bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficiency-Driven Heavy-Traffic Approximations for Many-Server Queues with Abandonments
Authors: Whitt Ward
Published: October 2004

To provide useful practical insight into the performance of service-oriented (non-revenue-generating) call centers, which often provide low-to-moderate quality of service, this paper investigates the efficiency-driven (ED), many-server heavy-traffic limiting regime for queues with abandonments. Attention is focused on the M/M/s/r + M model, having a Poisson arrival process, exponential service times, s servers, r extra waiting spaces, exponential abandon times (the final +M), and the first-come–first-served service discipline. Both the number of servers and the arrival rate are allowed to increase, while the individual service and abandonment rates are held fixed. The key is how the two limits are related: In the now common quality-and-efficiency-driven (QED) or Halfin-Whitt limiting regime, the probability of initially being delayed approaches a limit strictly between 0 and 1, while the probability of eventually being served (not abandoning) approaches 1. In contrast, in the ED limiting regime, the probability of eventually being served approaches a limit strictly between 0 and 1, while the probability of initially being delayed approaches 1. To obtain the ED regime, it suffices to let the arrival rate and the number of servers increase with the traffic intensity ρ held fixed with ρ > 1 (so that the arrival rate exceeds the maximum possible service rate). The ED regime can be realistic because with the abandonments, the delays need not be extraordinarily large. When the ED appropriations are appropriate, they are appealing because they are remarkably simple.
Redesigning Teams and Incentives in a Merger: An Experiment with Managers and Students
Authors: Montmarquette Claude , Rullière Jean-Louis , Villeval Marie-Claire , Zeiliger Romain
Published: October 2004

After a merger, company officials face the challenge of making compensation schemes uniform and of redesigning teams with managers from companies with different incentives, work habits, and recruiting methods. In this paper, we investigate the relationship between executive pay and performance after a merger by dissociating the respective influence of shifts, which occur in both compensation incentives and team composition. The results of a real task experiment conducted with managers within a large pharmaceutical company not only show that changes in compensation incentives affect performance, but also suggest that the sorting effect of incentives in the previous companies impact cooperation and efficiency after the merger. Replicating this experiment with students showed differences in strategy rather than in substance between the two groups of subjects with managers appearing performance driven, while students are more cost driven.
50th Anniversay Article: The Strategy Field from the Perspective ofManagement Science: Divergent Strands and Possible Integration
Authors: Gavetti Giovanni. , Levinthal Daniel A.
Published: October 2004

We reflect on the evolution of the strategy field as seen through the window of Management Science. Reflecting the diverse disciplinary roots of strategy research, we identify a broad-ranging body of work that varies with respect to the assumptions made regarding individual rationality and the level of analysis at which the research is carried out. We argue that recent developments begin to delineate a potentially unifying conceptual framework for treating the field's defining questions—the conceptual apparatus of evolutionary economics. We conclude by laying out important challenges for evolutionary economics if it is to serve as a foundation for both the positive and the normative research agendas of the strategy field.
Efficient Diversification According to Stochastic Dominance Criteria
Authors: Kuosmanen Timo
Published: October 2004

This paper develops the first operational tests of portfolio efficiency based on the general stochastic dominance (SD) criteria that account for an infinite set of diversification strategies. The main insight is to preserve the cross-sectional dependence of asset returns when forming portfolios by reexpressing the SD criteria in T-dimensional Euclidean space, with elements representing rates of return in T different states of nature. We characterize subsets of this state-space that dominate a given evaluated return vector by first- and second-order SD. This allows us to derive simple SD efficiency measures and test statistics, computable by standard mathematical programming algorithms. The SD tests and efficiency measures are illustrated by an empirical application that analyzes industrial diversification of the market portfolio.
The Optimal Timing of Living-Donor Liver Transplantation
Authors: Alagoz Oguzhan , Maillart Lisa M. , Schaefer Andrew J. , Roberts Mark S.
Published: October 2004

Living donors are a significant and increasing source of livers for transplantation, mainly because of the insufficient supply of cadaveric organs. We consider the problem of optimally timing a living-donor liver transplant to maximize the patient's total reward, such as quality-adjusted life expectancy. We formulate a Markov decision process (MDP) model in which the state of the process is described by patient health. We derive structural properties of the MDP model, including a set of intuitive conditions that ensure the existence of a control-limit optimal policy. We use clinical data in our computational experiments, which show that the optimal policy is typically of control-limit type.
Calcimimetics and the Treatment of Primary and Secondary Hyperparathyroidism
Authors: Joy Melanie S , Kshirsagar Abhijit V , Franceschini Nora
Published: October 2004

OBJECTIVE

To review the mechanism of action, development, and clinical application of the calcimimetic compounds being investigated for the treatment of primary and secondary hyperparathyroidism (HPT).

DATA SOURCES

A MEDLINE search (1990–April 2004) was performed to identify all published articles related to calcimimetics. Published abstracts over the previous 5 years from various scientific meetings (American Society of Nephrology, American Society for Clinical Pharmacology and Therapeutics, American Society of Bone and Mineral Research) were also searched for reports regarding investigational calcimimetic agents. Data on cinacalcet HCI were provided by Amgen, Inc.

STUDY SELECTION AND DATA EXTRACTION

Studies were selected based on number of patients included, relevance to the approved indications, and inclusion of pharmacokinetic and drug interaction information.

DATA SYNTHESIS

The investigational calcimimetic compounds directly modulate the calcium-sensing receptor and can produce at least a 30% reduction in parathyroid hormone (PTH) secretion in secondary HPT. Cinacalcet appears to have more predictable pharmacokinetics and a lower risk of symptomatic hypocalcemia than the older agent, R-568. The safety profile and effective reduction in PTH and simultaneous reductions in calcium and phosphorus (and the calcium–phosphorus product) induced by cinacalcet make this agent advantageous over previously used therapies, such as vitamin D and phosphate-binding agents. More studies are required to determine additional uses of cinacalcet.

CONCLUSIONS

Cinacalcet has a unique mechanism for reducing PTH concentration and appears to be a safe and effective oral therapy for both primary and secondary HPT.
Possible Reduction in Posttraumatic Stress Disorder Symptoms with Oxcarbazepine in a Patient with Bipolar Disorder
Authors: Malek-Ahmadi Parviz , Hanretta Allan T
Published: October 2004

OBJECTIVE

To report the effect of oxcarbazepine in a patient with bipolar illness and posttraumatic stress disorder (PTSD).

CASE SUMMARY

A 38-year-old white woman with PTSD and bipolar disorder who had partially responded to carbamazepine was treated with oxcarbazepine. Within a month of initiation of treatment with oxcarbazepine, she reported progressive improvement in her PTSD symptoms. As oxcarbazepine monotherapy with 750 mg twice daily continued, she reported significant reduction of her PTSD symptoms and stabilization of her mood. She tolerated oxcarbazepine without adverse effects.

DISCUSSION

PTSD symptoms tend to wax and wane. Spontaneous remission also occurs in some patients with PTSD. There are a few reports indicating that carbamazepine alleviates PTSD symptoms. Since oxcarbazepine is an analog of carbamazepine, it is theorized that oxcarbazepine also has efficacy in significantly reducing PTSD symptoms.

CONCLUSIONS

There are case reports and uncontrolled studies suggesting that antiepileptic drugs (AEDs) alleviate PTSD symptoms. Oxcarbazepine may also benefit patients with PTSD. However, controlled studies are needed to investigate the use of AEDs in patients with PTSD and bipolar disorder.
Insulin Strategies for Type 2 Diabetes Mellitus
Authors: Vivian Eva M , Olarte Sophia V , Gutierrez Ann M
Published: October 2004

OBJECTIVE

To review the currently available insulin analogs and the benefits of insulin therapy in the treatment of type 2 diabetes mellitus.

DATA SOURCES

A MEDLINE search (1990–March 2004) was conducted using insulin and type 2 diabetes mellitus as search terms to identify clinical trials and review articles. The bibliographies of identified articles were reviewed.

STUDY SELECTION AND DATA EXTRACTION

All articles identified from the data sources were evaluated and deemed relevant if they included and assessed clinical outcomes.

DATA SYNTHESIS

Since its discovery in 1922, insulin therapy has been the only available pharmacologic treatment for type 1 diabetes and a mainstay therapy for patients with type 2 diabetes who fail to obtain glycemic control with oral antidiabetic agents. This article reviews the current insulin analogs available on the market and insulin regimens that are designed to mimic the pancreatic β-cells’ response to a glucose load.

CONCLUSIONS

Insulin therapy is often withheld until late in the disease process for patients with type 2 diabetes mellitus. This results in an enormous burden of disease for patients. Insulin therapy is beneficial in obtaining glycemic control and may attenuate the complications associated with diabetes.
Pharmacologic Perspectives for Once-Daily Antiretroviral Therapy
Authors: Anderson Peter L
Published: October 2004

OBJECTIVE

To contrast available once-daily antiretroviral agents and combinations of these agents from a clinical pharmacologic viewpoint.

DATA SOURCES

Data were extracted from publications and major HIV conference proceedings cited in MEDLINE (1966–March 2004) using the search terms antiretroviral therapy, combination therapy, once-daily therapy, and pharmacokinetics. Additional references were obtained from the bibliographies of these sources.

STUDY SELECTION AND DATA EXTRACTION

Information pertaining to pharmacologic perspectives for once-daily antiretroviral agents was selected.

DATA SYNTHESIS

Maximal and durable suppression of plasma HIV RNA, the principal goal of therapy, depends on the intrinsic antiviral activity of the antiretroviral regimen. A favorable tolerability/toxicity profile is also fundamentally important. All once-daily agents exhibit some pharmacologic limitations or lack adequate long-term follow-up. Of available agents, efavirenz has a long and distinguished efficacy record, with reasonable safety and moderate tolerability. Lamivudine, and newer agents such as atazanavir (or atazanavir/ritonavir), emtricitabine, fosamprenavir/ritonavir, and tenofovir, may offer pharmacologic advantages in the current state of once-daily therapy. Important considerations exist for coadministering once-daily agents including drug–drug interactions, drug–food incompatibilities, and synergistic toxicities. Few controlled studies have compared once-daily regimens with conventional regimens.

CONCLUSIONS

Progress has been made toward once-daily therapy, but more clinical experience with available agents is needed, including comparative studies of entirely once-daily regimens versus conventional regimens. Limitations of currently available agents signify a need for improved antiretroviral utilization or new alternative agents.
Comparing Hyperlipidemia Control with Daily Versus Twice-Weekly Simvastatin
Authors: Mangin Emmanuelle FM , Robles Gisela I , Jones William N , Ford Marjorie A , Thomson Steven P
Published: October 2004

BACKGROUND

Costs associated with the use of hydroxymethylglutaryl coenzyme A reductase inhibitors are increasing. Finding ways to manage hyperlipidemia at lower costs is critical to all healthcare systems.

OBJECTIVE

To assess effectiveness, safety, cost, and patients’ satisfaction when converting hyperlipemic patients taking simvastatin daily to simvastatin twice weekly.

METHODS

This nonrandomized, open-label, proof-of-concept study converted patients treated with simvastatin 10 or 20 mg daily to 40 or 80 mg twice weekly, respectively, for 12 weeks. The lipid profiles at enrollment, week 6, and week 12 were compared using repeated-measures ANOVA. The percentage of patients attaining the appropriate low-density lipoprotein cholesterol (LDL-C) goal was determined.

RESULTS

Thirty-one patients completed the study. The proportion of patients at the LDL-C goal was not statistically different between enrollment and week 12 (87% vs 68%; p = 0.068). The mean LDL-C value ± SD at weeks 6 and 12 increased compared with enrollment (112 ± 20, 111 ±17, and 97 ± 17 mg/dL, respectively; p < 0.001). Three (10%) patients reported nonadherence to the twice-weekly regimen. Seventeen (55%) patients reported that both regimens were equally convenient or preferred the twice-weekly regimen. Estimated cost-savings at our institution associated with this regimen would be $32 000 per 1000 patients per year.

CONCLUSIONS

The twice-weekly regimen safely maintained most of the patients at their LDL-C goal level, and over half the patients found this regimen to be the same or easier to follow than a daily regimen. Large outcome studies evaluating this approach are needed.
Population-Based Medication Reviews: A Descriptive Analysis of the Medication Issues Identified in a Medicare Not-for-Profit Prescription Discount Program
Authors: Farris Karen B , Ganther-Urmie Julie M , Fang Gang , Doucette William R , Brooks John M , Klepser Donald G , Fries David J , Kuhle Carol L
Published: October 2004

BACKGROUND

Medication reviews may be an important strategy to improve medication use, especially for individuals receiving many drugs.

OBJECTIVE

To describe the types of medication issues and recommendations identified in the Iowa Priority Brown Bag Medication Reviews, compare individuals with medication issues with those without medication issues, and describe Iowa Priority enrollees’ experiences with and satisfaction of the review.

METHODS

A retrospective review of enrollment forms and medication review records and a survey of Iowa Priority members were conducted in 2002. Subjects were Medicare-eligible individuals who joined the Iowa Priority Prescription Savings Program. Frequency distributions and descriptive statistics were calculated. Analysis using t-test and χ2 test determined differences between individuals with and without issues regarding use of drug therapy.

RESULTS

Almost 13% of Iowa Priority enrollees received a review. There were 1167 individuals with 2123 medication issues identified. Nonprescription medications accounted for one-third of drug interactions and >40% of duplications. People with issues had poorer health, more chronic conditions, and took more drugs than people without medication issues. One-third of survey respondents discussed the review with their physicians, and 17.7% reported medication changes. Satisfaction with the review was good; however, only 24% were likely to have received an annual review.

CONCLUSIONS

Iowa Priority Brown Bag Medication Reviews showed that individuals with fair/poor health, higher numbers of medications, and more chronic conditions were likely to have medication issues. Reviews generated discussions between physicians and patients, produced some medication changes, and helped individuals save money.
Improved Fluorescent PCR-Based Assay for Sizing CGG Repeats at the FRAXA Locus
Authors: Houdayer Claude , Lemonnier Alban , Gerard Marion , Chauve Corinne , Tredano Mohammed , de Villemeur Thierry Billette , Aymard Pierre , Bonnefont Jean-Paul , Feldmann Delphine
Published: October 2004

Fragile X syndrome is the most frequent heritable genetic disease involving mental retardation and is usually caused by an expanded CGG repeat in the first exon of the FMR1 gene. Therefore, searching for CGG expansion at the FRAXA locus among the mentally retarded has become a routine investigation in neuropaediatric practice. Consequently, we have developed a fluorescent PCR-based assay for sizing repeats as an alternative to laborious and time-consuming Southern blot. The procedure utilises a reverse fluorescent labelled primer, and the Expand Long Template PCR system™ (Roche) with addition of dimethylsulfoxide and 7-deaza-dGTP. It allows precise determination of the CGG repeat number in males and females for alleles from normal to premutation size range and detection of full mutations in males. We believe that this PCR protocol, allowing a high sample throughput, is useful for first-line screening among mentally retarded males, possibly complemented by Southern blot analysis to assess the methylation status of large mutated alleles.
A Simple HPLC Method for Monitoring Mycophenolic Acid and Its Glucuronidated Metabolite in Transplant Recipients
Authors: Seebacher Gernot , Weigel Günter , Wolner Ernst , Mallinger Robert , Grimm Michael , Laufer Günter , El Menyawi Ibrahim , Griesmacher Andrea , Müller Mathias M.
Published: October 2004

Mycophenolic acid (MPA) is nowadays in broad clinical use as a substitute for azathioprine. An immunoassay for MPA recently received approval for clinical applications. The high performance liquid chromatography (HPLC) assay for measuring MPA and its glucuronide conjugate (MPAG) we describe here is not only rapid and simple but also extremely sensitive at plasma levels obtained during standard immunosuppressive regimens. The determination of MPAG is possible without any change of the chromatographic conditions (detection wavelength of 214 nm, mobile phase: acetonitrile and 50 mmol/l o-phosphoric acid (50:50, V/V), run time: 15 min). The required equipment is a standard HPLC system including a simple UV-detector. Sample volume of 400 μl is required for both determinations. Detection limit is 0.25 μmol/l for MPA and 5 μmol/l for MPAG. Linearity is excellent for serial dilutions (0.5–25 μmol/l for MPA, 25–500 μmol/l for MPAG) and high accuracies favour the method described.

More than 2000 plasma samples tested for MPA in patients after heart transplantation within one year and more than 500 samples for MPAG underline the clinical applicability of this assay.
The Activities of Some Glycosaminoglycan-Degrading Enzymes in the Wall of the Umbilical Cord Artery and Their Alteration in Edema, Proteinuria, Hypertension (EPH)-Gestosis
Authors: Romanowicz Lech , Bańkowski Edward , Jaworski Stefan
Published: October 2004

Edema, proteinuria, hypertension (EPH)-gestosis is associated with a premature replacement of hyaluronic acid by sulphated glycosaminoglycans (GAGs), both in the umbilical cord arteries (UCAs) and in Wharton's jelly. This phenomenon may be considered as a sign of premature ageing of the umbilical cord tissues. The decrease in hyaluronic acid content in the UCA was found to be the result of reduced biosynthesis of this substance, whereas an increase in sulphated GAGs-content is rather a result of slower degradation of newly synthesised GAGs. In this study the activities of GAGs-degrading enzymes in normal umbilical cord arteries and those taken from newborns delivered by mothers with EPH-gestosis were compared. It was found that EPH-gestosis results in a significant reduction in the activities of neutral endoglycosidases degrading most of the sulphated glycosaminoglycans (with the exception of heparan sulphate). The activities of exoglycosidases also decrease but to a lesser degree. These alterations are thought to be responsible for EPH-gestosis-associated accumulation of sulphated glycosaminoglycans in the extracellular matrix of the arterial wall. Such remodelling of the arterial wall may affect foetal blood circulation. The significance of these phenomena in the phathological mechanism of EPH-gestosis is discussed.
Increased Serum Neopterin Concentrations in Patients with Alzheimer’s Disease
Authors: Leblhuber Friedrich , Walli Johannes , Demel Ulrike , Tilz Gernot P. , Widner Bernhard , Fuchs Dietmar
Published: October 2004

We measured serum neopterin concentrations in 24 patients with Alzheimer's disease (8 males, 16 females; age: 73.1 ± 6.2 years; free of any infectious process) and fourteen controls of similar age (4 males, 10 females; age: 69.7 ± 8.8 years). Compared to controls, significantly higher concentrations of neopterin (p < 0.01) were found in patients with Alzheimer's disease. Among patients, concentrations of neopterin were higher in those with lower mini-mental-state (p < 0.05), and an invers correlation existed between mini-mental-state and neopterin concentrations. No such association existed with the duration of the disease. There were also significant correlations between neopterin and serum concentrations of immune activation markers such as soluble tumor necrosis factor (TNF) receptor and soluble interleukin-2 receptor (all p < 0.01). Thus, increased concentrations of neopterin in serum of patients with Alzheimer's disease correlate with the severity of dementia. The data imply a chronic state of peripheral immune activation in Alzheimer's disease.
Age Relationships and Sex Differences in Serum Levels of Pregnenolone and 17-Hydroxypregnenolone in Normal Subjects
Authors: Hill Martin , Lukáč Dušan , Lapčík Oldrrich , Šulcová Jarmila , Hampl Richard , Pouzar Vladimír , Stárka Luboslav
Published: October 2004

17-Hydroxypregnenolone (3β, 17α-dihydroxypregn-5-en-20-one) and pregnenolone (3β-hydroxypregn-5-en-20-one) were determined by radioimmunoassay following HPLC separation in serum of healthy subjects of both sexes from 2 to 66 years old (29 girls, 85 women, 30 boys, 89 men). The effects of age and sex on the levels of both steroids were investigated and the upper limits of normal in age groups were determined.

The 17-hydroxypregnenolone levels as a function of age were characterized by a statistically significant maximum at the age of 18 and 20 years followed by a local minimum at the age of 39 and 37 years and by a statistically insignificant local maximum at the age of 55 and 49 years in men and women, respectively.

Pregnenolone age-dependence was similar and the statistically significant maximum was reached at the age of 17 and 16 years, the local minimum occurred at the age of 37 and 38 years and the second, statistically insignificant, local maximum at the age of 48 and 47 years in men and women, respectively.

Both 17-hydroxypregnenolone and pregnenolone in both sexes exhibited similarly shaped peaks with age. Both peaks of the polynomial fit in 17-hydroxypregnenolone were more pronounced in men than in women (13.0 and 9.20 nmol/l in the first peak; 7.72 and 4.78 in the second peak respectively). The situation with pregnenolone was the opposite. Both peaks of the polynomial fit in pregnenolone were lower in men than in women (2.29 and 3.21 nmol/l in the first peak; 0.92 and 1.78 in the second peak, respectively).

The higher serum levels of pregnenolone at puberty and during fertile age and their wider variance in comparison with men could, be explained by the different gonadal steroidogenesis depending on the menstrual cycle, where the pregnenolone serves as a substrate for progesterone formation.

The age dependencies of 17-hydroxypregnenolone and pregnenolone in women resembled that of unconjugated dehydroepiandrosterone. These results indicate that the increased metabolic activity in gonads in adolescence concerns not only dehydroepiandrosterone as the product of the 5-ene metabolic pathway but also its precursors.
A Study of Hypermagnesaemia in a Hospital Population
Authors: Crook Martin
Published: October 2004

The purpose of this present study was to assess the prevalence of hypermagnesaemia in a hospital population. Furthermore, the relationship between hypermagnesaemia and other common electrolyte disturbances such as hypo- and hypercalcaemia, hypo- and hyperkalaemia and hypo- and hyperphosphataemia was studied.

Twenty-seven percent of magnesium requests showed a serum magnesium concentration equal to, or greater than, 1.0 mmol/l.

Hyperkalaemia (a plasma potassium concentration of equal to, or greater than, 5.0 mmol/l) was found in 18 % of the patients with hypermagnesaemia and 25 % of these patients showed hyperphosphataemia (a plasma phosphate concentration of equal to, or greater than, 1.5 mmol/l).

Of the serum magnesium requests, hypermagnesaemia was particularly common on the intensive care (23 %) and the renal unit (43 %). Hypermagnesaemia was also seen in patients undergoing cardiothoracic surgery (17 %) and who had an acute myocardial infarction (8 %). Seventy-three percent of patients with a plasma magnesium of greater than 1.0 mmol/l showed abnormal renal function. However, it was rare to find a serum magnesium of greater than 2.0 mmol/l (less than1 % of magnesium requests).
Multiple Regression Analysis of Interference Effects from a Hemoglobin-Based Oxygen Carrier Solution
Authors: Kazmierczak Steven C. , Catrou Paul G. , Best Ann E. , Sullivan Steven W. , Briley Kimberly P.
Published: October 2004

The use of hemoglobin-based oxygen carrier solutions in patients requiring blood transfusion will necessitate that clinical laboratories have mechanisms in place to evaluate the potential interference effect of these substances on testing methods. Because these oxygen carrier solutions contain acellular hemoglobin, but do not contain many of the intracellular enzymes and ions present in erythrocytes, interference effects from blood substitutes may be quite different when compared to in vivo or in vitro lysis of erythrocytes. We evaluated the potential interference effect of Diaspirin Cross-linked Hemoglobin on 29 different clinical laboratory analytes. Various combinations of these analytes were tested using the Hitachi 747 and 911 systems, a Beckman CX3, an Abbott AxSym, a Bayer Immuno I, and a Dade ACA IV; a total of 60 analyte/instrument combinations. We used the method of multiple regression analysis to classify interferences as analyte-dependent, analyte-independent, or a combination of the first two types. The presence of clinically significant test interference was derived by using the criteria for maximum allowable error specified in the Clinical Laboratory Improvement Amendments of 1988. Using these criteria, we found significant interference from Diaspirin Cross-linked Hemoglobin with 13 of 29 analytes tested. Interference was noted with the Hitachi 747 and 911 methods for albumin, alkaline phosphatase, total and conjugated bilirubin, cholesterol, total carbon dioxide, iron, lactate dehydrogenase, magnesium, total protein, and triglyceride. In addition, Diaspirin Cross-linked Hemoglobin interfered with measurement of L-lactate using the ACA IV and minor interference was noted with glucose measured using the Beckman CX3. Data from the interference studies was graphically displayed in the form of interference plots. These plots show the maximum allowable test error, due to Diaspirin Cross-linked Hemoglobin, as a function of analyte and interferent concentrations. Evaluation of the potential interference effect of hemoglobin-based oxygen carrier solutions with use of multiple regression analysis and graphical display of the resultant data in the form of interference plots allows for more reliable reporting of test results from specimens containing these products.
Automated Prozone Effect Detection in Ferritin Homogeneous Immunoassays Using Neural Network Classifiers
Authors: Papik Kornel , Molnar Bela , Fedorcsak Peter , Schaefer Rainer , Lang Fridl , Sreter Lydia , Feher Janos , Tulassay Zsolt
Published: October 2004

The application of turbidimetric homogeneous immunoassays made the determination of several plasma components widely available. The sensitivity and accuracy of these assays are appropriate enough for routine laboratory use; however, in the case of many pathologically high concentration samples, prozone effect (high dose hook effect) can be observed, that leads to false-negative determination. Up to the present there are no cost-effective algorithms available for the safe detection of the prozone effect. Pathological serum ferritin values can be elevated up to 5000 ng/ml, while the measuring range covers only the 0–440 ng/ml range by a commercial assay. The determination of samples with ferritin concentration higher than 1500 ng/ml results in false-negative values because of the overlapping measuring range and prozone effect range. The prozone effect can be recognised by analysis of reaction kinetics after measurement. We have developed a neural network classifier system to analyse reaction kinetics of the measurements and check the prozone effect. One thousand five hundred determinations and 77 patient samples were used for neural network training and test. Using the trained neural networks, false-negative results can be filtered immediately after the determination, without re-run; thus, the sensitivity of plasma ferritin determination may become reliable enough, even in the case of high concentration samples. Applying this new technology, false-negative serum ferritin determinations can be avoided, thus even a relatively high hook effect rate (5–12 % in different patient groups) can be handled safely.
Web Applications for Total Quality Management
Authors: Golaz Olivier , Hochstrasser Denis
Published: October 2004

Total quality management involves the consideration of many quality subjects as part of the management, such as quality processes, quality education, quality assurance, quality planning, quality results and quality document management. But crucial quality elements are also communication, data management and information sharing. Web applications and other associated computer communication applications such as E-mail and newsgroups, for example, offer to the laboratory environment the best tools to achieve proper communication and data management/sharing. These applications, enabling the set-up of Internet and Intranet sites, are used to share the information in the form of simple text pages or of completely interactive pages, which could comprise audio and video files, web page formulae and web data management applications. These applications are being associated to several applications and also being integrated into the laboratory information system (LIS).
Autoantibodies against Oxidised Low-Density Lipoprotein in Patients with Obstructive Sleep Apnoea
Authors: Saarelainen Seppo , Lehtimäki Terho , Jaakkola Olli , Poussa Tuija , Nikkilä Matti , Solakivi Tiina , Nieminen Markku M.
Published: October 2004

Autoantibodies against oxidised low-density lipoprotein (OxLDL-Abs) have been proposed to be an indicator of endothelial dysfunction and a novel tool for finding individuals with a high cardiovascular risk. In a cross-sectional study, OxLDL-Abs were measured in 297 patients with obstructive sleep apnoea (OSA) and 54 controls using an enzyme-linked immunosorbent assay.

The autoantibodies were increased in patients with OSA when compared to controls (age, body mass index (BMI) and gender adjusted, p = 0.001). However, within the OSA patients, OxLDL-Abs were not related to smoking, hypertension or BMI, and there was a weak negative correlation (r = −0.16, P = 0.007) between age and levels of OxLDL-Abs. In conclusion, at present the measurement OxLDL-Abs still remains a method for basic research and is not applicable for screening of at-risk patients with OSA.
Inter-α-Inhibitor (IαI) Concentration in Pig Plasma Is Independent of Acute-Phase Protein Response
Authors: Carrette Odile , Mizon Charlotte , Marquette Charles Hugo , Lampreave Fermin , Mizon Jacques
Published: October 2004

Human inter-α-inhibitor (IαI) has been shown to exert a beneficial therapeutic effect in a porcine model of endotoxin shock. It is therefore useful to have a better understanding of IαI metabolism during severe inflammatory syndromes.

Experimental bacterial pneumonia was induced in pigs. The acute phase response was highlighted by an increase in pig major acute phase protein (pig-MAP) and haptoglobin concentrations in plasma collected daily over 4 days. In the same samples, the IαI levels remained unchanged. Moreover, crossed-immunoelectrophoretic and immunoblot analyses did not show any qualitative modification of IαI throughout the experiment.

IαI has been reported to be a negative acute phase protein in both humans and rats. Here we demonstrated that IαI behavior clearly differs in humans and pigs and is definitively species specific.
Determination of Ascorbic Acid in Plasma and Urine by High Performance Liquid Chromatography with Ultraviolet Detection
Authors: Rümelin Andreas , Fauth Ulrich , Halmágyi Miklos
Published: October 2004

A reliable simple reversed-phase liquid chromatographic method for the routine determination of ascorbic acid in plasma and urine with ultraviolet detection is described. This method enables the complete separation of the ascorbic acid peak from others with a recovery of above 95 % within 8 minutes. The method can be used for analysing multiple samples within a day. In addition, the storage conditions and stability of ascorbic acid in plasma and urine were investigated. Samples of plasma and urine can be stored on ice in darkness for at least 60 min without reduction of ascorbic acid concentration. Prepared samples can be stored in darkness at 4 °C for at least 120 min and in liquid nitrogen for 42 days.
A New Liquid Homogeneous Assay for the Determination of HDL-Cholesterol
Authors: Nauck Matthias , Neumann Inga , März Winfried , Wieland Heinrich
Published: October 2004

We evaluated a new ready to use liquid assay for the homogeneous determination of HDL-cholesterol (HDL-C; Merck, Darmstadt, Germany) in comparison to phosphotungstic acid precipitation and a homogeneous assay, based on sulfated α-cyclodextrin and polyethylene glycol-modified enzymes (Roche Diagnostics/Boehringer Mannheim, Germany). The new liquid homogeneous HDL-C assay had inter-assay coefficients' of variation of less than 2.1 %. The method is linear up to at least 3.11 mmol/l HDL-C, but even at 4.40 mmol/l the deviation from the expected value is less than 5%.

Spinking experiments with low density lipoproteins and very low density lipoproteins proved that the new assay was specific for high density lipoproteins up to cholesterol associated with low density lipoproteins (LDL-C) and very low density lipoproteins (VLDL)-triglyceride concentrations of 18.13 and 22.60 mmol/l, respectively. Free fatty acids above 2 mmol/l did not interfere. Icteric samples with bilirubin concentrations between 170 and 400 μmol/l did not show any systematic deviation compared to the precipitation procedure. In addition, serum hemoglobin concentrations up to 7.0 mmol/l and ascorbic acid up to 3000 μmol/l did not interfere with the HDL-C assay. An intermethod comparison including 120 samples revealed good agreement of the liquid HDL-C assay and the precipitation procedure (y = 0.943x + 0.074 mmol/l; r = 0.992). The new homogeneous HDL-C assay is thus precise, comparable and robust. Due to its ease of handling this assay will significantly facilitate attempts to include the differentiation between HDL-C and LDL-C in the routine screening for cardiovascular risk factors and in the monitoring of lipid lowering therapy.
On the Standardization of Total Prostate-Specific Antigen: an Exercise with Two Reference Preparations
Authors: Blijenberg Bert G. , Storm Bert N. , Boeken Kruger Arto E. , Schröder Fritz H.
Published: October 2004

In this study, 112 serum samples were analyzed for total prostate-specific antigen with three well-established assays i.e. Tandem R and Tandem E (both from Hybritech Inc., San Diego, USA) and Prostatus Free/Total from Wallac Oy, Turku, Finland. Thirty-two samples were collected from prostate cancer patients, 32 from patients with benign prostate hyperplasia and 48 from men participating in a screening study for prostate cancer.

The aim of the study was to compare the results before and after recalculation with the data obtained with two reference preparations for total prostate-specific antigen: Stanford 90:10 PSA Calibrator and Certified Reference Material 613 Prostate-Specific Antigen.

Comparing the actual results revealed almost perfect correlations between Tandem R and Tandem E and between both Tandem assays and Prostatus. We observed statistically significant differences in accuracy between Tandem R and Tandem E:

y(Tandem E)= 1.05 × (Tandem R)+0.07,

and between Tandem E and Prostatus:

y(Prostatus)= 0.94 × (Tandem E)+0.02

In both comparisons prostate-specific antigen values ranged from 0–40 μg/l.

Recalculation with both reference preparations did not solve these discrepancies. One exception was the combination Tandem R and Tandem E. The application of either reference preparation solved the differences in accuracy here.

In conclusion, even after recalibration, assays for total prostate-specific antigen are still not completely interchangeable.
Analytical Quality Specifications for Serum Lactate Dehydrogenase Isoenzyme 1 Based on Clinical Goals
Authors: von Eyben Finn Edler , Hyltoft Petersen Per , Blaabjerg Ole , Lindegaard Madsen Ebbe
Published: October 2004

The aim of the study was to deduce analytical quality specifications for the determination of catalytic concentration of serum lactate dehydrogenase isoenzyme 1 (S-LD-1) according to clinical goals (the clinical utility model). We defined clinical goals for false positive and false negative S-LD-1 measurements in the monitoring of patients with testicular germ cell tumors (TGCT), clinical stage I, on a surveillance only program. The absolute S-LD-1 catalytic concentrations were routinely corrected for contamination from preanalytical hemolysis. A reference group of 37 men had a near ln-Gaussian distribution for the absolute S-LD-1 catalytic concentration. The geometric mean was 76 U/l and an S-LD-1 > 128 U/l (99.72 percentile, the decision limit) indicated a high risk of a relapse of TGCT. We have previously shown that an S-LD-1 > 160 U/l (treatment limit) was associated with a suboptimal outcome from the treatment of metastatic TGCT. The maximum allowable analytical positive bias was 5 U/l, and the maximum allowable analytical negative bias was −32 U/l. The maximum allowable analytical coefficient of variation, CVA, was 11 % (≈14 U/l) at a bias = −5 U/l. For S-LD-1 measurements not corrected for hemolysis, the decision limit was 145 U/l, the maximum allowable negative bias −19 U/l, and CVA 8 % (≈12 U/l). A routine correction for hemolysis had a large impact on the analytical quality specifications.
Leukocyte Activation Markers in Clinical Practice
Authors: Viedma Contreras José Antonio
Published: October 2004

The response against tissue injury and infection begins with the early activation of molecular and cellular elements of the inflammatory and immune response. Severe tissue injury, necrosis, and infection induce imbalanced inflammation associated with leukocyte over-stimulation and excessive or dysregulated release of cellular mediators. Clinical and experimental studies have shown that these mediators are directly related to progressive post-injury complications. Persistent increased levels of pro-inflammatory mediators produce tissue injury. Excessive production and activity of anti-inflammatory mediators cause anergy and/or immune dysfunction with increased susceptibility to infection. Leukocyte activation is assessed by cell surface phenotype expression, cellular mediators determination, or by measuring functional responses using isolated cells. Potential routine clinical uses are: evaluation of severity and prognosis in critically ill patients, immunomonitoring of sepsis, and detection of tissue injury, necrosis, and infection. In practice, the determination of cellular activation markers is restricted by a limited number of automated methods and by the cost of reagents. The availability of flow cytometry and immunoassay automated systems can contribute to a wider use in pracice. Here we review the immunopathophysiology of polymorphonuclear neutrophil, monocyte, macrophage, and lymphocyte activation in response to tissue injury and infection. In addition, laboratory methods for their determination, and clinical applications in practice, are discussed.
Hepatitis C Virus-Specific DNA Sequences in Human DNA: Differentiation by Means of Restriction Enzyme Analysis at the DNA Level of Healthy, Anti-HCV-Negative Individuals
Authors: Dennin Reinhard H. , Wo Jianer , Chen Zhi
Published: October 2004

This study aimed to look for further HCV-specific sequences at the DNA level of healthy, HCV-negative individuals. Here, the sequence section from nt 57 to nt 328 within the 5′-NCR was assayed. Different combinations of primers were used in the nested PCR without a preceding reverse transcriptase step, resulting in fragments of the expected molecular weight size and also shorter and longer ones. It shows that the major part of the 5′-non-coding region (5′-NCR) of the hepatitis C virus genome is present in the DNA fraction from peripheral blood mononuclear cells (PBMCs) of healthy, anti-HCV-negative individuals tested. Furthermore we designed experiments to prove the specificity of these findings, by using restriction enzymes for digest assays of the target DNA before PCR (pre-PCR digest) and of the products after PCR (post-PCR digest). In conclusion, our study indicates that the main part of the internal ribosome entry site (IRES) structure of HCV at least is contained in the DNA of the individuals tested.
Rapid Analysis of Parathion in Biological Samples Using Headspace Solid-Phase Micro-Extraction (HS-SPME) and Gas Chromatography/Mass Spectrometry (GC/MS)
Authors: Musshoff Frank , Junker Heike , Madea Burkhard
Published: October 2004

A simple and rapid method for the analysis of parathion in biological samples is presented. The method consists of the extraction of parathion from blood samples by headspace solid-phase micro-extraction (SPME), followed by capillary gas chromatography and mass spectrometry detection. The recoveries in the blood samples after addition of ammonium sulphate and sulphuric acid were between 85 % and 89% compared to samples prepared in water. Linearity was established over a concentration range of 0.1–5 μg/g blood with acceptable coefficients of correlation and limits of detection reached 0.02–0.05 μg/g. The time for an analysis is 57 minutes for one sample, including the extraction step. In conclusion, HS-SPME in combination with GC/MS is an effective method for the determination and quantification of parathion-ethyl and parathion-methyl in biological material.
Semi-Automated Rapid Isoelectric Focusing of Apolipoproteins C from Human Plasma Using PhastSystem™ and Immunofixation
Authors: Noll Bernd , Hackler Rolf , Pelzer Mirko , Pelzer Sabine , Nusser Petra , Maisch Bernhard , Schaefer Juergen R. , Steinmetz Armin
Published: October 2004

Apolipoproteins (apo) C-I, C-II, and C-III play crucial roles in intravascular lipid metabolism. Whereas apo C-II is an obligate cofactor for lipoprotein lipase, apo C-III was shown to inhibit its action. Apo C-I can be a potent cofactor of human lecithin:cholesterol acyltransferase. Structural mutants and deficiencies of apo C-II lead to hypertriglyceridemia. A similar phenotype is associated with apo C-III mutants and is inducible by overexpression of human apo C-III in transgenic animals. No structural variant has so far been reported for apo C-I. The present paper describes a rapid semi-automated procedure for isoelectric focusing analysis of these C-apolipoproteins from whole plasma or serum and their visualization by immunofixation and silver staining. The procedure allows detection of charged variants of C-apolipoproteins. As applied to 295 patients with coronary heart disease and 85 controls, it also serves to detect deficiency syndromes of these apolipoproteins. The procedure provides reliable, easy and quick analysis of C-apolipoproteins applicable as a routine or screening procedure not restricted to specialized laboratories.
The c-erbB-2 Oncogene Amplification by Competitive PCR in Aneuploid Cell Clones Flow Sorted from Breast Cancer Samples
Authors: Vona Giovanna , Caldini Anna , Sestini Roberta , Rapi Stefano , Bianchi Simonetta , Fanelli Alessandra , Pazzagli Mario , Orlando Claudio
Published: October 2004

The amplification of c-erbB-2 oncogene has been reported to have clinical relevance as a prognostic index in breast cancer. However, controversies still remain about its interpretation, mainly due to the inaccuracy of methods used for this purpose and to the unpredictable variability of the ratio between cancer and normal cells. Accurate quantitative assay, combined with strategies for selection or enrichment of tumor cell populations, could shed a new light on the relationships between molecular alterations and their clinical relevance. In this study, amplification of c-erbB-2 was measured by competitive PCR in 21 aneuploid breast cancers using a multiple DNA competitor both in whole homogenized cancer cells and in aneuploid enriched clones obtained after flow cytometry cell sorting. Most breast cancers (10/12) carrying c-erbB-2 oncogene amplification showed a significant increase in copy number in sorted aneuploid clones, and 2/9 apparently not amplified in basal samples were found to be amplified after being sorted for the aneuploid population. A general concordance between amplification and c-erbB-2 overexpression was found. The mean degree of amplification in sorted aneuploid clones is increased in breast cancers with the highest levels of cerbB-2 protein overexpression. These data indicate that in breast cancers the amplification of c-erbB-2 oncogene is mainly associated with aneuploid cells.
The Index of Individuality Is Often a Misinterpreted Quantity Characteristic
Authors: Hyltoft Petersen Per , Fraser Callum G. , Sandberg Sverre , Goldschmidt Henk
Published: October 2004

The concept of the “index of individuality” was introduced by Eugene Harris in 1974. The index of individuality, calculated as (CVA
2 + CVI
2)1/2/CVG, where CvA, CvI, and CvG are analytical, within-subject, and between-subject coefficients of variation respectively, has been used by many to investigate the utility of conventional population-based reference values. For a high index of individuality, >1.4, it has been said that reference intervals will be more useful than for a low index, < 0.6. The validity of these concepts is investigated here and a number of our findings are at odds with the generally held opinion. The index of individuality has no impact on the fraction of individuals classified using population-based reference values, as long as the change in concentration from the usual state is of the same absolute magnitude and one sample is assayed to detect disease. However, when a measurement falling outside a reference limit is repeated in order to verify the finding, the index of individuality has considerable influence. For quantities with very low indices, the repeat test result, will be close to the first and give no new information, whereas for quantities with high indices, a repeat test will decrease the number of true positives and false positives.