrant splicing and the detailed characterization of the splice variants may prove crucial to our understanding of malignant transformation. This review discusses the basic mechanism of alternative splicing, alternative splicing in cancer-associated genes, tools to identify splice variants, and the development of clinical tests based on alternatively spliced biomarkers.

Alternative Splicing↗