bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Prediction of Fatal Myocardial Infarction Using the Ankle Brachial Index in Addition to Conventional Risk Factors
Authors: Lee A.J. , Price J.F. , Russell M.J. , Smith F.B. , van Wijk M.C.W. , Fowkes F.G.R.
Published: October 2004

Background—

Prediction of major cardiovascular and cerebrovascular events using conventional risk factor models is limited. Noninvasive measures of subclinical atherosclerosis such as the ankle brachial index (ABI) could improve risk prediction and provide more focused primary prevention strategies. We wished to determine the added value of a low ABI in the prediction of long-term risk of cardiovascular and cerebrovascular events and death.

Methods and Results—

In 1988, 1592 men and women 55 to 74 years of age were randomly selected from the age-sex registers of 11 general practices in Edinburgh, Scotland, and followed up over a period of 12 years for incident events. After adjustment for age and sex, an ABI ≤0.9 was predictive of an increased risk of fatal myocardial infarction (MI), cardiovascular death, all-cause death, combined fatal and nonfatal MI, and total cardiovascular events. After further adjustment for prevalent cardiovascular disease, diabetes, and conventional risk factors, a low ABI was independently predictive of the risk of fatal MI. Addition of the ABI significantly (
P
≤0.01) increased the predictive value of the model for fatal MI compared with a model containing risk factors alone. Comparison of areas under receiver operator characteristic curves confirmed that a model including the ABI discriminated marginally better than one without.

Conclusions—

Addition of the ABI significantly improved prediction of fatal MI over and above that of conventional risk factors. We recommend that the ABI be incorporated into routine cardiovascular screening and that the potential of its inclusion into cardiovascular scoring systems (with a view to improving their accuracy) now be examined.
Opposite Patterns of Left Ventricular Remodeling After Coronary Revascularization in Patients With Ischemic Cardiomyopathy
Authors: Rizzello Vittoria , Poldermans Don , Boersma Eric , Biagini Elena , Schinkel Arend F.L. , Krenning Boudewijn , Elhendy Abdou , Vourvouri Eleni C. , Sozzi Fabiola B. , Maat Alexander , Crea Filippo , Roelandt Jos R.T.C. , Bax Jeroen J.
Published: October 2004

Background—

In patients with ischemic cardiomyopathy, left ventricular (LV) remodeling is an important prognostic indicator. The precise relation between viable myocardium, revascularization, and ongoing or reversed remodeling is unknown and was evaluated in the present study.

Methods and Results—

A total of 100 patients with ischemic cardiomyopathy underwent dobutamine stress echocardiography to assess myocardial viability and LV geometry (volumes and shape). At a mean of 10.2 months and 4.5 years after revascularization, resting echocardiography was repeated to evaluate LV remodeling. Long-term follow-up (mean 5±2 years) data were obtained. According to dobutamine stress echocardiography, 44 patients (44%) were defined as viable (≥4 viable segments) and 56 as nonviable. After revascularization, 40 patients (43%) had ongoing LV remodeling and 53 (57%) did not (in 7 patients who died early after revascularization, postoperative echocardiographic evaluation was not available). On multivariable analysis, the number of viable segments was the only predictor of ongoing LV remodeling (OR 0.60, 95% CI 0.48 to 0.75;
P
<0.0001). The likelihood of LV remodeling decreased as the number of viable segments increased. During the follow-up, reverse remodeling was present in viable patients, whereas in nonviable patients, LV volumes significantly increased, which indicates ongoing LV remodeling. At follow-up, viable patients also showed a persistent improvement of heart failure symptoms and fewer cardiac events than nonviable patients (
P
<0.05).

Conclusions—

In patients with ischemic cardiomyopathy, a substantial amount of viable myocardium prevents ongoing LV remodeling after revascularization and is associated with persistent improvement of symptoms and better outcome.
There Is No Evidence for an Increase in Acute Coronary Syndromes After Short-Term Abrupt Discontinuation of Statins in Stable Cardiac Patients
Authors: McGowan Mary P.
Published: October 2004

Background—

For a variety of reasons, many patients abruptly discontinue statin therapy. The present analysis was conducted to determine whether the risk of cardiovascular outcomes increases after withdrawal of statin therapy in a stable cardiac population.

Methods and Results—

In the Treating to New Target (TNT) study, 2 doses of atorvastatin (10 and 80 mg once daily) are being used in a double-blind parallel-group design. Of the 18 468 patients screened for study participation, 16 619 entered a dietary lead-in/drug-washout period, and of these, 15 432 eligible participants began treatment with atorvastatin 10 mg/d on an open-label basis. Of the subjects who entered the dietary lead-in/drug-washout period, 57% were receiving prior statin therapy. During the 6-week drug-washout period, there were 24 primary events (defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke); throughout the subsequent 8-week open-label period, there were 31 primary events. This equated to monthly Kaplan-Meier event rates of 0.20% during washout and 0.26% in the open-label phase. Event rates were therefore similar during the 2 phases.

Conclusions—

The present analysis demonstrates that short-term discontinuation of statin therapy in stable cardiac patients apparently does not lead to a clinically important increased risk of acute coronary syndromes.
Atrial Fibrillation After Surgical Correction of Mitral Regurgitation in Sinus Rhythm
Authors: Kernis Steven J. , Nkomo Vuyisile T. , Messika-Zeitoun David , Gersh Bernard J. , Sundt Thoralf M. , Ballman Karla V. , Scott Christopher G. , Schaff Hartzell V. , Enriquez-Sarano Maurice
Published: October 2004

Background—

The incidence, determinants, and outcome of postoperative atrial fibrillation (AF) after surgery for mitral regurgitation (MR) are poorly defined but may have important implications for timing of mitral valve surgery.

Methods and Results—

In 762 patients in sinus rhythm with no AF history undergoing MR surgical correction, we examined the rates and prognostic implications of postoperative AF for early AF (within 2 weeks postoperatively) and late AF (>2 weeks after surgery). During postoperative follow-up, 180 patients (24%) experienced new AF (early AF in 136 and late AF in 111). Isolated early AF without recurrence was observed in 69 patients characterized by high angina class and lower left ventricular ejection fraction but no significant left atrial (LA) enlargement. However, overall early AF predicted late AF: 62±5% of patients with early AF had late AF at 10 years compared with 9±1% of patients without early AF (
P
<0.0001). Large LA size strongly and independently predicted early AF (
P
=0.01) and late AF (
P
=0.003). For late AF, the predictive value of an enlarged LA was cumulative to that of early AF. Postoperative AF was associated with an increased subsequently higher risk of stroke or congestive heart failure (adjusted risk ratio=1.46 [1.04 to 2.05],
P
=0.03).

Conclusions—

Postoperative AF is common after surgical correction of MR in patients with no prior history of AF and is associated with increased subsequent morbidity. LA enlargement is independently predictive of postoperative AF and as such, should be integrated into the clinical decision-making process in patients with MR.
Role of
I
Kur
in Controlling Action Potential Shape and Contractility in the Human Atrium
Authors: Wettwer Erich , Hála Ottó , Christ Torsten , Heubach Jürgen F. , Dobrev Dobromir , Knaut Michael , Varró András , Ravens Ursula
Published: October 2004

Background—

The ultrarapid outward current
I
Kur
is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of
I
Kur
by low concentrations of 4-aminopyridine or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF).

Methods and Results—

AP duration at 90% repolarization (APD
90
) was shorter in AF than in SR (300±16 ms, n=6, versus 414±10 ms, n=15), whereas APD
20
was longer (35±9 ms in AF versus 5±2 ms in SR,
P
<0.05). 4-Aminopyridine (5 μmol/L) elevated the plateau to more positive potentials from −21±3 to −6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD
90
from 414±10 to 350±10 ms in SR but prolonged APD
90
from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 μmol/L). Computer simulations of
I
Kur
block in human atrial APs predicted secondary increases in
I
Ca,L
and in the outward rectifiers
I
Kr
and
I
Ks
, with smaller changes in AF than SR. The indirect increase in
I
Ca,L
was supported by a positive inotropic effect of 4-aminopyridine without direct effects on
I
Ca,L
in atrial but not ventricular preparations. In accordance with the model predictions, block of
I
Kr
with E-4031 converted APD shortening effects of
I
Kur
block in SR into AP prolongation.

Conclusions—

Whether inhibition of
I
Kur
prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.
Cystatin C
Authors: Jernberg Tomas , Lindahl Bertil , James Stefan , Larsson Anders , Hansson Lars-Olof , Wallentin Lars
Published: October 2004

Background—

Patients with suspected or confirmed non–ST-elevation acute coronary syndrome (ACS) constitute a large and heterogeneous group. Measurements of renal function such as serum creatinine and estimation of creatinine clearance carry independent prognostic information in this population. Cystatin C is a new and better marker of renal function than creatinine. The aim was therefore to evaluate the prognostic value of cystatin C in this population.

Methods and Results—

Cystatin C was analyzed on admission in 726 patients admitted because of symptoms suggestive of an acute coronary syndrome and no ST-segment elevations. Patients were followed up with regard to death and myocardial infarction for a median of 40 and 6 months, respectively. The median cystatin C level was 1.00 mg/L (25th to 75th percentile, 0.83 to 1.24 mg/L). The risk of death during follow-up increased with increasing levels of cystatin C. In the group with non–ST-elevation ACS, patients in the second, third, and fourth quartiles had a relative risk of subsequent death of 1.8 (95% CI, 0.6 to 5.3), 3.2 (95% CI, 1.2 to 8.5), and 11.7 (95% CI, 4.7 to 29.3) compared with the lowest quartile. In Cox regression models including well-known predictors of outcome, cystatin C level was independently associated with mortality but not with the risk of subsequent myocardial infarction. In a comparison of the markers of renal function in receiver-operating curve analyses, cystatin C had the best ability to discriminate between survivors and nonsurvivors.

Conclusions—

A single measurement of cystatin C will substantially improve the early risk stratification of patients with suspected or confirmed non–ST-elevation ACS.
Impact of Prior Use or Recent Withdrawal of Oral Antiplatelet Agents on Acute Coronary Syndromes
Authors: Collet J.P. , Montalescot G. , Blanchet B. , Tanguy M.L. , Golmard J.L. , Choussat R. , Beygui F. , Payot L. , Vignolles N. , Metzger J.P. , Thomas D.
Published: October 2004

Background—

Oral antiplatelet agents (OAAs) can prevent further vascular events in cardiovascular disease. How prior use or recent discontinuation of OAA affects clinical presentation of acute coronary syndromes (ACS) and clinical outcomes (death, myocardial infarction [MI]) is unclear.

Methods and Results—

We studied and followed up for up to 30 days a cohort of 1358 consecutive patients admitted for a suspected ACS; of these, 930 were nonusers, 355 were prior users of OAA, and 73 had recently withdrawn OAA. Nonusers were at lower risk, more frequently presented with ST-elevation MI on admission, and more frequently had Q-wave MI at discharge than prior users (36.6% versus 17.5%,
P
<0.001; and 47.8% versus 28.2%,
P
<0.001, respectively). However, there was no difference regarding the incidence of death or MI at 30 days between nonusers and prior users (10.3% versus 12.4%,
P
=NS). In addition, prior users experienced more major bleeds within 30 days compared with nonusers (3.4% versus 1.4%, respectively;
P
=0.04). Recent withdrawers were admitted on average 11.9±0.8 days after OAA withdrawal. Interruption was primarily a physician decision for scheduled surgery (n=47 of 73). Despite a similar cardiovascular risk profile, recent withdrawers had higher 30-day rates of death or MI (21.9% versus 12.4%,
P
=0.04) and bleedings (13.7% versus 5.9%,
P
=0.03) than prior users. After multivariate analysis, OAA withdrawal was found to be an independent predictor of both mortality and bleedings at 30 days.

Conclusions—

Among ACS patients, prior users represent a higher-risk population and present more frequently with non–ST-elevation ACS than nonusers. Although patients with a recent interruption of OAA resemble those chronically treated by OAA, they display worse clinical outcomes.
Selecting Patients With Atrial Fibrillation for Anticoagulation
Authors: Gage Brian F. , van Walraven Carl , Pearce Lesly , Hart Robert G. , Koudstaal Peter J. , Boode B.S.P. , Petersen Palle
Published: October 2004

Background—

The rate of stroke in atrial fibrillation (AF) depends on the presence of comorbid conditions and the use of antithrombotic therapy. Although adjusted-dose warfarin is superior to aspirin for reducing stroke in AF, the absolute risk reduction of warfarin depends on the stroke rate with aspirin. This prospective cohort study tested the predictive accuracy of 5 stroke risk stratification schemes.

Methods and Results—

The study pooled individual data from 2580 participants with nonvalvular AF who were prescribed aspirin in a multicenter trial (Atrial Fibrillation, Aspirin, Anticoagulation I study [AFASAK-1], AFASAK-2, European Atrial Fibrillation Trial, Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study, and Stroke Prevention and Atrial Fibrillation [SPAF]-III high risk or SPAF-III low risk). There were 207 ischemic strokes during 4887 patient-years of aspirin therapy. All schemes predicted stroke better than chance, but the number of patients categorized as low and high risk varied substantially. AF patients with prior cerebral ischemia were classified as high risk by all 5 schemes and had 10.8 strokes per 100 patient-years. The CHADS
2
scheme (an acronym for Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) successfully identified primary prevention patients who were at high risk of stroke (5.3 strokes per 100 patient-years). In contrast, patients identified as high risk by other schemes had 3.0 to 4.2 strokes per 100 patient-years. Low-risk patients identified by all schemes had 0.5 to 1.4 strokes per 100 patient-years of therapy.

Conclusions—

Patients with AF who have high and low rates of stroke when given aspirin can be reliably identified, allowing selection of antithrombotic prophylaxis to be individualized.
Relationship of Alcohol Drinking Pattern to Risk of Hypertension
Authors: Stranges Saverio , Wu Tiejian , Dorn Joan M. , Freudenheim Jo L. , Muti Paola , Farinaro Eduardo , Russell Marcia , Nochajski Thomas H. , Trevisan Maurizio
Published: October 2004

Epidemiological studies have demonstrated a positive relationship between heavy alcohol use and hypertension, but few studies have directly addressed the role of drinking pattern. This study was designed to investigate the association of current alcohol consumption and aspects of drinking pattern with hypertension risk in a sample of 2609 white men and women from western New York, aged 35 to 80 years, and free from other cardiovascular diseases. Hypertension was defined by systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. Odds ratios (95% confidence intervals) were computed after adjustment for several covariates. Compared with lifetime abstainers, participants reporting drinking on a daily basis (1.75 [1.13 to 2.72]) or mostly without food (1.64 [1.08 to 2.51]) exhibited significantly higher risk of hypertension. When analyses were restricted to current drinkers, daily drinkers and participants consuming alcohol without food exhibited a significantly higher risk of hypertension compared with those drinking less than weekly (1.65 [1.18 to 2.30]) and those drinking mostly with food (1.49 [1.10 to 2.00]), respectively. After additional adjustment for the amount of alcohol consumed in the past 30 days, the results were follows: 0.90 (0.58 to 1.41) for daily drinkers and 1.41 (1.04 to 1.91) for drinkers without food. For predominant beverage preference, no consistent association with hypertension risk was found across the various types of beverages considered (beer, wine, and liquor). In conclusion, drinking outside meals appears to have a significant effect on hypertension risk independent of the amount of alcohol consumed.
Insight from a Breastfeeding Peer Support Pilot Program for Husbands and Fathers of Texas WIC Participants
Authors: Stremler Jewell , Lovera Dalia
Published: October 2004

A Father-to-Father Breastfeeding Support Pilot Program conducted by the Texas Department of Health provides a model of a viable way to increase breastfeeding rates in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC Program). The pilot concept was based on previous success with a breastfeeding peer counselor program and research documenting the father’s attitude as an important influence on a mother’s decision to breastfeed. Peer dads are fathers of breastfed infants participating in the WIC Program. They are recruited, trained, and hired to give breastfeeding and parenting information to other WIC fathers. WIC fathers rated the information they received as “very important” and indicated that counseling sessions would help them support their infants’mothers with breastfeeding and be better fathers. Breastfeeding initiation rates increased at clinics employing peer dads. Father-to-father breastfeeding education was successful in educating and empowering fathers, enabling them to support their breastfeeding family members.
Tragedy in the fog of war
Authors: Sambrook Richard
Published: October 2004

Life's events have provided plenty of experience for those of us in BBC News over the last year, writes the BBC's former editor of news. Following both the Hutton and Butler Inquiries, what is his view now about what happened a year ago? "I am not one of those who would argue that Andrew Gilligan was 'mainly right'. In journalism 'mainly right' is like being half pregnant - it's an unsustainable condition. The facts as they continue to emerge show we got some things right and we got one big thing wrong. At the time it seemed very complicated. On reflection, it was quite simple. Today set out to broadcast a report about genuine and, as we now know, well founded reservations among parts of the intelligence community about the September 2002 Iraq dossier. That was the script which the programme approved. In a live interview Andrew Gilligan used a form of words which wrongly suggested bad faith on the part of the Government. The BBC, concentrating on what it had intended to broadcast, was slow to recognise the significance of this departure from the script. Alastair Campbell launched a sweeping attack on the BBC before the Foreign Affairs Committee. From that point on there could be no happy ending.".
Media, schmedia
Authors: Hackett Dennis
Published: October 2004

Hackett looks at the media's obsession with itself, expressed through the many media pages contained in the national press and numerous radio and TV programmes dedicated to the press and other branches of the trade. Navel-gazing has its problems, he concludes, including pitfalls that can inhibit careers:" Another inhibition on the media journalist (odd term really) is that they have to be careful what they say about personalities who work elsewhere. Memories are long in the media business. I have written press or publishing columns myself, but in The Spectator and Campaign, outside the main arena. I remember, in the former, I once took [Sun editor] Larry Lamb to task over something. I received a telephone call from Rupert Murdoch's then number two, Alex McKay, whom I knew well. "Very funny, Dennis," he said. "You go on writing like that and you won't get a job in Fleet Street." He had a point."
The boys done good
Authors: Davis Victor
Published: October 2004

Davis started out as a copyboy and the Daily Express, an inauspicious beginning to a long and hugely successful career as a writer. Looking back, he writes: "Even if I changed my name to Murdoch or Rothermere, I wouldn't land a national newspaper job today. No chance. No university degree, you see. Most of my Fleet Street contemporaries of more than half-a-century ago also lacked this desirable qualification, yet were formidably well read and informed - more so than the graduate journalists of today, it seems to me. But then we did not have television, pop music and obsessive football to distract us from furnishing our minds." And he concludes: "Journalism, like acting and prostitution, is not a profession but a vocation. You either have what it takes or you don't, and general experience shows that some of the best journalists, those who can write and instinctively know what is news, began as copyboys or printers' devils."
Evaluation of sense-strand mRNA amplification by comparative quantitative PCR
Authors: Goff Loyal A , Bowers Jessica , Schwalm Jaime , Howerton Kevin , Getts Robert C , Hart Ronald P
Published: October 2004

Background

RNA amplification is required for incorporating laser-capture microdissection techniques into microarray assays. However, standard oligonucleotide microarrays contain sense-strand probes, so traditional T7 amplification schemes producing anti-sense RNA are not appropriate for hybridization when combined with conventional reverse transcription labeling methods. We wished to assess the accuracy of a new sense-strand RNA amplification method by comparing ratios between two samples using quantitative real-time PCR (qPCR), mimicking a two-color microarray assay.

Results

We performed our validation using qPCR. Three samples of rat brain RNA and three samples of rat liver RNA were amplified using several kits (Ambion messageAmp, NuGen Ovation, and several versions of Genisphere SenseAmp). Results were assessed by comparing the liver/brain ratio for 192 mRNAs before and after amplification. In general, all kits produced strong correlations with unamplified RNAs. The SenseAmp kit produced the highest correlation, and was also able to amplify a partially degraded sample accurately.

Conclusion

We have validated an optimized sense-strand RNA amplification method for use in comparative studies such as two-color microarrays.
An unusual case of an ulcerative colitis flare resulting in disseminated intravascular coagulopathy and a bladder hematoma: a case report
Authors: Suskind David L , Murray Karen , Christie Dennis
Published: October 2004

Background

Disorders of coagulation have long been associated with inflammatory bowel disease. Children, as well as adults, with both active and inactive ulcerative colitis have been found to have abnormal coagulation and fibrinolysis. Disseminated intravascular coagulation arises from an overwhelming of the haemostatic regulatory mechanisms leading to an excessive generation of thrombin and a failure of the normal inhibitory pathways to prevent systemic effects of this enzyme. Ulcerative colitis has been associated with disseminated intravascular coagulation in conjunction with septicemia, toxic megacolon and surgery.

Case presentation

A fourteen-year-old boy with a history of poorly controlled ulcerative colitis presented with nonbilious emesis, hematochezia, and hematuria. Laboratory workup revealed disseminated intravascular coagulation. He was placed on triple antibiotics therapy. An infectious workup came back negative. A computerized tomography (CT) scan of the abdomen revealed a marked thickening and irregularity of the bladder wall as well as wall thickening of the rectosigmoid, ascending, transverse, and descending colon. Patient's clinical status remained stable despite a worsening of laboratory values associated with disseminated intravascular coagulation. Patient was begun on high dose intravenous steroids with improvement of the disseminated intravascular coagulation laboratory values within 12 hours and resolution of disseminated intravascular coagulopathy within 4 days. A thorough infectious workup revealed no other causes to his disseminated intravascular coagulation.

Conclusions

The spectrum of hypercoagulable states associated with ulcerative colitis varies from mild to severe. Although disseminated intravascular coagulation associated with ulcerative colitis is usually related to septicemia, toxic megacolon or surgery, we present a case of an ulcerative colitis flare resulting in disseminated intravascular coagulation and a bladder hematoma.
A step ahead: combining protein purification and correct folding selection
Authors: de Marco Ario
Published: October 2004

The success of recombinant protein expression seems unpredictable and even good yields of soluble proteins do not guarantee the correct folding. The search for soluble constructs can be performed by exploiting libraries and speeded up by automation, but these approaches are money and time consuming and the tags used for affinity purification can mask the real stability of the target proteins. The ideal purification protocol would include the structure quality control. A recent paper commented in this article describes a phage-display method to screen for antibodies that are able to re-fold after heat-denaturation and can be selectively affinity-purified only if monodispersed. It turned out that the proteins with high recovery performance after heat-shock were also suitable for efficient recombinant expression.
The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia
Authors: Al-Shaer Moutasim H , Choueiri Nabil E , Suleiman Ehab S
Published: October 2004

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal.

Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication.
The Years of Emerging Market Crises: A Review of Feldstein
Authors: Williamson John
Published: October 2004

This is a review article of the book Economic and Financial Crises in Emerging Market Economies, edited by Martin Feldstein and published in 2003.
Rational Exuberance
Authors: LeRoy Stephen F
Published: October 2004

This article reviews the theory of speculative bubbles. Bubbles are a promising candidate as an explanation for the stock price run-up and collapse of the 1990s in the United States. The theory considers both irrational and rational bubbles, with emphasis on the latter. Rational bubbles, defined as the excess of security or portfolio prices over present values, can occur under conditions that are well understood. One argument relies on the assumed Pareto-optimality of equilibrium that rules out rational bubbles, but it is suggested that this argument is implausible.
A Conserved Gβ Binding (GBB) Sequence Motif in Ste20p/PAK Family Protein Kinases
Authors: Leberer E. , Dignard D. , Thomas D.Y. , Leeuw T.
Published: October 2004

Serine/threonine protein kinases of the Ste20p/PAK family are highly conserved from yeast to man. These protein kinases have been implicated in the signaling from heterotrimeric G proteins to mitogen-activated protein (MAP) kinase cascades and to cytoskeletal components such as myosin-I. In the yeast Saccharomyces cerevisiae, Ste20p is involved in transmitting the mating-pheromone signal from the βγ-subunits of a heterotrimeric G protein to a downstream MAP kinase cascade. We have previously shown that binding of the G-protein β-subunit (Gβ) to a short binding site in the non-catalytic carboxy-terminal region of Ste20p is essential for transmitting the pheromone signal. In this study, we searched protein sequence databases for sequences that are similar to the Gβ binding site in Ste20p. We identified a sequence motif with the consensus sequence S S L ϕP L I/V x ϕϕβ (x: any residue; ϕ: A, I, L, S, or T; β: basic residues) that is solely present in members of Ste20p/PAK family protein kinases. We propose that this sequence motif, which we have designated GBB (G̱β̱ ḇinding) motif, is specifically responsible for binding of Gβ to Ste20p/PAK protein kinases in response to activation of heterotrimeric G protein coupled receptors. Thus, the GBB motif is a novel type of signaling domain that serves to link protein kinases of the Ste20p/PAK family to G protein coupled receptors.
Identification of a CpG Island in the Human LRP-2 Gene and Analysis of Its Methylation Status in Parathyroid Adenomas
Authors: Knutson A. , Lillhager P. , Westin G.
Published: October 2004

Methylation of CpG residues in mammalian genomes is a mechanism of vital importance for many cellular functions, which all relate to gene expression. In this study we describe the identification of a CpG island in the 5′-region of the gene encoding human megalin/LRP-2, a receptor capable of binding multiple ligands, which is involved in the regulation of calcium metabolism. Southern blot analysis and genomic bisulfite sequencing revealed that the CpG island is methylated in a non-expressing cell line, largely unmethylated in an expressing cell line and unmethylated in human parathyroid tissue. In addition, we show that artificial methylation of LRP-2 promoter reporter plasmids leads to strong transcriptional repression, in vitro as well as in transfected cells. No evidence for aberrant LRP-2 gene methylation in parathyroid adenomas, in which the LRP-2 protein is generally down-regulated, was found.
Cooperativity of Binding Epitopes and Receptor Chains in the BMP/TGFß Superfamily
Authors: Knaus Petra , Sebald Walter
Published: October 2004

Bone morphogenetic proteins (BMP) are dimeric factors
initiating several distinct signaling cascades by binding to two types of
transmembrane serine/threonine kinase receptors (BRI and BRII), and are thus
regulating several steps in embryonal development and adult tissue homeostasis.
BMP-2 contains two symmetrical pairs of juxtaposed epitopes: the wrist epitope
with high affinity to BRI consists of residues from both BMP-2 monomers, while
the knuckle epitope resembles the low affinity site for BRII and comprises
residues from only one monomer. Here we generated heterodimeric BMP-2 muteins
with one monomer mutant in either epitope I for BRI (eI) or epitope II for BRII
(eII) and the second monomer wild type for receptor interactions (m). These
muteins (B2eI/B2m and B2eII/B2m) were analyzed by biosensor analysis as well as
by measuring their biological activity and compared to their homodimeric forms
(either wild type or mutant). Depletion of only one epitope II results in the
loss of biological activity as measured by alkaline phosphatase (ALP) activity
and Smad induced reportergene assays. However, depletion of only one epitope I
shows a reduction of ALP activity to about 25%, while the activation of the
Smad pathway remained normal. Homomeric muteins are nonfunctional for both Smad
and ALP activation. This suggests that two functional epitopes II have to be
present on one BMP-2 molecule for receptor activation. Futhermore, both
pathways (Smad and ALP) are triggered differently by distinct BMPreceptor
complexes. Heteromeric BMP-2 mutants therefore allow a distinguishable
manipulation of either pathway and thus represent important tools for the
generation of specific BMP-2 antagonists or agonists.
Zinc Induces Apoptosis That Can Be Suppressed by Lanthanum in C6 Rat Glioma Cells
Authors: Haase Hajo , Wätjen Wim , Beyersmann Detmar
Published: October 2004

Zinc ions have both essential and toxic effects on mammalian cells. Here we report the ability of zinc to act as an inducer of apoptosis in C6 rat glioma cells. Incubation with 150 to 300 M ZnCl2 caused cell death that was characterized as apoptotic by internucleosomal DNA fragmentation, formation of apoptotic bodies, nuclear fragmentation and breakdown of the mitochondrial membrane potential. On the other hand, zinc deprivation by the membrane permeable chelator TPEN [N,N,N,N,tetrakis (2-pyridylmethyl)ethylenediamine] also induced programmed death in this cell line, indicating the existence of intracellular zinc levels below and above which apoptosis is induced. Zincinduced apoptosis in C6 cells was independent of major signaling pathways (protein kinase C, mitogen activated protein kinase and guanylate cyclase) and protein synthesis, but was increased by facilitating zinc uptake with the ionophore pyrithione. Lanthanum(III)chloride was also able to increase the net zinc uptake, but nevertheless apoptotic features and zinc toxicity were reduced. Remarkably, lanthanum suppressed the zincinduced breakdown of the mitochondrial membrane potential. We conclude that in C6 cells lanthanum acts in two different ways, as a promoter of net zinc uptake and as a suppressor of zincinduced apoptosis.
A Structural Role for Asp83 in the Photoactivation of Rhodopsin
Authors: Breikers Githa , Bovee-Geurts Petra H.M. , DeCaluwé Godelieve L.J. , DeGrip Willem J.
Published: October 2004

Asp83 is a highly conserved residue in the second transmembrane domain of visual pigments and many members of other G proteincoupled receptor subfamilies. Upon illumination, the rod visual pigment rhodopsin proceeds through various intermediate states (Batho BSI Lumi Meta I Meta II). Meta II represents the active state of rhodopsin, which binds and activates the G protein transducin. Evidence has been presented that Asp83 participates in the formation of Meta II and undergoes a change in Hbonding. To investigate whether this role of Asp83 requires its protondonating capacity and/or its Hbonding capability, we constructed the mutants D83C and D83N. Both mutants appear to effectively activate transducin, indicating that Asp83 is not essential for signal transduction. Differential effects of the mutations D83C and D83N are observed in the spectral properties and the pH sensitivity of the Meta I Meta II transition. In general, D83C behaves much more like wildtype than D83N. We conclude that the structural role of Asp83 also involves the acidic nature of its carboxyl group. In addition, the participation in Meta II formation of Cys83 in D83C manifests itself as a change in the vibrational properties of the sulfhydryl group, demonstrating that the SH group can be used as a noninvasive probe for local structural changes.
Structure, Function and Clinical Significance of Transferrin Receptors
Authors: Feelders Richard A. , Kuiper-Kramer Ellen P. A. , van Eijk Henk G.
Published: October 2004

Iron plays an essential role in a spectrum of metabolic processes. Cellular iron uptake is facilitated by transferrin receptor (TfR)-mediated endocytosis. In recent years more insight has been obtained in TfR physiology and the regulation of cellular iron homeostasis. The synthesis of TfR and the iron storage protein ferritin is regulated reciprocally at the post-transcriptional level according to the cellular iron status. As a result of externalization of TfR during the endocytic cycle, a soluble form of TfR can be detected in serum. The serum TfR (sTfR) level is closely related to erythroid TfR turnover and the prime determinants of the sTfR concentration are cellular iron demands and erythroid proliferation rate. In the absence of a hyperplastic erythropoiesis the sTfR level is a sensitive parameter of early tissue iron deficiency. The entire spectrum of body iron status can be assessed by measurement of serum ferritin and sTfR levels, with ferritin as marker of tissue iron stores and sTfR as index of tissue iron needs. The sTfR may be a promising tool to detect iron deficiency in inflammatory states and in the anaemia of chronic disease as its concentration is, in contrast to ferritin levels, not influenced by the acute phase response. Determination of sTfR levels may also improve assessment of body iron stores during pregnancy and in neonates. Finally, the sTfR may be a useful parameter to monitor erythropoiesis in various clinical settings, for instance in the prediction of the haematological response to erythropoietin treatment. However, standardization of the sTfR assay, with definition of reference and pathological ranges, is necessary for the definitive introduction of the sTfR as major parameter of iron metabolism.
Cardiac Troponin I and Troponin T: Recent Players in the Field of Myocardial Markers
Authors: Chapelle Jean-Paul
Published: October 2004

The troponin (Tn) complex consists of three subunits referred to as TnT, TnI and TnC. Myocardium contains TnT and TnI isoforms which are not present in skeletal muscles and which can be separated from the muscular isoforms by immunological techniques. Using commercially available immunoassays, clinical laboratories are able to determine cardiac TnT and TnI (cTnT and cTnI) quickly and reliably as classical cardiac markers. After acute myocardial infarction, cTnT and cTnI concentrations start to increase in serum in a rather similar way than CK-MB, but return to normal after longer periods of time (approximately one week). Because of their excellent cardiac specificity, Tn subunits appear ideally suited for the differential diagnosis of myocardial and muscular damage, for example in noncardiac surgery patients, in patients with muscular trauma or with chronic muscular diseases, or after intense physical exercise. cTnT and cTnI may also be used for detecting evidence of minor myocardial damage: therefore they have found new clinical applications, in particular risk stratification in patients with unstable angina. In spite of the possible reexpression of cTnT in human skeletal muscles, and of the lack of standardization of cTnI assays, Tn subunits are not far to meet the criteria of ideal markers for acute myocardial injury. Only an insufficient sensitivity in the first hours following the acute coronary syndroms requiries to maintain an early myocardial marker in the cardiac panel for routine laboratory testing.
Fecal Tumor Necrosis Factor alpha, Eosinophil Cationic Protein and IgE Levels in Infants with Cows Milk Allergy and Gastrointestinal Manifestations
Authors: Kapel Nathalie , Matarazzo Pellegrino , Haouchine Djamel , Abiola Nadine , Guérin Sylvie , Magne Denis , Gobert Jean-Gérard , Dupont Christophe
Published: October 2004

Infants with atopic eczema exhibit a specific fecal protein pattern after oral challenge with cow's milk, characterized by an increase in both eosinophil cationic protein (ECP) and tumor necrosis factor (TNF)α. The aim of our study was to determine the pattern of these proteins in allergic infants with intestinal manifestations. TNFα, ECP and immunoglobulin E (IgE) were measured in stools from 13 infants with intestinal symptoms and 10 healthy infants. The allergic infants underwent two stool collections, one before a cow's milk challenge and the other after the challenge, either at the onset of clinical manifestations (n=6) or 15 days after the challenge if no clinical manifestations occurred (n=7). Baseline TNFα, ECP and IgE levels were low in all infants. The concentration of TNFα increased after the challenge in infants positive to challenge (p<0.05) but not in those negative to challenge. ECP and IgE levels remained low after the challenge in all the allergic infants. These data confirm that fecal TNFα and ECP levels indicate various reaction types of food allergy and that different immunologic disturbances lead to atopic eczema or intestinal symptoms during food allergy. Fecal protein pattern can thus be a useful tool in diagnosing food allergy in infants with intestinal manifestations.
Detection of GB Virus C/Hepatitis G Virus RNA by Reverse-Transcription Polymerase Chain Reaction
Authors: Chang Jinhong , Tao Qimin , Wei Lai , Du Shaocai , Wang Hao , Sun Yan
Published: October 2004

Recently, a novel RNA virus, designated GB virus C or hepatitis G virus (GBV-C/HGV) has been identified which may possibly be associated with human hepatitis. In this study, the nucleotide sequences of the partial nonstructural 5 (NS5) gene of GBV-C/HGV derived from sera of eight Chinese patients were determined. The overall degree of nucleotide conservation and the existence of regional highly conserved sequences make this part of the genome suitable for the development of diagnostic reagents. On the basis of sequence analysis, two sets of oligonucleotide primers were designed to establish a nested polymerase chain reaction (PCR) for detection of GBV-C/HGV RNA. The efficacy of three PCR methods (first, one stage PCR, second, nested PCR with primers from the NS5 region designed according to the prototype sequence and the third, our newly developed PCR) was compared in 133 Chinese patients with liver disease. The positive rates of these three methods were 8.3 %, 11.3 % and 18.0 % respectively. The specificity of our PCR detecting system was verified by sequencing and restriction fragment length polymorphism (RFLP). In conclusion, because of the heterogeneity and geographic distribution character of GBV-C/HGV, it is necessary to assess the sequence variation among Chinese patients infected with GBV-C/HGV. This may allow to identify GBV-C/HGV RNA with high sensitivity and specificity.
Intracellular and Extracellular, Ionized and Total Magnesium in Pre-Eclampsia and Uncomplicated Pregnancy
Authors: Sanders Renata , Konijnenberg Alice , Huijgen Henk J. , Wolf Hans , Boer Kees , Sanders Gerard T. B.
Published: October 2004

Magnesium (Mg) and calcium (CA) concentrations in women with pre-eclampsia, women with an uncomplicated pregnancy and non-pregnant women were compared. Ionized serum magnesium and calcium concentrations and intracellular magnesium concentrations were measured in 15 pregnant women with severe pre-eclampsia, 34 uncomplicated pregnant women early, at midterm and preterm in their pregnancy and 24 non-pregnant women.

The ionized calcium concentration did not chance during normal pregnancy or during pre-eclampsia relative to non-pregnant women. In contrast, elevated total and ionized magnesium serum concentrations were found in women with severe pre-eclampsia (total Mg = 0.85 ± 0.11 mM, ionized Mg = 0.61 ± 0.06 mM) relative to uncomplicated pregnant women (total Mg = 0.72 ± 0.06 mM, ionized Mg = 0.53 ± 0.03 mM). Total magnesium in pre-eclamptic women were similar to non-pregnant women.

Intracellular ionized and total magnesium concentrations in mononuclear blood cells and erythrocytes were similar in pre-eclamptic women and women with uncomplicated pregnancy.

Serum magnesium concentrations are elevated in severe pre-eclamptic women relative to women with uncomplicated pregnancy and are related to birth weight and gestational age at delivery. There may be a causal relationship since magnesium is involved in blood pressure regulation through an intracellular inhibition of NO synthase in endothelial cells.
Phospholipases A2 in Gastric Juice of Helicobacter pylori – Positive and Negative Individuals
Authors: Huhtinen Heikki T. , Grönroos Juha M. , Haapamäki Markku M. , Nevalainen Timo J.
Published: October 2004

Gastric juice is known to have phospholipase A2 catalytic activity. Helicobacter pylori (H. pylori) has been reported to produce phospholipase A2, which is believed to hydrolyse the protective layer of gastric mucosal phospholipids and to promote mucosal damage. The current study aimed at identifying secretory phospholipase A2 subtypes (pancreatic group I phospholipase A2 and synovial-type group II phospholipase A2) in gastric juice and their relation to the presence of H. pyloriin gastric mucosal biopsies in the same individuals. Gastric juice was collected from 29 individuals during gastroscopy. Biopsies were taken from the antrum and body of the stomach to determine the H. pylori status. We found catalytically active phospholipase A2 and both group I and group II phospholipases A2 in the gastric juice samples. The catalytic activity and the mass concentrations of group I and group II phospholipases A2 correlated significantly with the pH value in gastric juice. The gastric juice of H. pylori positive individuals did not contain higher amounts of phospholipases A2 than the juice of H. pylori negative individuals. Rather, the mass concentration of group II phospholipase A2 in gastric juice seemed to be somewhat lower in individuals with H. pylori infection than in uninfected individuals. The results of the current study show that both group I and group II phospholipases A2 are present in gastric juice. The main sources of phospholipases A2 in gastric juice are probably other than H. pylori.
Low Levels of Plasma Proteins: Malnutrition or Inflammation?
Authors: Johnson Andrew Myron
Published: October 2004

Levels of several plasma proteins, including albumin, transferrin, and transthyretin (prealbumin), have been proposed as markers for protein energy malnutrition. However, many other factors, especially inflammatory disease and drug or hormone therapy, affect levels of these proteins. These factors probably account for the majority of low levels of transthyretin. Levels of albumin and other proteins may be helpful in determining increased risk of morbidity and mortality, but better markers are needed for diagnosis of protein energy malnutrition per se.
Laboratory Medicine: The Need for a Broader View. The “Multiple Bundle” Model of Clinical Laboratory Function
Authors: Dominiczak Marek H.
Published: October 2004

The essence of the nineties in health care, in business, in organizational management and in education, has been change. As always in a changing environment, there will be winners and losers. In the September issue of CCLM, Williamson wrote: “Poor clinical chemistry. It is a field trapped between pressures from increasing electronic automation of assays, simplified technology and reductionism of molecular genetics and the growing pressure of economic accountability and cost cutting. It may not survive” (1). Should we all be on Prozac and wait for the doomsday?

Our problems are not unique. Some time ago, traditional cardiology was “trapped” between the advent of new invasive techniques on the one hand and a pressure to increase emphasis on prevention on the other. How did it end? Most of today's cardiologists are invasive cardiologists and many became leaders in cardiovascular prevention in addition to their “traditional” tasks (2). This is a classical example of a paradigm shift.

The present article suggests that at least some of our problems may stem from too narrow a view of laboratory medicine that we present to decision makers who allocate funds to laboratory services.