bluuebunny/crossref_metadata_2025 huggingface dataset:
Endotoxin Inactivation by Enterally Applied Colostrum of Different Composition
Authors: Seifert J. , Molkewehrum M. , Oesser S. , Nebermann L. , Schulze C.
Published: April 2003

Background and Purpose: Enteral applied bovine colostrum can significantly reduce endotoxin concentration in plasma. Since colostrum is a mixture of biological active ingredients 3 possible substances which are able to influence the endotoxin elimination were concentrated in 3 different colostrum products. Immunoglobulin-, lactoferrin- and casein-enriched colostra and lactoferrin alone were orally administered to endotoxinaemic rats. Methods: Endotoxinaemia was induced to rats by enteral application of 1010E. coli together with 40 mg Nebacetin. Control animals received albumin. From all rats plasma samples were taken over the time of 5 h and endotoxin concentration determined with limulus lysate and chromogenic substrate. Results: Whereas in control animals as well as in animals treated with casein-enriched colostrum a marked increase of endotoxin values to over 130 EU/dl could be observed after 5 h, the oral application of gammaglobulin-enriched and especially lactoferrin-enriched colostrum decreased endotoxin values by more than 50%. The most effective endotoxin elimination was seen with lactoferrin alone. Conclusions: From this results it can be concluded that not only gammaglobulin but especially lactoferrin seems to be responsible for the elimination of endotoxin with regard to enterally applied colostrum preparations.
The Marginated Pool
Authors: Kuebler Wolfgang M. , Goetz Alwin E.
Published: April 2003

The pulmonary circulation harbors a large intravascular reservoir of leukocytes refered to as the Marginated Pool. This marginated pool is balanced by propeling and retaining forces acting on leukocytes during their passage through the pulmonary circulation. The present paper discusses these factors and their underlying mechanisms.
Biomarkers and Exercise Training: A Possible Missing Link between Physical Activity and Mortality Benefit in Patients with Heart Failure
Authors: Serebruany Victor L. , Davis Christopher J. , Meister Andrew F. , Atar Dan , Whellan David J. , O’Connor Christopher M.
Published: April 2003

Knowledge of the pathogenesis of congestive heart failure (CHF) has improved greatly in recent years. Nevertheless, this disease still causes high morbidity and mortality in the Western world. In particular, there have been many advancements in our understanding, treatment and prophylaxis of CHF in recent years, yet the incidence of this disease continues to rise. Due to the staggering numbers of patients afflicted, CHF is becoming the most expensive burden on the health care system. The relationship between the deterioration of cardiac function and ongoing ischemic events has not been fully investigated and could conceivably be both monitored and modulated via various biomarkers. Recent data also indicate that heart failure is associated with altered hemostasis, i.e. a prothrombotic state which can lead to complications arising from occlusive and/or thromboembolic phenomena. Although the incidence of overt and clinically apparent thrombotic events is low, it is possible that subclinical events contribute to the increasing morbidity and mortality from this disease. These subclinical events may include silent ischemic events or microinfarcts which are being recognized as contributing to the progression of heart failure. As far as nonpharmacologic approaches to heart failure are concerned, the use of uniform exercise training regimens in heart failure is still a very controversial topic. Before more definitive recommendations can be made regarding the justification of such procedures, further large-scale studies investigating the effects of physical exercise on the development and progression of heart failure are needed. Furthermore, these studies must have sufficient statistical power to detect effects on clinical outcomes, specifically mortality. The purpose of this review article is to bridge the gap between biomarkers, exercise training and heart failure by discussing our current knowledge of different markers of platelet activation, thrombin generation, inflammation, endothelial dysfunction and myocardial necrosis in CHF patients undertaking physical exercise.
Neutral Peptidase Inhibitors
Authors: Ray Indranill Basu , Reddy Kathi Narasimha
Published: April 2003

End-stage heart disease has a high mortality. Despite considerable advancement in therapy, the overall prognosis remains dismal. This has spurred the search for newer agents that can effectively attenuate the aberrant physiological changes evident in heart failure. Multiple clinical trials have made it evident that opposing the aberrant neurohormonal stimulation is associated with a better outcome. Thus ACE inhibitors which reduce afterload by reducing the formation of angiotensin II have a better effect on mortality and morbidity than hydralazine, a direct vasodilator. Similarly, certain studies albeit small ones have shown that natriuretic agents which promote diuresis by augmenting the body’s defence against the abnormal neurohormonal milieu evident in heart failure might have a better effect on long-term prognosis than the symptomatically much more effective diuretics. These findings have led to the development of novel agents that not only block the overstimulated renin-angiotensin system but also augment the natriuretic peptide system, the body’s defence against the abnormal neurohormonal milieu that is evident in heart failure. This article reviews the clinical pharmacology of novel agents that augment the natriuretic peptide system in the body.
Treatment of Atrial Fibrillation and Flutter: Focus on Oral Dofetilide, a New Selective Class III Antiarrhythmic Agent
Authors: Chong Pang H. , Franklin Cory , Yim Barbara T.
Published: April 2003

Atrial fibrillation and atrial flutter, the most common forms of supraventricular tachyarrhythmias, are associated with a high risk of embolic complications, tachycardia-induced ventricular dysfunction, and disabling symptoms. Pharmacological therapy is used to restore or maintain sinus rhythm, prevent recurrences, or control ventricular response rate. The selection of an antiarrhythmic drug for maintenance of sinus rhythm following termination of persistent atrial fibrillation or flutter should balance clinical effectiveness against the potential for adverse events. The risk of drug-induced proarrhythmias is a pertinent safety concern, particularly in patients with underlying structural heart disease. One specific proarrhythmia, polymorphic ventricular tachycardia, commonly known as torsade de pointes, is associated with QT interval prolongation as a result of sodium and potassium channel blockade, observed with the use of class IA and III drugs, respectively. Dofetilide is a new class III antiarrhythmic drug that works by selective potassium channel blockade. As an extension of its pharmacological action, it may exhibit dose-dependent QT prolongation and torsade de pointes. This review focuses on treatment of atrial fibrillation and atrial flutter emphasizing the drug profile of oral dofetilide, its use in clinical studies, and its role in treatment of these arrhythmias.
Selective Serotonin Reuptake Inhibitors: Future Treatment of Vascular Disease?
Authors: Malinin Alex I. , Atar Dan , Serebruany Victor L.
Published: April 2003

There is substantial clinical evidence today that the incidence of depression and mortality after acute coronary syndromes are strongly related. The main effectors of coronary thrombosis are platelets, and hence, alterations of platelets and their functional characteristics may represent a conceptual bridge between these events. Selective serotonin reuptake inhibitors (SSRI), such as sertraline, have become an established therapy in patients with depression. These drugs provide not only a safe blockade of serotonin reuptake in the brain, but also in platelets, thus potentially protecting them from activation. However, the ability of sertraline therapy to deliver clinically meaningful antiplatelet effects and reduce thrombotic events, particularly acute coronary syndromes, is yet unexplored. Nevertheless, the platelet-related properties of SSRI may strongly affect the incidence of complications in patients with ischemic heart disease. Moreover, even marginal clinical benefits, together with recently reported severe bleeding events in some patients receiving oral platelet glycoprotein IIb/IIIa therapy, may potentially advance sertraline as a safe and efficient adjunct to the current therapeutic approach to the acute coronary syndrome. Further well-designed and carefully conducted clinical trials should elucidate the potential benefits of SSRI in an expanding array of clinical conditions, including myocardial infarction and unstable angina, with a prospect of SSRI to become suitable drugs, for example, in the convalescent phase of an ischemic event.
Changes of Sequestered Leukocytes and Platelets by Inhalation Prostaglandin E1 in the Pulmonary Microvasculature of Rats with Monocrotaline-Induced Pulmonary Hypertension
Authors: Kato Shiro , Kishiro Izumi , Sugimura Hiroyuki , Machida Suguru , Fuse Daisuke , Kaneko Noboru
Published: April 2003

The role of leukocytes (WBCs) and platelets (PLTs) in the pulmonary circulation may be important in the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. We investigated the suppressive effects of long-term prostaglandin E1 (PGE1) aerosol on the changes in WBCs and PLTs in the peripheral blood and the pulmonary microvasculature during the development of chronic pulmonary hypertension in MCT rats by real-time confocal scanning laser microscopy. The number of WBCs and PLTs in peripheral blood did not significantly change by inhalation of PGE1. The number of WBCs and PLTs sequestered in the pulmonary microvasculature of rats subjected PGE1 inhalation immediately after MCT injection rats with (MCT plus PGE1 inhalation) significantly decreased from 1 to 4 weeks compared to rats not subjected to PGE1 inhalation (p < 0.01). The pulmonary systolic arterial pressure and the weight ratio of the right ventricle to the intraventricular septum plus the left ventricle (RV/IVS + LV weight ratio or RV weight ratio) in rats with MCT plus PGE1 inhalation significantly decreased compared to rats not subjected to PGE1 inhalation (p < 0.01). The levels of peripheral CD62L-positive WBCs in rats with MCT plus PGE1 inhalation significantly decreased from 1 to 2 weeks compared to rats not subjected to PGE1 inhalation, but the levels of peripheral CD18 and CD49d-positive WBCs did not significantly change. We conclude that long-term inhalation of PGE1 is a very useful therapy in chronic pulmonary hypertension, and the mechanism of suppressing pulmonary hypertension is associated with suppressive effects on sequestered WBCs, especially CD62-positive WBCs and PLTs in the pulmonary microvasculature.
Elevated Levels of Serum Prolactin in Patients with Advanced Multiple Myeloma
Authors: Gadó Klára , Rimanóczi Éva , Hasitz Ágnes , Gigler Gábor , Tóth Béla E. , Nagy György M. , Pálóczi Katalin , Domján Gyula
Published: April 2003

Background and Objective: The role of prolactin in immunoregulation and normal hemopoiesis is well known. However, prolactin also seems to be involved in the pathomechanism of malignancies and autoimmune diseases. Elevated serum prolactin levels were reported in patients with malignant lymphoma, colon and breast carcinoma, systemic lupus erythematosus and rheumatoid arthritis. Recently we demonstrated prolactin immunostaining in bone marrow cells of patients with multiple myeloma. Design and Methods: Serum prolactin levels of 56 patients with multiple myeloma, as well as serum β2-microglobulin, and interleukin-6 concentrations were determined in this study. Results: Patients with advanced disease showed a significant increase in serum prolactin concentration, while patients with a clinical stage of I and II, and also control patients had normal values. The concentration of serum β2-microglobulin and interleukin-6 changed in parallel with that of serum prolactin in patients with multiple myeloma. Determining serum prolactin levels several times during the disease process in a given patient clearly showed that the prolactin concentration was increasing during the disease progression. Interpretation and Conclusions: Our results indicate a role of prolactin in disease progression in multiple myeloma.
Prostate-Specific Antigen in Hemodialysis Patients and the Influence of Dialysis in Its Levels
Authors: Tzanakis Ioannis , Kazoulis Savas , Girousis Nikolaos , Kagia Stella , Spandidakis Vlassis , Karefillakis Nektarios , Georgila Maria , Cristoulakis Ioannis , Hatzilias Petros , Kallivretakis Nikolaos
Published: April 2003

The determination of prostate-specific antigen (PSA) is a useful tool in the diagnosis and follow-up of prostate cancer in males, but its diagnostic validity is uncertain in hemodialysis patients. We prospectively evaluated PSA in male hemodialysis patients as well as the influence of a single dialytic session on its levels. We measured pre- and postdialysis total PSA (tPSA) in 63 hemodialysis patients (mean age 68.44 ± 11.16 years, range 33–86 years) who had received dialysis with low flux membranes as well as in 729 normal subjects (mean age 63.22 ± 16.85 years, range 28–92 years). We also measured pre- and postdialysis hematocrit (Hct) in patients in order to estimate the degree of hemoconcentration after the dialysis session. If any of the examined patients or subjects had abnormal tPSA levels then free PSA (fPSA) and the f/tPSA ratio were additionally measured. Patients had lower levels of tPSA compared with those of the subjects (2.41 ± 4.06 vs. 3.76 ± 7.16 ng/ml, p < 0.05) while both of the two groups had near equal prevalence of individuals with abnormal values of tPSA or f/tPSA ratio (patients 12.69 and 7.93%, subjects 11.01 and 7.11%, respectively; nonsignificant. Dialysis resulted in a 9.48% increase in mean tPSA levels (2.41 ± 4.06 vs. 2.69 ± 4.06 ng/ml, nonsignificant) and in a 10.09% increase in mean Hct; the correlation between these increases was significant (r = 0.79, p < 0.001). In conclusion, our male hemodialysis patients had lower PSA levels compared with the general population, while both groups of individuals had a similar prevalence of abnormal values of tPSA and f/tPSA ratio. Dialysis with low flux membranes does not eliminate PSA and its postdialysis increase is due to hemoconcentration.
The Renal Glomerulus and Vasculature in ‘Aggregation’ Chimeric Mice
Authors: Gattone II Vincent H. , Goldowitz Daniel
Published: April 2003

In glomerular development, the glomerular epithelium is derived from the lower loop of the S-shaped renal vesicle. However, it is unclear whether the capillary endothelium is derived directly by vasculogenesis (e.g. differentiated directly from local metanephric mesenchyme) or whether they are derived by angiogenesis (i.e. derived from pre-existing vasculature in the metanephros). This question has been addressed in other laboratories using surgically created chimeric kidney model systems. In the present study, chimeric kidneys were developed by aggregating the cells from 4- to 8-cell embryos from Mus musculus with ones from Mus caroli and implanting the aggregated embryos into pseudopregnant hosts [Goldowitz D: Neuron 1989;3:705–713]. Species specific DNA clones were used in conjunction with in situ hybridization to identify the species origin of cells. Interspecies aggregate chimeras had varying proportions of renal cells derived from Mus caroli and Mus musculus; however, regions were identified in which the renal tubular and Bowman’s capsule or parietal epithelia were from one species while vessel endothelium and cells in the interstitium were from the other species. In those regions, glomeruli always contained an admixture of cells from both species however; many of the glomerular endothelial cells appear to be from the same species as the vessel endothelium and interstitial cells. These findings support the hypothesis that angiogenesis may contribute cells that help form the glomerular capillary endothelium. Most intrarenal arteries contained cells from both species. However a few vessels were found in which the endothelium was derived from one species while the smooth muscle cells were from the other species. This finding suggests that intrarenal arterial development has two cells of origin: the endothelial tube develops and is surrounded by mesenchymal cells that form the tunica media. The aggregation chimeric mouse kidney may become a useful model system for studying in situ aspects of the complex processes involved in kidney development.
Elevated Plasma Vascular Endothelial Growth Factor Levels in Non-Diabetic Predialysis Uraemia
Authors: Harper Steven J. , Downs Lee , Tomson Charles R.V. , Dwight Jeremy S.J. , Bolton Colin
Published: April 2003

Chronic renal impairment is associated with increased vascular morbidity and mortality. The pathogenesis of this aggressive vascular pathology is unknown but believed to be multi-factorial in origin. There is accumulating in vivo and in vitro evidence to suggest that the vascular endothelium is dysfunctional in uraemia, including the propensity of endothelial cells to produce VEGF in response to acidosis. There is also preliminary data to suggest abnormally increased endothelial permeability in uraemia. To investigate the potential abnormal circulating levels of VEGF in uraemia, EDTA plasma samples were collected from 20 non-diabetic predialysis patients and matched controls. Free plasma VEGF levels were detected using a commercially available ELISA kit. There were significantly higher plasma levels of VEGF predialysis group (median 351 pg/ml, range 70–636 pg/ml) compared to matched controls (median 125.5 pg/ml, range 22–450 pg/ml), p < 0.002. In conclusion, free plasma VEGF levels are high in chronic renal impairment. We hypothesise that this potent growth and permeability factor may contribute to the endothelial dysfunction of uraemia.
Molecular Analysis of Plasma α1,3-Fucosyltransferase Deficiency and Development of the Methods for Its Genotyping
Authors: Tanaka Susumu , Yazawa Shin , Noguchi Kasumi , Nishimura Toyo , Miyanaga Kazuo , Kochibe Naohisa , Poland Dennis C.W. , van Dijk Willem , Matta Khushi L.
Published: April 2003

Four patients with mental illness were found to be deficient in plasma α1,3-fucosyltransferase for the first time in Japan [Exp Clin Immunogenet 1999;16:125–130]. Complete sequencing of FUT6 genes in these individuals revealed the presence of two point mutations, i.e., G739 to A (Glu→247 to Lys) and C945 to A (Tyr→315 to stop). In addition to two reported alleles having G739 to A (pf1) and G739 to A and C945 to A (pf3), a new mutated allele having C945 to A (pf2) was found to be present and all the individuals who lack α1,3-fucosyltransferase activity in plasma were found to possess pf genes homozygously (pf/pf). In order to detect such lethal mutations in FUT6 genes easily, PCR-RFLP methods have also been developed and applied for the screening of FUT6 deficiency in a large number of samples which resulted in the demonstration of three additional FUT6-deficient individuals. The absence of α1,3-fucosylated molecules on α1-acid glycoprotein in plasma from all the 7 individuals was confirmed to result from the plasma α1,3-fucosyltransferase deficiency.
Lack of FasL Expression in Cultured Human Retinal Pigment Epithelial Cells
Authors: Kæstel C.G. , Madsen H.O. , Prause J.U. , Jørgensen A. , Liang Y. , la Cour M. , Lui G.M. , Ødum N. , Nissen M. Holst , Röpke C.
Published: April 2003

Retinal pigment epithelial (RPE) cells have been proposed to play a part in maintaining the eye as an immune privileged organ. However, our knowledge of the implicated mechanism is still sparse. Fas ligand (FasL) expression of RPE cells is generally recognized to be essential for the immune privilege of the eye, but due to contradictory published results, it is unclear whether RPE cells express this molecule. The purpose of this study was to investigate the expression of FasL in RPE cells in vitro and in vivo. Cultured human fetal and adult RPE cells were examined by flow cytometry, Western blotting, RT-PCR and RNase Protection assay for FasL expression. Additionally, sections of ocular tissue were stained for FasL by immunohistochemistry. None of the used methods indicated FasL expression in cultured fetal or adult RPE cells of various passages. However, RPE cells in vivo, as judged from tissue sections, were positive for FasL, indicating a discrepancy between RPE cells in vitro and in vivo with regard to this molecule.
Fluoride – Is It Capable of Fighting Old and New Dental Diseases?
Authors: Brambilla Eugenio
Published: April 2003

Since researchers first became aware of the anticaries action of fluoride, they have been investigating the effect of this preventive agent in inhibiting or arresting caries development. Many forms of systemic or topical fluoride have been studied and tested for clinical application. Water, salt, milk fluoridation and the use of fluoride supplements were introduced for systemic fluoridation mainly using sodium fluoride. Solutions, gels, toothpastes and rinses of sodium fluoride, stannous fluoride, amine fluorides, acidulated phosphate fluoride and monofluorophosphate were used for topical fluoridation. More recently nonaqueous fluoride varnishes in an alcoholic solution of natural resins and difluorosilane agents in a polyurethane matrix were introduced. Although all of these fluoridation methods have a caries-preventive action, these benefits and the ease of application is variable. As fluoride is a key component of oral health promotion a coordinated approach on a community and individual basis seems to be needed to maximize the cost-benefit ratio of prevention.
Slow-Release Devices for Fluoride Delivery to High-Risk Individuals
Authors: Toumba K.J.
Published: April 2003

The latest fluoride research is investigating the use of slow-release devices for the long-term intra-oral provision of fluoride. 174 children aged 8 years with fluoride slow-releasing glass devices were shown to develop 67% fewer new carious teeth and 76% fewer new carious surfaces in a 2-year double-blind caries study. There were 55% fewer new occlusal fissure carious cavities showing that occlusal surfaces were also protected by the fluoride released from the devices. The fluoride devices release low levels of fluoride for at least 2 years and have great potential for use in preventing dental caries in high-caries-risk groups and irregular dental attenders in addition to a number of other applications.
How to Improve Oral Fluoride Retention?
Authors: Sjögren Karin
Published: April 2003

This paper reviews current ideas relating to oral fluoride retention after topical applications of various fluoride preparations. The oral fluoride reservoirs, which serve as a store for fluoride, gradually releasing its content into saliva, will be discussed. The present paper also deals with fluoride kinetics in the oral cavity. The answer to the title of the paper has, however, not yet been found but remains a goal for researchers studying caries prophylaxis worldwide in the search for possible ways of increasing and improving oral fluoride retention.
The Future of Preventive Programs in Countries with Different Systems for Dental Care
Authors: Seppä Liisa
Published: April 2003

From 1990 onward the decline of caries has leveled off in economically developed countries and the effectiveness of preventive programs seems to have diminished. The aim of this paper is to consider the future of caries prevention in the light of the studies conducted during the past decade. A shift from population-based prevention to a high-risk strategy has been promoted in countries where caries is strongly polarized. In Finland, however, an intensive preventive program targeted to high-risk individuals had little effect on caries increment, which suggests that the utility of a high-risk strategy is questionable. The relative effects of population-based methods have also decreased during the last decades. Although discontinuation of water fluoridation had no effect on caries in Kuopio, Finland, water fluoridation is still effective in countries with a lower level of basic prevention and a less homogenous social structure. From the standpoint of cost-effectiveness, the use of professionally applied fluoride gels has been questioned in children with a low caries rate, and the same is probably true for fluoride varnishes. In countries with a high caries rate, a low level of basic prevention, and an unorganized dental care system any preventive program seems to be effective. The importance of fluoride toothpastes as a cost-effective and feasible method of fluoride delivery is indisputable and will be so in all countries irrespective of the caries level and dental care systems. Population-based dental health education continues to be important, also in the countries where the caries rate has so far been low.
CaF2 Formation: Cariostatic Properties and Factors of Enhancing the Effect
Authors: Øgaard Bjørn
Published: April 2003

CaF2 or a CaF2-like material/phosphate-contaminated CaF2 is a major reaction product during topical treatment of dental hard tissues. Recently, evidence has suggested that CaF2 is formed not only on surfaces but also to some extent in the enamel. The minimum concentration of fluoride required for CaF2 formation is not well known and may depend on whether calcium is available from plaque fluid or only through dissolution of the dental hard tissue. Furthermore, surface adsorption of fluoride to crystals may cause local concentrations necessary for CaF2 formation. It has been suggested that CaF2 acts as a pH-controlled reservoir of fluoride. The rate-controlling factor appears to be phosphate, which controls the dissolution rate of CaF2 at high pH. Increasing fluoride concentration, prolonging the exposure time or using a fluoride solution with low pH can increase CaF2 formation. CaF2 formed at low pH contains less internal phosphate which has been shown to be less soluble. This may be of clinical significance for fluoride applied topically a few times per year.
Advantages of Lipid-Lowering Therapy in Cerebral Ischemia: Role of HMG-CoA Reductase Inhibitors
Authors: Gil-Núñez Antonio C. , Villanueva José A.
Published: April 2003

Dyslipemia as a risk factor for ischemic stroke and indications for statins in the prevention of ischemic stroke are revised. The role of cholesterol levels as a risk factor for ischemic stroke is controversial. This could be due to failures in the design of early epidemiological studies. Recent studies, however, do suggest a clearer risk relationship between cholesterol levels and ischemic stroke. Studies conducted on the prevention of ischemic heart disease (IHD) with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), using pravastatin and simvastatin, unequivocally show reductions in overall mortality, cardiovascular mortality, acute myocardial infarction and other coronary events. These studies show a reduction in the risk of ischemic stroke, and although relative risk reduction is great, absolute risk reduction is low; the reasons for this are analyzed. Apart from lipid mechanisms, statins act on the atheroma plaque; they have antithrombotic and possibly neuroprotecting properties. Statins reduce the number of strokes due to the decrease of atherothrombotic strokes, cardioembolic strokes secondary to IHD, and lacunar strokes related to atherothrombosis and probably to microatheromas. Although there are currently no specific studies available on the secondary prevention of stroke with statins, which are required to clarify certain points, according to European and American guidelines for prevention, statins would be indicated in the secondary prevention of atherothrombotic stroke, and in cardioembolic and lacunar stroke associated with clinical or silent atherosclerosis (IHD, peripheral artery disease). Patients with ischemic stroke of other etiologies, except for stroke in the young or other unusual causes, are patients with a high vascular risk (cardiac and cerebral) owing to the stroke itself, age and other vascular risk factors, and they should also be treated with statins, at least from the point of view of primary prevention of IHD. Natural statins (pravastatin and simvastatin) play an essential part in secondary prevention of ischemic stroke, together with antiaggregants, anticoagulants, angiotensin-converting enzyme inhibitors and the treatment of other vascular risk factors.
Current Oral Antiplatelet Agents to Prevent Atherothrombosis
Authors: Hankey Graeme J.
Published: April 2003

Aspirin inhibits platelet activation by irreversibly inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of serious vascular events (stroke, myocardial infarction or vascular death) by about one quarter in a range of patients with symptomatic atherosclerosis at high risk of a subsequent event. The adenosine diphosphate (ADP) receptor antagonists clopidogrel and ticlopidine are significantly more effective than aspirin in high-risk vascular patients, further reducing the odds of serious vascular events by about 10% (95% CI 2–19%) over the benefit provided by aspirin. The ADP receptor antagonists are also associated with a significant 30% reduction in the odds of gastrointestinal haemorrhage (odds ratio 0.71, 95% CI 0.59–0.86). Ticlopidine increases the odds of skin rash and of diarrhoea by more than twofold compared with aspirin, whereas clopidogrel is associated with a one-third increase in the odds of rash and of diarrhoea. Only ticlopidine increases the odds of neutropenia compared with aspirin. There is no clear evidence as yet for the benefit of dipyridamole or an oral GP IIb/IIIa receptor antagonist as single antiplatelet agents in atherothrombotic patients. Amongst high vascular risk patients, the combination of low-dose aspirin and high-dose dipyridamole is associated with about a 10% (95% CI 0–20%) reduction in the odds of a serious vascular event. Most of this reduction is due to a 23% reduction in non-fatal stroke. The size of this estimate continues to be investigated in an ongoing study of patients with transient ischaemic attack and stroke. The combined use of aspirin and ticlopidine is markedly superior to heparin, warfarin and aspirin for reducing thrombotic complications after coronary artery stenting. Clopidogrel plus aspirin has been shown to be safer than aspirin and ticlopidine in coronary stenting, and is now under long-term evaluation in unstable angina, and other conditions in which patients are at high risk of atherothrombotic events.
Imaging of White Matter Lesions
Authors: Barkhof Frederik , Scheltens Philip
Published: April 2003

Magnetic resonance imaging (MRI) is very sensitive for the detection of white matter lesions (WML), which occur even in normal ageing. Intrinsic WML should be separated from physiological changes in the ageing brain, such as periventricular caps and bands, and from dilated Virchow-Robin spaces. Genuine WML are best seen with T2-weighted sequences such as long TR dual-echo spin-echo or FLAIR (fluid-attenuated inversion recovery); the latter has the advantage of easily separating WML from CSF-like lesions. Abnormal T2 signal in MRI is not specific, and can accompany any change in tissue composition. In the work-up of WML in small vessel disease, magnetic resonance angiography can be used to rule out (concomitant) large vessel disease, and diffusion-weighted MRI to identify new ischaemic lesions (amidst pre-existing old WML). The differential diagnosis of WML includes hereditary leukodystrophies and acquired disorders. The leukodystrophies that can present in adult age include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenomyeloneuropathy, mitochondrial disorders, vanishing white matter, and cerebrotendinous xanthomatosis. These metabolic disorders typically present with symmetrical abnormalities that can be very diffuse, often with involvement of brainstem and cerebellum. Only the mitochondrial disorders tend to be more asymmetric and frequently involve the grey matter preferentially. Among the acquired white matter disorders, hypoxic-ischaemic causes are by far the most prevalent and without further clinical clues there is no need to even consider the next most common disorder, i.e. multiple sclerosis (MS). Among the nonischaemic disorders, MS is far more common than vasculitis, infection, intoxication and trauma. While vasculitis can mimic small vessel disease, MS has distinctive features with preferential involvement of the subcortical U-fibres, the corpus callosum, temporal lobes and the brainstem/cerebellum. Spinal cord lesions are very common in MS, but do not occur in normal ageing nor in small vessel disease.
New Approaches to Clinical Trials in Vascular Dementia: Memantine in Small Vessel Disease
Authors: Möbius H.J. , Stöffler A.
Published: April 2003

Although criteria for the diagnosis of vascular dementia (VaD) are established, the diagnostic concept is still controversial and there is no regulatory guidance for clinical drug development. Clinical trials in VaD present a number of pitfalls and challenges and, so far, no compound has received regulatory approval for this indication. The methodological issues of clinical VaD trials are discussed using the development of memantine for this indication as an example. In a pooled analysis of two placebo-controlled trials with the NMDA-antagonist memantine in VaD, the cognitive benefit by memantine treatment was more pronounced for patients with ‘small vessel disease’ than for those with other neuroradiological findings at baseline. In a subgroup of patients with ‘large vessel disease’ or macrolesions, there was less cognitive decline among the placebo patients. It may therefore be helpful to use predefined diagnostic subcategories in clinical studies in this indication. The findings further suggest that stroke or multiple infarctions may not be the primary reason for cognitive decline in VaD patients.
Genotyping Interleukin-10 High and Low Producers with Single-Tube Bidirectional Allele-Specific Amplification
Authors: Karhukorpi Jari , Karttunen Riitta
Published: April 2003

A simple bidirectional allele-specific PCR method is described for determining the -1082 A and G alleles in the interleukin-10 (IL-10) promoter region. This polymorphism is associated with IL-10 production capacity, and it is thus interesting to see whether different infectious and autoimmune conditions are associated with it. With our method, the A and G alleles may be studied simultaneously in a single PCR reaction, as amplification of the different alleles is performed by using 3′-mismatched and partly overlapping allele-specific upstream and downstream primers around the -1082 site. The fast and simple method described here is especially suitable for large-scale association studies.
Abnormal Organogenesis in Salivary Gland Development May Initiate Adult Onset of Autoimmune Exocrinopathy
Authors: Cha Seunghee , van Blockland Saskia C.A. , Versnel Marjan A. , Homo-Delarche Françoise , Nagashima Hiroyuki , Brayer Jason , Peck Ammon B. , Humphreys-Beher Michael G.
Published: April 2003

Objectives: Salivary gland organogenesis was evaluated in NOD mice, an animal model for autoimmune exocrinopathy, to determine when disease onset is first present in the target tissues. Methods: Submandibular glands were removed for histological, immunohistochemical and biochemical evaluation from neonatal NOD and congenic strains as well as healthy control C57BL/6 mice. Results: Histomorphological analyses of neonatal submandibular glands, the primary target for autoimmune exocrinopathy at 1 day postpartum, revealed delayed morphological differentiation during organogenesis in autoimmune-susceptible NOD mice when compared to nonsusceptible C57BL/6 mice. Acinar cell proliferation was reduced, while expression of Fas, FasL and bcl-2 were increased. Acinar cell proliferation was reduced, while expression, of Fas, FasL and bcl-2 were increased. Throughout the preweaning period (21 days) submandibular glands from NOD and NOD congenic strains aberrantly expressed an increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. Substitution of two susceptibility alleles (Idd3 and Idd5) in NOD mice resulted in an hierarchical and additive reversal of delayed organogenesis, elevated MMP-9 activity, and aberrant expression of parotid secretory protein. Discussion: NOD-derived mice whose submandibular glands showed normal organogenesis did not progress to develop autoimmune exocrinopathy. Altered organogenesis of target tissue may therefore provide a cellular microenvironment capable of activating autoimmunity.
Increased Frequency of the C3*F Allele and the Leiden Mutation of Coagulation Factor V in Patients with Severe Coronary Heart Disease Who Survived Myocardial Infarction
Authors: Császár Albert , Duba Jenõ , Melegh Béla , Kramer Judith , Szalai Csaba , Prohászka Zoltán , Karádi István , Kovács Margit , Méhes Károly , Romics László , Füst George
Published: April 2003

The aim of the present study was to compare the frequencies of the F allele of C3 complement component and the Leiden mutation of coagulation factor V in patients with severe coronary heart disease (CHD) who survived myocardial infarction (MI; group A), and those who had no MI in their case history (group B). We have determined the C3 allele frequencies by electrophoresis, and Leiden mutation by PCR in 338 patients with severe CHD and in 490 and 523 healthy controls, respectively. The C3*F allele frequency was significantly (p = 0.006) higher in group A (0.213) that in group B (0.132). A significant (p = 0.045) difference was found between ≤60-year group A (0.077) and group B (0.029) patients in the frequency of Leiden mutation. These findings indicate that the C3*F allele and the Leiden mutation may be associated with an increased risk of developing myocardial infarction in CHD patients.
Sleep and Sleep-Wake Manipulations in Bipolar Depression
Authors: Riemann Dieter , Voderholzer Ulrich , Berger Mathias
Published: April 2003

In the last 30 years, it has been convincingly demonstrated that sleep in major depression is characterized by disturbances of sleep continuity, a reduction of slow wave sleep, a disinhibition of REM sleep including a shortening of REM latency (i.e. the time between sleep onset and the occurrence of the first REM period) and an increase in REM density. Furthermore, manipulations of the sleep-wake cycle like total or partial sleep deprivation or phase advance of the sleep period have been proven to be effective therapeutic strategies for patients with unipolar depression. The database concerning sleep and sleep-wake manipulations in bipolar disorder in comparison is not yet as extensive. Studies investigating sleep in bipolar depression suggest that during the depressed phase sleep shows the same stigmata as in unipolar depression. During the hypomanic or manic phase, sleep is even more curtailed, though subjectively not experienced as disturbing by the patients. REM sleep disinhibition is present as well. An important issue is the question, whether sleep-wake manipulations can also be applied in patients with bipolar depression. Work by others and our own studies indicate that sleep deprivation and a phase advance of the sleep period can be used to treat bipolar patients during the depressed phase. The risk of a switch into hypomania or mania does not seem to be more pronounced than the risk with typical pharmacological antidepressant treatment. For patients with mania, sleep deprivation is not an adequate treatment – in contrast, treatment strategies aiming at stabilizing a regular sleep-wake schedule are indicated.
Clozapine as Add-On Medication in the Maintenance Treatment of Bipolar and Schizoaffective Disorders
Authors: Hummel B. , Dittmann S. , Forsthoff A. , Matzner N. , Amann B. , Grunze H.
Published: April 2003

Atypical neuroleptics are increasingly used in the treatment of bipolar and schizoaffective disorders. Currently, numerous controlled short-term studies are available for clozapine, olanzapine, risperidone or quetiapine, but long-term data are still missing. Three patients (2 with bipolar disorder, 1 with schizoaffective disorder) are described who showed a marked reduction of affective symptomatology after clozapine had been added to mood stabilizer pretreatment. The patients were seen once a month before and after the introduction of clozapine for at least 6 months. Treatment response was evaluated using different rating scales (IDS, YMRS; GAF; CGI-BP) and the NIMH Life Chart Methodology. All patients showed a marked improvement after the add-on treatment with clozapine had been initiated. Clozapine was tolerated well with only transient and moderate weight gain and fatigue as only side effects. This case series underlines the safety and efficacy of clozapine as add-on medication in the treatment of bipolar and schizoaffective disorders.
The Influence of Familial Loading on the Course of Schizophrenic Symptoms and the Success of Psychoeducational Therapy
Authors: Feldmann Reinhold , Hornung W.-Peter , Buchkremer Gerd , Arolt Volker
Published: April 2003

This prospective study examines the influence of familial loading on the course of schizophrenic illness and the extent to which this is modifiable by psychoeducational training as a form of psychotherapy. 182 schizophrenic patients enrolled in the study were allocated at random into four different treatment groups and one control group. 40% of the patients had mentally ill relatives, 20% with some form of schizophrenia. Patients attending the treatment group and those in the control group were examined before and immediately after psychoeducational training and at 2-year and 5-year follow-ups. Control group patients with mentally ill relatives displayed a significant increase in psychopathological symptoms and rehospitalization rate compared to those without. The psychoeducational training arrested or even improved the increase in psychopathological symptoms in patients with mentally ill relatives. Familial loading contributes substantially to a high rehospitalization rate and a poor outcome in schizophrenic patients. Psychoeducational interventions are an appropriate means of arresting this unfavorable development.
Worry and Anxiety: Is There a Causal Relationship?
Authors: Gana Kamel , Martin Bettina , Canouet Marie-Dominique
Published: April 2003

The aim of this study was to examine the relationship between worry and anxiety and depression. Path analysis was used to estimate a nonrecursive model which describes the reciprocal causal relation between worry and anxiety. The final model fits the data well and leads to the conclusion that the association between these two constructs is not bidirectional. Indeed, we observed a significant positive effect of worry on anxiety, but no effect in the opposite direction. This result provides a supporting argument for researchers wishing to distinguish these two constructs. Moreover, depression is not directly affected by worry, but is indirectly affected through anxiety.
Physiological Changes Associated with Downsizing of Personnel and Reorganisation in the Health Care Sector
Authors: Hertting Anna , Theorell Töres
Published: April 2003

Background: The objective of this study was to assess potential physiological changes associated with downsizing/reorganisation in the health care sector. The personnel reductions (1995–1997) in the studied regional hospital corresponded to one fifth of the personnel. Methods: In a longitudinal study, female personnel had blood sampled twice (8 a.m. and 4 p.m.) during a working day in 1997 (in connection with the last completed round of personnel redundancies) and 1 year later in 1998. The participants were 31 women (82% of those initially sampled ); there were 14 registered nurses, 11 assistant nurses and 6 medical secretaries. No additional drop outs took place during follow-up. Outcome variables were changes in the difference in serum cortisol levels between the morning and afternoon and in serum/plasma concentrations of immunoglobulin G (IgG), oestradiol, dehydroepiandrosterone sulphate (DHEAS), prolactin and apolipoproteins AI and B. Results: Significantly decreased serum/plasma concentrations of IgG (p < 0.001), apolipoprotein AI (p < 0.001) and oestradiol (p < 0.001) were found. The difference between morning and afternoon serum cortisol decreased, with a change at the significance level of p = 0.05. No significant changes were observed regarding prolactin, DHEAS and apolipoprotein B. Conclusions: These results could be an indication that protective and anabolic functions had suffered in these remaining ‘ageing’ female work groups. The circadian cortisol rhythm was possibly flattened, which could be a sign of physiological dysfunction associated with the long-lasting adaptation process. These conclusions are tentative, given the small size of the sample and the lack of a control group. However, the findings point to the significance of studies of physiological changes possibly associated with restructuring of the health care sector.
Validation of a Central Review Board of Staging prior to Surgery for Non-Small-Cell Lung Cancer – Impact on Prognosis: A Multicenter Study
Authors: López-Encuentra Angel , Goméz de la Cámara Agustín
Published: April 2003

Background: In non-small-cell lung cancer (NSCLC), the evaluation of anatomic tumor extension [tumor, node, metastasis (TNM) stage] is indispensable for the exchange of scientific information or determining prognosis. Objective: To quantify changes in TNM stages (numerical migration) and survival (prognostic migration) resulting from the application of classificatory certainty criteria to patients with NSCLC who had undergone surgical treatment. Methods: The study population included 1,844 patients registered by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S). For every patient, two evaluations were made of each component of the TNM classification: an initial classification, defined by a local representative, and a confirmed classification resulting from the application of stricter classificatory criteria by the GCCB-S Central Review Board. Results: The results revealed scant numerical migration in the cT category (11.5% of the study population) and a general tendency toward a downstaging. In contrast, the initial cN1 category experienced a complete numerical migration and the initial cN2 category a very large numerical migration (from 200 to 22 cases). In the small group of patients for whom there was a classificatory change in cT (n = 212), the migration for the cT2 category was accompanied by a less favorable prognosis (p = 0.039, log-rank test). However, the migration of this small subset of patients did not affect the general prognosis of the study population for cT2. In cN2, the 3-year survival rate migrated from 0.42 to 0.29. Conclusions: Numerical migration resulting from the application of stricter classificatory criteria was relevant, but had little, although unfavorable, global prognostic impact.