Can a blood test predict the onset of menopause?
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BACKGROUND: Diagnosis of acute coronary syndromes (ACS) is a major challenge for emergency physicians. Because soluble fibrin (sF) has been suggested as a potential early marker of impending myocardial ischemia, we were interested whether a sF bedside test could help in early identification of patients with ACS in the emergency department. METHODS: We evaluated plasma coagulation markers, including a newly developed sF bedside test, prothrombin fragment (F(1+2)), sF, and D-dimer, in a cross-sectional trial with 184 patients suggestive of ACS. RESULTS: Whereas 76% (13 of 17) of patients with unstable angina pectoris (UAP) had a positive sF bedside test, only 10 of 33 patients (30%) with non-ST-segment-elevation myocardial infarction and 10 of 44 patients (23%) with ST-elevation myocardial infarction tested positive. Three percent of controls (1 of 33) and 11% of patients (6 of 57) with preexisting stable angina had a positive sF bedside test (P <0.001 for noncardiac chest pain vs ACS), yielding an overall specificity of 92% and a sensitivity of 35%. The sensitivity of the established coagulation markers was significantly less to detect ACS (11% for F(1+2), 20% for thrombus precursor protein, and 18% for D-dimer; P <0.02 vs sF bedside test). The sF bedside test presented the earliest objective indicator of impending myocardial damage in the majority (10 of 13) of ACS patients with a normal or nondiagnostic electrocardiogram (ECG). CONCLUSIONS: A sF bedside test offers a specific tool for early identification of patients with ACS in an emergency department setting, although its sensitivity seems sufficient only for the early identification of patients with UAP. A sF bedside test could be useful, particularly in UAP patients with a nondiagnostic ECG.
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OBJECTIVE: To submit serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) to statistical analyses to test their exact degrees of clinical usefulness as biomarkers for detecting high disease activity in ankylosing spondylitis (AS), comparing them with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). METHODS: Serum levels of MMP-1, -3, -9 and TIMP-1 and -2 were measured in 42 AS patients and 20 healthy controls. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) provided the gold standard for measuring disease activity. Patients with BASDAI > or =4 were regarded as having high disease activity. The results were compared with results for a separate cohort of 41 AS patients. RESULTS: Only MMP-3 levels were significantly higher in AS patients than in healthy controls (P<0.001). Within AS patients, MMP-3 levels were also higher in patients with high disease activity compared with those with low disease activity, and correlated significantly with BASDAI (r = 0.366, P = 0.017) and functional indices (r = 0.344, P = 0.026). The correlation with BASDAI was stable in a 1-yr follow-up (r = 0.464, P = 0.095) and reproducible with two different enzyme-linked immunosorbent assays. For detecting high disease activity, the sensitivity and specificity of MMP-3 level was 69.2 and 68.8% respectively. Most importantly, using receiver operating characteristic plots to analyse the two cohorts, MMP-3 was more accurate than ESR and CRP in detecting AS patients with high disease activity (P = 0.01 and P = 0.009, respectively). CONCLUSION: Using several analytical approaches that have never been reported previously, we showed that MMP-3 is a more useful biomarker than ESR and CRP to detect high disease activity in AS.
PURPOSE OF REVIEW: A major goal of current clinical research in neurodegenerative diseases is to improve early detection of disease and presymptomatic detection of neuronal dysfunction. We also need better tools to assess disease progression in this group of disorders. Currently, many potential disease-modifying therapies are being developed and evaluated at the preclinical stage, and will lead to clinical trials in the near future for which biomarkers are urgently needed. This review summarizes the field of biomarker research in the major neurodegenerative diseases. RECENT FINDINGS: Many different approaches are being undertaken to identify biomarkers and include imaging, neurophysiological and cognitive testing in addition to newer technologies such as biochemical, proteomic, metabanomic and gene array profiling of tissue and biofluids from patients. Key recent findings in each of these areas are discussed. SUMMARY: The ideal biomarker needs to be easy to quantify and measure, reproducible, not subject to wide variation in the general population and unaffected by co-morbid factors. For evaluation of therapies the biomarker needs to change linearly with disease progression and closely correlate with established clinico-pathological parameters of the disease. It is unlikely that any one biomarker will fulfil all these characteristics, and it is likely that more than one biomarker will be needed for early diagnosis and similarly for evaluation of disease progression for therapeutic trials. For example, the combination of more detailed clinical assessments encompassing specific cognitive and neurophysiological testing, in addition to imaging, biochemical and genomic profiling, is likely to be needed.
OBJECTIVE: To review screening for cancer in high risk families. METHODS AND RESULTS: Screening for hereditary cancer involves three steps: it is first necessary to identify families at high risk by examining the number and sites of cancer in a family. Special attention is given to cancers appearing at an early age, to unusual sites, and multiple primary cancers. Second, a molecular diagnostic test is performed in order to identify family members who carry a mutant copy of the suspected gene. DNA-based diagnostic testing is now available for hereditary breast-ovarian cancer, for hereditary nonpolyposis colon cancer, for Gardner syndrome (familial polyposis coli), for neurofibromatosis, multiple endocrine neoplasia, and for Von-Hippel Lindau disease. Third, individuals found to carry susceptibility genes are offered screening for the early detection of tumours. Some screening methods are in conventional use (e.g., colonoscopy and mammography); others are reserved for the investigation of familial cancers (e.g., pentagastrin challenge test). CONCLUSION: A comprehensive clinic for hereditary cancer must consider all three phases of the screening program and will provide expert genetic counselling to family members involved in the process.
The purpose of this review is to discuss some of the recent hypotheses regarding the dietary etiology of colorectal cancer. We will review some of the epidemiological background and animal studies that were performed to test these hypotheses. The use of the rectal mucosal proliferation rate as measured by thymidine labelling index as an intermediate endpoint for clinical studies is discussed, including the results of testing these hypotheses using this marker. We believe that all hypotheses must eventually be tested in the human model and that carefully controlled, sequential analyses of each acceptable hypothesis is the most prudent road to understanding the environmental causes of colorectal cancer.
Serum activity of five lysosomal marker enzymes was measured in patients with acute myocardial infarction (AMI) and unstable angina pectoris (UAP) with consideration of the disease severity. A significant increase of enzyme activity was found both in patients with UAP and AMI on the first day of hospitalization. The enzymes activity was higher in patients with more severe form of AMI. Lysosomal enzyme activity was closely related to severity of the disease: clinical improvement occurred in patients with decreased activity (on day 7-10), while in aggravation of the disease lysosomal hyperenzymemia stayed high up to the end of the observation period (on day 30). The above findings demonstrate feasibility of using lysosomal enzymes test both for differentiation between AMI and UAP and for predicting the disease recurrences.
Laboratory markers for ethanol intake and abuse and chronic alcoholism currently in use have been critically reviewed. The merits and pitfalls of each test have been evaluated. The clinical use of the new test of carbohydrate-deficient transferrin has been particularly emphasized. Carbohydrate-deficient transferrin currently provides the highest specificity and sensitivity of all commonly used markers of alcoholism.
Prostate cancer prevention is now one of the most aggressively investigated areas of urologic oncology, with > 30,000 men currently participating in clinical trials in the United States alone. The Prostate Cancer Prevention Trial will complete end-of-study prostate biopsies in May 2004, and the Selenium and Vitamin E Cancer Prevention Trial is rapidly reaching its accrual goal 1-2 years ahead of schedule. These 2 studies will give definitive answers regarding 3 of the most important potential preventive interventions: finasteride, vitamin E, and selenium. Many phase II and biomarker-modulation studies are also ongoing, testing a host of other interventions. It is hoped that, within a short period of time, the clinician will be provided with strategies to reduce the risk of the disease.
We have developed a medium-term bioassay system of 8 weeks duration utilizing male Fischer 344 (F344) rats for detection of liver carcinogens and modifiers of hepatocarcinogenesis. The system consists of a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg), 6-weeks-administration of test chemical beginning 2 weeks after the DEN injection, and 2/3 partial hepatectomy (PH) performed at week 3. Carcinogenic potency of test chemicals is predicted based on the results of quantitative analyses of immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive liver cell foci. At present, a total of 140 chemicals have been tested using this system, and the findings show a good correlation with reported carcinogenic activities in long-term tests. Furthermore, the reliability of the system has been extensively examined: the results from the medium-term bioassay were compared with those from long-term experiments using the same doses of selected chemicals; the data from presently-used 2-dimensional analysis were compared with calculated values utilizing mathematical formulae for three-dimensional analysis: conformity of phenotypic expression of enzymes in preneoplastic lesions was examined in relation to their growth activity. In conclusion, although the results with non-hepatocarcinogens were less than satisfactory, the present experimental protocol, which requires far fewer animals and shorter duration than a long-term carcinogenicity test, appears of advantage for rapid screening of the large number of environmental chemicals which may possess hazard potential for induction of liver cancer in man.
Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC Global is a new global dotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N=15) as well as all the patients with low activated protein C (APC) resistance ratio (N=15) had a ProC Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (>5.0 IgG U/mL) had a ProC Global NR less than 0.8, while six and eight, respectively, had a ProC Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC Global is a new screening test to identify patients with defects of the protein C system and an activated dotting system in preeclampsia but cannot correctly cover each thrombophilic component.
Plasma fibrinolytic activity has been measured by the euglobulin clot lysis time (ELT) since the late 1950s. The euglobulin clot lysis assay (ECLA) method has been modified using a computerized kinetic spectrophotometric microtiter plate reader and measures optical density changes of recalcified euglobulin fraction of plasma samples over time. This method has been applied to normal healthy adults, children, pregnant women and newborn infants, which represent physiologic extremes of the ELT. The ECLA method adds measurements of maximum absorbance (Max Abs), area under the curve (AUC) and mean velocity to the standard clot lysis time. The resulting curves are unique to this method and have been analyzed and compared in order to establish normal ranges. Fibrinogen levels, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity and thrombin activatable fibrinolytic inhibitor (TAFI) antigen levels were measured in each individual of the four groups. Each protein measured within each study group except TAFI correlated with the lysis time, maximum absorbance and area under the curve. Considering all four groups together, PAI correlates most highly with lysis time, fibrinogen correlates the highest with Max Abs; fibrinogen and PAI-1 antigen have equally high correlations to AUC. Area under the curve is highly correlated with all coagulation parameters measured; the most significant contributor is fibrinogen. These observations are interesting, but at this time, it cannot be said that any of the test parameters are better than lysis time in distinguishing between these normal physiologic states.
Construction of a medical network for each region and organization has become possible by utilization of information technology. Standardization of the data on the medical network is urgent. Especially, the standardization of immunoserological data is much delayed. In this study, the possibility of standardization of such data was reconsidered based on the findings from various control surveys. Regarding the measurement items for serum concentrations of proteins and other compounds, we concluded that standardization should occur in a manner similar to the method for standardization of biochemical data and accurate control. The data on CRP, IgG, IgA, IgM and AFP, which are determined using the respective standard compound, were converged to a range with inter-facility differences of less than 10% CV. The data on CEA were also converged to achieve an inter-facility difference of less than 10% CV through repeated survey. Automatic measurement for the markers of infection diseases has progressed, and the expression of measurements was changed to the absolute value of COI, U/ml or IU/ml although it was titer in the past. Since these expressions now coexist, it is impossible to standardize the data with absolute qualitative values. It seemed necessary to present them uniformly with qualitative or clinical criteria values or express the presence or absence of infection by a combination of related markers. The measurements obtained from autoantibody-related tests using identical reagent were found coincident, but measurements obtained using different reagents were discrepant and the differences were greater than the sensitivity of measurement. In immunoserological testing and immunochemical testing, it is most important whether the antigen/antibody used as the reagent is the same preparation or not. Therefore, the test should be reconsidered through setting a certain restrictions on each recognition site of epitope and antibody. Thus, we concluded that use of a suitable standard substance is effective for standardization of immunological data.
Field trials were conducted in late April to early May of 1995 and 1996 in central Israel to assess the potential for controlling rabies in red foxes (Vulpes vulpes) and golden jackals (Canis aureus) by using vaccine-laden baits. Of the bait types which were field tested, polymer fish meal baits were selected as the most suitable for both species. Fish meal baits containing tetracycline hydrochloride, an oral biomarker, were distributed by four-wheel-drive vehicle at a density of approximately 30 baits/km2 in two test areas of 35 km2. Of the animals which were trapped and euthanized seven to ten days after treatment, 65% of foxes and 56% of jackals gave positive results when tested for the biomarker. These results indicate the potential effectiveness of oral rabies vaccination of these species in Israel and possibly elsewhere in the Middle East, where rabies is a problem in wild canids.
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