Lower Cut-off Levels Research Articles

The contribution of galactomannan detection in the diagnosis of invasive aspergillosis in bone marrow transplant recipients

Until recently, accurate microbiological diagnosis of invasive aspergillosis (IA) was seldom established in HSCT recipients. Blood samples are rarely positive for Aspergillus species, the reliability of the cultures depends of the specimen (if taken from a normally sterile site or not) and biopsy samples require invasive procedures, rarely recommended in patients with severe thrombocytopenia. Implementing the international consensus defining the microbiological criteria for the diagnosis of Aspergillus infection, we retrospectively evaluated the role of serum galactomannan (GM) detection by EIA to diagnose IA among HSCT patients with proven invasive fungal infection (IFI) and the impact of serum storage in GM concentrations. The EIA assay allowed categorizing as "probable" 5 of the 10 cases of "possible" aspergillosis (50%). Considering a lower cut-off level for the reaction (1.0), 80% of the cases could be categorized as "probable" aspergillosis. Positive or undetermined results were detected one to 4 months before the diagnosis of IA in eight of the 11 patients (72.7%) with proven IFI. Retesting the stored samples after a second storage for four years, we could observe lower reactivity in 20% of the samples. The detection of galactomannan by the EIA test represents a major advance in the diagnosis of IA in HSCT recipients at high risk of IA. A better understanding of the kinetics of the GM in different clinical situations is necessary to maximize the benefit of the test in Aspergillus surveillance.

Biochemical diagnosis of myocardial infarction evolves towards ESC/ACC consensus: Experiences from the Nordic countries

Objectives. To investigate the diagnostic approach in Nordic hospitals receiving patients suspected of acute myocardial infarction (MI), especially focusing on implementation of the recently proposed criteria by the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) for the definition of MI. Design. A survey with questionnaires of the diagnostic approach was conducted among all relevant departments (220) in the Nordic countries. Results. Seventy-six percent (167) of hospitals responded. Troponins I and T (TnI and TnT) and creatinine kinase monobasic fraction (mass concentration) (CKMBmass) covered 93 and 65% of hospitals, respectively. Of troponin users, 34% indicated use of TnI vs 66% using TnT. Sporadic use of AST, CK, LD and myoglobin was reported. There was a tendency to lower cut-off levels in Sweden and Finland. Among troponin assays, there was considerable heterogeneity regarding cut-off levels. Conclusions. The Nordic countries are approaching ESC/ACC consensus on cardiac markers. Compared with previous national surveys (1995–1999), there is a shift towards the use of troponins. However, differences in cut-off levels of troponin emphasize the need for harmonization of assays.

Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes.

The aim of this study was to assess the level of urinary albumin excretion (microalbuminuria), which is associated with increased risk of coronary heart disease and death, in the population. Microalbuminuria has been suggested as an atherosclerotic risk factor. However, the lower cutoff level of urinary albumin excretion is unknown. It is also unknown whether impaired renal function confounds the association. In the Third Copenhagen City Heart Study in 1992 to 1994, 2762 men and women 30 to 70 years of age underwent a detailed cardiovascular investigation program, including a timed overnight urine sample. The participants were then followed up prospectively by registers until 1999 with respect to coronary heart disease and until 2001 with respect to death. During follow-up, 109 incident cases of coronary heart disease and 276 deaths were traced. A urinary albumin excretion above the upper quartile, ie, 4.8 microg/min, was associated with increased risk of coronary heart disease (RR, 2.0; 95% CI, 1.4 to 3.0; P<0.001) and death (RR, 1.9; 95% CI, 1.5 to 2.4; P<0.001) independently of age, sex, renal creatinine clearance, diabetes mellitus, hypertension, and plasma lipids. Lower levels of urinary albumin excretion were not associated with increased risk. Microalbuminuria, defined as urinary albumin excretion >4.8 microg/min (corresponding to approximately 6.4 microg/min during daytime), is a strong and independent determinant of coronary heart disease and death. Our suggestion is to redefine microalbuminuria accordingly and perform intervention studies.

Clinical significance of serum thyroglobulin and antithyroglobulin antibody in differentiated thyroid cancer after thyroid ablation

Serum thyroglobulin (Tg) is a suitable marker for differentiated thyroid carcinoma following total thyroid ablation. Between 1998 and 2003, serum samples from 715 papillary and 179 follicular tumor patients treated with total/nearly total thyroidectomy and radioiodine ablation therapy were collected. According to the "Guidelines for Oncotherapy in Hungary", serum Tg, antithyroglobulin antibody (TgAb), TSH and FT4 levels were measured in periods of 3 months following the first treatment and of 6 months after 2 years. In the present work the prognostic value of Tg and TgAb data of cancer patients with hormone substitution therapy were evaluated individually and retrospectively. Serum Tg and TgAb concentrations were measured with a highly sensitive immunoradiometric (IRMA) method, and with a second generation, broad epitope specificity competitive radioimmunoassay, respectively. TSH levels determined by fourth generation LIAISON kit were in a range of 0.05-0.10 mIU/L. Accuracy of measuring of Tg <1 ng/ml made it possible to select the low cut-off level (Tg <2 ng/ml) following total thyroidectomy. In the predominant part of TSH-suppressed patients (746/774, 96%) the serum Tg concentration was below the cut-off level of 2 ng/ml. The sensitivity of Tg determination in 59 TSH-suppressed thyroid cancer patients with lung and bone metastases was as high as 86 to 100%. On the contrary, the number of false negative data was high in cases with lymph node metastases of papillary cancer, and sensitivity did not exceed 62%. Specificity and sensitivity of Tg in TgAb negative patients were 91 to 100%. Based on our results it could be concluded that measuring of Tg and TgAb, using a current IRMA method and a second generation RIA kit, proved to be effective tools for the postoperative monitoring of differentiated thyroid tumours. It has to be noted that determination of TgAb is highly recommended for the adequate interpretation of serum Tg levels. Persistently high and/or increasing serum TgAb concentration with low Tg result had a diagnostic value during the follow-up and can be connected with the recurrence or persistence of the differentiated thyroid cancer.

Pressure pain thresholds of tender point sites in patients with fibromyalgia and in healthy controls

Pressure pain threshold (PPT) is defined as the minimum force applied which induces pain. This measure has proven to be commonly useful in evaluating tenderness symptom. Our aim was to study the intra-examiner reproducibility of PPT measurement, define cutoffs in normal groups, and compare these results with patients with fibromyalgia (FM). Fifty healthy females, 50 healthy males, and 20 patients with FM participated in the study. PPTs were assessed for 18 specific tender point sites by a dolorimeter. The intra-individual coefficient of variation determined by a test – retest PPT measurement procedure with 3-days interval reached, respectively, 17% and 13% in healthy females and males, versus 24% in patients with FM. PPTs were significantly lower in healthy females than in healthy males ( p<0.01). Statistical analysis failed to show any differences between the dominant and nondominant side for both normal groups. PPTs were lower over all examined areas in patients with FM than those obtained in healthy females ( p<0.000). Lower cutoff levels were calculated from normal values for all specific tender point sites. On average, 14 tender point sites in patients with FM were under the established lower cutoffs. In conclusion, pressure pain sensitivity was influenced by the anatomical localization of tender point and gender differences. Lowest PPTs were localized in trapezius, occiput, anterior cervical, and second rib. The reduction of total tender point score in patients with FM averaged 60% comparatively with normal values. PPT reproducibility and discrimination between the two groups were optimal for the gluteal and knee sites.

392 Effects of screening with low PSA cut-off levels on total PSA, % free PSA, PSA density, PSADT, and gleason scores of biopsies and radical prostatectomy specimens in a screening population

392 Effects of screening with low PSA cut-off levels on total PSA, % free PSA, PSA density, PSADT, and gleason scores of biopsies and radical prostatectomy specimens in a screening population

Enzyme-linked immunosorbent assay for Helicobacter pylori needs adjustment for the population investigated.

Helicobacter pylori infection and peptic ulcer disease are common in developing countries, e.g., Vietnam. An enzyme-linked immunosorbent assay (ELISA) for screening of patients and for seroepidemiology is a useful tool but needs to be validated in the population studied. We used in-house ELISA with sonicated Swedish and Vietnamese strains as antigens to measure immunoglobulin G antibodies after absorption with sonicated Campylobacter jejuni in sera from 270 H. pylori culture-confirmed peptic ulcer patients, 128 Swedish urea-breath test and immunoblot-positive healthy controls, and 432 Vietnamese immunoblot-positive population controls. Sonicated whole-cell antigen based on the local strains showed a significantly better performance. Immunoblot-positive peptic ulcer patients had significantly higher antibody concentrations than immunoblot-positive population controls, necessitating a lower cutoff level if serology is used for screening or epidemiological purposes. The study shows that the parameters of ELISA for H. pylori need to be adjusted for the population being investigated.

Evaluation and risk stratification of acute coronary syndromes using a low cut-off level of cardiac troponin T, combined with CK-MB mass determination

Objectives: To study the usefulness of combined cardiac Troponin T (cTnT) and CK-MB mass determinations in risk stratification of acute coronary syndromes. Design and methods: Blood samples for cTnT and CK-MB mass were collected at arrival and 4, 8, and 12–24 later in 301 consecutive patients with recent acute chest pain (ACP). Data were also collected for cardiac events. Results: Combined cardiac mortality/nonfatal myocardial infarction over a period of 15 months was lowest in patients with <0.04 μg/l cTnT and -<5.0 μg/l CK-MB mass intermediate in those with elevated cTnT but normal CK-MB mass and highest when both markers were elevated, in absence of early reperfusion. Conclusion:The use of a low cut-off point of cTnT, combined wit CK-MB mass determination, offers a good strategy for risk stratification of ACP patients.

Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery

ObjectivesThe aim of this study was to determine the long-term prognosis with postoperative markers of myocardial ischemia and infarction. BackgroundCardiac troponins (cTn) are superior to creatine kinase-MB fraction (CK-MB) in detecting perioperative myocardial infarction (PMI). However, their threshold levels signifying PMI and their long-term prognostic value are not yet determined. MethodsA cohort of 447 consecutive patients who underwent 501 major vascular procedures was prospectively studied. Perioperative continuous 12-lead electrocardiogram monitoring, cardiac troponin-I (cTn-I) and/or cardiac troponin-T (cTn-T), and CK-MB levels on the first three postoperative days, and long-term survival were determined. The association of different cutoff levels of CK-MB, troponin, and ischemia duration with long-term survival was investigated. ResultsBetween 14 (2.9%) and 107 (23.9%) of the patients sustained PMI, depending on the biochemical criteria used. Elevated postoperative CK-MB, cTn, and prolonged (>30 min) ischemia, at all cutoff levels examined, predicted long-term mortality independent of the preoperative predictors: patient's age, type of vascular surgery, previous myocardial infarction, and renal failure (Cox multivariate analysis). Both CK-MB >10% and cTn-I >1.5 ng/ml and/or cTn-T >0.1 ng/ml independently predicted a 3.75-fold and 2.06-fold increase in long-term mortality (p = 0.006 and 0.012, respectively). Similarly, both CK-MB >5% and cTn-I >0.6 ng/ml and/or cTn-T >0.03 ng/ml independently predicted a 2.15-fold and 1.89-fold increase in mortality (p = 0.018 and 0.01, respectively). Patients with both these markers elevated had a 4.19-fold increase in mortality (p < 0.001). ConclusionsPostoperative CK-MB and troponin, even at low cutoff levels, are independent and complementary predictors of long-term mortality after major vascular surgery.

Early detection of prostate cancer with low PSA cut-off values leads to significant stage migration in radical prostatectomy specimens.

The introduction of prostate-specific antigen (PSA) contributed to a shift in tumor stage at diagnosis in patients with prostate cancer. The aim of the present study was to evaluate the effects of PSA screening with low PSA cut-off values on mean total and percent-free PSA levels in patients with prostate cancers at the time of diagnosis as well as on pathologic stage and mean Gleason scores in positive biopsies and radical prostatectomy specimens. Data of 875 patients who were diagnosed with prostate cancers between 1996 and 2001 were analyzed. Patients were stratified into six groups according to the year of biopsy. Annual changes in total and percent-free PSA values, in Gleason scores of biopsies and radical prostatectomy specimens, and in pathologic stages of radical prostatectomy specimens were assessed. Mean PSA of patients diagnosed with prostate cancer decreased from 13.11 ng/ml (percent-free PSA: 11.89%) in 1996 to 7.33 ng/ml (percent-free PSA: 12.58%) in 2001 (P < 0.05). The percentage of organ-confined prostatectomy specimens increased from 64.3% in 1996 to 81.5% in 2001 (P < 0.05). However, mean Gleason scores increased from 5.23 to 6.33 over the 6 years (P < 0.05). The percentage of patients with biopsy-proven prostate cancers and PSA values below 4 ng/ml increased from 14.0% in 1996 to 39.2% in 2001. In the group with PSA values below 4 ng/ml organ-confined cancers were found in 80.0-95.2% of patients. PSAg screening with low cut-off levels has led to a significant reduction of mean baseline PSA levels in prostate cancer patients and to a significant increase in the percentage of organ-confined radical prostatectomy specimens, whereas mean Gleason scores have remained relatively constant.

Detection of antibodies in sera of weaned pigs after contact infection with Sarcoptes scabiei var. suis and after treatment with an antiparasitic agent by three different indirect ELISAs

Three commercial enzyme-linked immunosorbent assays (ELISAs) were compared for the detection of antibodies to Sarcoptes scabiei var. suis using experimental sera of six 8-week-old pigs after contact infection with Sarcoptes scabiei var. suis. Six non-infected pigs were monitored as a control group. Blood sera were taken once a week from all animals. After successful infection the pigs were treated with an antiparasitic agent (12 weeks post infection (p.i.)) and the antibody titres were monitored until they were negative. The antibody levels of the experimental pigs reached the cut-off level 5 weeks after introduction of an infected animal to the group and were positive by both the Sarcoptes-ELISA 2001 ® PIG and the Acar-Test P ▪ -ELISA ®. Four weeks after treatment mean results showed optical densities (% OD) below the cut-off level in the Sarcoptes-ELISA 2001 ® and 8 weeks after treatment in the Acar-Test P ▪ -ELISA ®. In the Chekit ® Sarcoptest pigs had elevated antibody levels in comparison to control animals, but ODs remained below the given cut-off level at all times. In a second examination with Chekit ® Sarcoptest (different lot) and at a lower cut-off level, the sera of most of the piglets tested positive. Eight weeks after treatment, four from six pigs still had positive OD values. Therefore this investigation showed a higher sensitivity for the Sarcoptes-ELISA 2001 ® and the Acar-Test P ▪ -ELISA ® than for the Chekit ® Sarcoptest. Different test sensitivities must be considered when serologic methods are used for the diagnosis of swine sarcoptic mange, especially for monitoring and controlling eradication programs.

Evaluation of tumor markers for the detection of hepatocellular carcinoma in Yangon General Hospital, Myanmar.

Levels of alpha-fetoprotein (AFP), its glycoforms AFP-L3 and AFP-P4, and proteins induced by vitamin K absence or antagonist-II (PIVKA-II) were determined in sera obtained from patients in Yangon General Hospital (20 with hepatocellular carcinoma (HCC), 29 with chronic liver diseases, including 3 with chronic hepatitis and 26 with cirrhosis of the liver, and 9 with other hepatobiliary diseases). Forty-five percent of the patients with HCC had serum AFP levels above 10,000 ng/ml, indicating that nearly half of the HCC patients were at an advanced stage of the disease. Thus, the AFP sensitivity was as high as 70% with 100% specificity for a cutoff level of 200 ng/ml. The sensitivity of AFP-L3 was 75% and a specificity 90% for a cutoff level of 15%. AFP-P4 showed a higher sensitivity of 80% and a similar specificity of 86% for a cutoff level of 12%. Combined evaluation of AFP-L3 and/or AFP-P4 increased the sensitivity to 90% with the same specificity of 86%, indicating that AFP-L3 and AFP-P4 are useful as adjuncts for diagnosis of HCC in the present population. PIVKA-II had a high sensitivity of 90%, although the specificity was lower than 45%, probably due to the low cutoff level, as some cholestatic patients were included in the control group.

Screening with low PSA cutoff values results in low rates of positive surgical margins in radical prostatectomy specimens.

In the literature, positive margins in radical prostatectomy specimens, the rate of which ranges between 7% and 46%, are associated with adverse patient survival. The aim of the present study was to determine the predictive value of preoperative serum prostate specific antigen (PSA) values for the rate of positive margins in radical retropubic prostatectomy. The study included a cohort of 845 patients who underwent radical retropubic prostatectomy between October of 1993 and December of 1999. All patients were stratified in groups on the basis of their preoperative PSA values: PSA group I, 0-1.99 ng/ml; PSA group II, 2-3.99 ng/ml; PSA group III, 4-5.99 ng/ml; PSA group IV, 6-7.99 ng/ml; PSA group V, 8-9.99 ng/ml; and PSA group VI, >10 ng/ml. For each group, the pathologic stage, Gleason score, and the incidence of positive margins were analyzed. For statistical analysis, the Mann Whitney U-test was used. Our data show a significantly higher rate of organ-confined prostate cancers and a significantly lower rate of positive surgical margins in patients with preoperative total PSA values of less than 4 ng/ml compared with patients with higher preoperative total PSA levels. As tumor stage and surgical margin status after radical prostatectomy are important predictors of the likelihood of PSA recurrence, which necessitates additional therapy, these findings support the concept of PSA screening by using low PSA cutoff levels.

Hepatitis B and C in peritoneal dialysis patients

In most countries the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in peritoneal dialysis (PD) patients is lower than in hemodialysis (HD) patients. Besides a history of blood transfusions, previous HD is an important risk factor for developing HCV infection in PD patients. Many HCV-positive patients already are anti-HCV-positive before initiation of PD. Seroconversion to HCV during PD treatment is, therefore, a rare event. HCV RNA in serum is positive in 53% to 84% of anti-HCV-positive patients. Routine screening for HBV and HCV by using a second- or third-generation enzyme-linked immunosorbent assay (ELISA) should be performed in PD patients every 6 months. Asymptomatic HBV and HCV infection may be detected by elevation of transaminases, but lower cut-off levels should be preferred in PD patients. Prophylactic strategies include hygienic measures and HBV vaccination. The staff should be aware of the infectiousity of the PD effluent, especially in hepatitis B surface antigen (HBsAg)-positive patients. Because of the smaller number of required blood transfusions and the increased use of home therapy, which reduces the risk for environmental contamination, PD is considered to be an important strategy for prevention of hepatitis in end-stage renal disease patients.

In-vitro-Diagnostik von Nahrungsmittel- Allergien

Measurement of allergen-specific IgE represents the most useful diagnostic in-vitro test in food allergy, usually being performed after case history and skin test. Hundreds of single allergens and combinations are offeredby a number of manufacturers. Different allergens, detection and calibration methods lead to a lack of comparibility of test results, which can also differ substantially from case history, skin test and food challenge results. Cellular laboratory tests should be used for food allergy testing only in individual cases or scientific studies. Food allergens: Food proteins of higher stability (predominantly relevant in early infancy) do rarely cause problems in terms of IgE-testing. At present, use of defined proteins for routine diagnosis of allergen-specific IgE has no advantage compared to whole food allergens. Resulting from sensitizations to pollen allergens or natural rubber latex, IgE will be found to cross reactive, mostly labile allergens from various fruit, vegetable or plant species, being clinically relevant only in case of corresponding symptoms. This supports the recommendation of selected in-vitro testing, focussing on suspected foods. Indication for IgE-testing: Reasonable probability of food allergy, but no clear-cut evidence after case history and skin test; sensitization to foods not suitable for skin testing; severe reactions to foods; skin test or its interpretation not possible. Interpretation of in-vitro results: False positive or negative results due to inappropriate reagents or laboratory errors; clinically irrelevant results by strongly elevated total serum IgE, low cut-off levels or cross reactive allergens. Not suitable for diagnosis of food allergy: Allergen-specific IgG, cytotoxic food test, electroacupuncture, bioresonance. Unsolved problems: Optimized quality ofreagents; calibration and comparability of results from different methods; serological cross reactivity. Future studies adressing clinical relevance of in-vitro results will help to improve diagnosis and interpretation of food allergy.

Can the endometrial thickness as measured by trans‐vaginal sonography be used to exclude polyps or hyperplasia in pre‐menopausal patients with abnormal uterine bleeding?

To combine findings of normal mid-line echoes from TVS (trans-vaginal sonography) with cut-off levels for endometrial thickness, in order to examine the associated risk of abnormalities in the uterine cavity. Two center prospective study at a university clinic and a central hospital in Denmark. Three hundred and fifty-five pre-menopausal patients with abnormal uterine bleeding, and indications for endometrial sampling or surgery. The thickness of the endometrium was measured, and the mid-line echoes were evaluated using TVS. The findings from the endometrial sampling, combined with the evaluation of the uterine cavity using operative hysteroscopy (115), hysterectomy (74) or HSE (hysterosonographic examination) (166), were used as the true values. The mean (+/-s.d.) endometrial thickness was significantly different in patients with hyperplasia 11.5 mm (+/-5.0), polyps 11.8 mm (+/-5.1), sub-mucous myomas 7.1 mm (+/-3.4) and in patients without these abnormalities 8.37 (+/-3.9) (p<0.001). Hyperplasia and/or polyps were present in 20% of all patients, and in 8% of 143 patients with an endometrial thickness of < or =7 mm. This proportion did not decrease with lower cut-off levels for endometrial thickness. Receiver operating characteristic (ROC) curves were not optimal for excluding hyperplasia or polyps by endometrial thickness. In 173 cases with a distinct, regular midline echo without echo-dense foci in TVS the proportion of patients with abnormalities was 16% (11-23). This proportion did not decrease with cut-off levels for endometrial thickness. Using TVS, low levels of endometrial thickness reduced the possibility of abnormalities such as polyps and hyperplasia, but did not exclude them. Low cut-off levels for endometrial thickness did not increase the diagnostic performance in cases with normal sonograms.

Screening for 21-hydroxylase–deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study

Objective: To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase–deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women. Design: Prospective observational trial. Setting: Tertiary care academic medical centers. Patient(s): Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism. Intervention(s): All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation. Main Outcome Measure(s): Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 a.m. and 3 and 5 p.m. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL. Result(s): Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively. Conclusion(s): A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.

Percent free prostate-specific antigen: the next frontier in prostate-specific antigen testing

P cancer (PCa) has become a major concern for men and health organizations worldwide. In the United States, approximately 317,000 new cases and 40,000 deaths from this disease are expected for 1996.1 This makes PCa the most frequently detected malignancy in men and the second leading cause of cancer death in the adult male population. In recent years, major efforts have been put forth to reduce the mortality rate from this entity. In short, this means early detection and local definitive therapy, since there is no curative systemic treatment for prostate cancer. Since its isolation and description in seminal fluid and prostatic tissue and ultimately in human serum nearly two decades ago, prostate-specific antigen (PSA) has been under intensive basic science and clinical investigation by the urologic community.2–4 As a result of such efforts and due to its unique characteristics, PSA has established itself as the most clinically useful tumor marker for the early detection and staging of PCa as well as for monitoring response to therapy.5,6 Though unique, PSA has important limitations that prevent it from being the ideal tumor marker for early detection of prostate cancer.7–12 This comes from the fact that PSA is not cancer-specific; as a result, serum PSA levels above normal are not pathognomonic for PCa and values within the reference range are not always indicative of the absence of cancer. Nevertheless, several studies have demonstrated that PSA alone detects a greater number of malignancies than digital rectal examination (DRE) or any other isolated parameter.13–15 Most importantly, the majority of such tumors have histopathologic features of clinically-important, lifethreatening cancer.16–18 In order to reliably detect PCa at an early stage, a low serum PSA cutoff level is used in screening programs (4.0 ng/mL). Use of this cutoff level is associated with a considerable number of falsepositive findings and false-negative findings (65% false-positive and a 20% false-negative rate), demonstrating PSA’s lack of power in discriminating PCa from other benign prostate pathologies (benign prostatic hyperplasia, BPH).5,19,20 On the other hand, at least 20% of men with biopsyproven PCa at the time of diagnosis have a serum PSA concentration within the reference range of 0.0 to 4.0 ng/mL.21 Had the total serum PSA concentration been the sole diagnostic criterion used, those patients would not have had their cancer detected. The obvious conclusion is that the immunotechniques currently employed in the determination of serum PSA concentration have limited ability in distinguishing early PCa from BPH. This lack of sensitivity and specificity have led researchers to investigate various methods for improving the reliability of the total serum PSA test with respect to diagnosing PCa. Several concepts have been developed and investigated recently, with the purpose of optimizing the clinical use of PSA by improving its specificity and yet preserving its sensitivity. These new techniques include PSA density, PSA velocity, and age/ race-specific PSA reference ranges.22–26 Moreover, investigations have shown that PSA is present in the human serum in several molecular forms and that the concentration of these forms may vary according to specific pathologic states present in the prostate gland.26a The objective of this presentation is to review our current understanding of the so-called molecular forms of PSA and assess their clinical utility in 1997.

The case for mild hyperhomocysteinaemia as a risk factor.

The high incidence of vascular complications in severe hyperhomocysteinaemia in homozygotes for cystathionine beta-synthase deficiency has focused attention upon homocysteine as an atherogenic and thrombophilic agent. For two decades there has been accumulating evidence of mild hyperhomocysteinaemia as risk factor of vascular disease. Pooled data on hundreds of coronary, cerebrovascular and peripheral arterial disease patients show that mild hyperhomocysteinaemia was detectable in about 20-30%. In a recent meta-analysis of 27 studies up to 1994, including about 4000 patients and as many controls, it is calculated that the summary odds ratio of elevated homocysteine levels was 1.7, with 95% confidence interval (CI) 1.5-1.9, for coronary heart disease; it was 2.5, with 95% CI 2.0-3.0, for cerebro-vascular disease; and it was 6.8, with 95% CI 2.9-15.8, for peripheral vascular disease. The relevance of this newly recognized risk factor will be demonstrated by the outcome of the European Comac study on 'Hyperhomocysteinaemia and Vascular Disease', a multicentre case-control study on 800 vascular patients and 750 controls. Despite the selection for epidemiological reasons of a relatively low cut-off level as the criterion for mild hyperhomocysteinaemia in this study-the upper 20% of the distribution of control levels-the relative risk of thus-defined hyperhomocysteinaemia for arterial disease is about 2. This equals the relative risk of hypercholesterolaemia and of smoking; hypertension leads to a higher excess risk. The observed synergistic interaction between hyperhomocysteinaemia and hypertension and smoking may warrant a change in the now generally followed procedure of screening for hyperhomocysteinaemia only if conventional risk factors have not been detected in the patient. Those vascular patients with combined risk factors leading to synergism in their joint effect may profit most from homocysteinelowering intervention.

GEOTAIL observation at the dayside magnetopause—Confirmation of reconnection events

Geotail has surveyed the dayside magnetopause in the equatorial plane and studied the dayside reconnection of the interplanetary magnetic field (IMF) with the magnetospheric field lines. When the IMF is directed southward leakage of ions from the low latitude boundary layer (LLBL) to the magnetosheath boundary layer (MSBL) are observed. Reconnection is shown to be responsible for the leakage. A variation in lower cut-off levels occurring in the velocity distribution function of the leakage ions is explained by the “velocity filter effect” model with a finite source region. In addition to such conditions, reconnection occurs also when the IMF has low-inclination angles, i.e., the condition between the southward and northward IMF conditions. Between the magnetosphere and the magnetosheath, two types of boundary region develop, i.e., the inner-LLBL and the outer-LLBL. The inner-LLBL is characterized by the bi-directional cold electrons and trapped cold ions coexisting with hot magnetospheric plasma. The field lines are regarded to be closed. The outer-LLBL is, on the other hand, open to the magnetosheath. It is characterized by the uni-directional cold electrons escaping to the magnetosheath. Newly penetrating solar wind ions are overtaking the trapped cold ions. The formation of the outer-LLBL is explained by the high-latitude reconnection at the equatorward regions of the cusp.