bluuebunny/crossref_metadata_2025 huggingface dataset:
Down Syndrome Cell Adhesion Molecule is conserved in mouse and highly expressed in the adult mouse brain
Authors: Barlow G.M. , Micales B. , Lyons G.E. , Korenberg J.R.
Published: April 2003

Down Syndrome (DS) is a major cause of mental retardation and is associated with characteristic well-defined although subtle brain abnormalities, many of which arise after birth, with particular defects in the cortex, hippocampus and cerebellum. The neural cell adhesion molecule DSCAM (Down syndrome cell adhesion molecule) maps to 21q22.2→q22.3, a region associated with DS mental retardation, and is expressed largely in the neurons of the central and peripheral nervous systems during development. In order to evaluate the contribution of DSCAM to postnatal morphogenetic and cognitive processes, we have analyzed the expression of the mouse DSCAM homolog, Dscam, in the adult mouse brain from 1 through 21 months of age. We have found that Dscam is widely expressed in the brain throughout adult life, with strongest levels in the cortex, the mitral and granular layers of the olfactory bulb, the granule cells of the dentate gyrus and the pyramidal cells of the CA1, CA2 and CA3 regions, the ventroposterior lateral nuclei of the thalamus, and in the Purkinje cells of the cerebellum. Dscam is also expressed ventrally in the adult spinal cord. Given the homology of DSCAM to cell adhesion molecules involved in development and synaptic plasticity, and its demonstrated role in axon guidance, we propose that DSCAM overexpression contributes not only to the structural defects seen in these regions of the DS brain, but also to the defects of learning and memory seen in adults with DS.
The canine ERBB2 gene maps to a chromosome region frequently affected by aberrations in tumors of the dog (Canis familiaris)
Authors: Murua Escobar H. , Becker K. , Bullerdiek J. , Nolte I.
Published: April 2003

The dog offers an increasingly important model for several human diseases, including cancer. Accordingly, the results of canine gene mapping studies will be of considerable significance. Herein, we have addressed the mapping of the canine gene ERBB2 (alias HER2, NEU). ERBB2 is a protooncogene encoding a tyrosine kinase receptor protein, the overexpression of which correlates with a more rapid progression and a worse prognosis in breast cancer. In addition, it apparently plays a role in the development of other tumors as well. By fluorescence in situ hybridization (FISH), we have mapped the canine ERBB2 to 1q13.1. Cytogenetic studies of canine tumors revealed that this region is very often affected by clonal chromosome aberrations in tumors of the dog.
Advantage of Expressing the Variations in Some Digestive Parameters as a Function of Gastric Emptying instead of Time
Authors: Carrière Frédéric , Renou Christophe , Ville Eric , Grandval Philippe , Laugier René
Published: April 2003

Background/Aim: Gastric emptying is a major cause of variability when studying gastrointestinal parameters as a function of time. Here, we investigate whether the parametric variability could be reduced by running experiments on a gastric emptying basis rather than on a time basis. Methods: Healthy volunteers were intubated with gastric and duodenal tubes and were given a liquid meal containing polyethylene glycol to monitor gastric emptying. Gastric pH and human gastric lipase (HGL) concentrations were measured. Their variations were plotted as a function of either time or gastric emptying (%). In both cases, mean curves of variation were established by polynomial regression. Results: When time was the variable used, the overall deviation of the experimental values from the values given by the best-fitting curve was high (χ2 = 33 for gastric pH; χ2 = 1,744 for HGL), and the individual deviations increased with time. When gastric emptying was the variable used, the overall deviation of the experimental values from the values given by the best-fitting curve was much lower (χ2 = 10 for gastric pH; χ2 = 642 for HGL). Conclusions: Expressing gastric pH or HGL concentration as a function of gastric emptying instead of time makes it possible to reduce the individual variability. This new type of data analysis may be of a general interest to observe specific variations of gastrointestinal parameters induced by drugs, hormones, and meals, and that might be masked by the large intrinsic variability induced by gastric emptying.
Pioglitazone Inhibits Growth of Carcinoid Cells and Promotes TRAIL-Induced Apoptosis by Induction of p21waf1/cip1
Authors: Göke Rüdiger , Göke Alexandra , Göke Burkhard , El-Deiry Wafik S. , Chen Youhai
Published: April 2003

Background/Aims: We investigated the effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on growth and TRAIL-induced apoptosis in carcinoid cells. Methods: Carcinoid cells were incubated without and with pioglitazone. Effects on growth were examined by cell count and cell cycle analysis. p21waf1/cip1 expression was determined by Western blotting. Cytotoxicity assay was performed by FACS analysis. Results: Pioglitazone suppressed the growth and induced apoptosis of carcinoid cells. Additionally, pioglitazone significantly enhanced carcinoid cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The enhancement of TRAIL-induced apoptosis was associated with an upregulation of cyclin-dependent kinase inhibitor p21waf1/cip1 in pioglitazone-treated carcinoid cells. Importantly, overexpression of p21waf1/cip1 in carcinoid cells by adenoviral gene transfer of p21 sensitized them to TRAIL-induced apoptosis. Conclusions: These results suggest that pioglitazone inhibits cell growth and sensitizes cells to TRAIL-induced apoptosis by induction of p21waf1/cip1. Therefore, pioglitazone can be an effective therapeutic adjuvant for the treatment of carcinoid tumors.
Acupuncture Treatment for Irritable Bowel Syndrome
Authors: Fireman Zvi , Segal Arieh , Kopelman Yael , Sternberg Amos , Carasso Rafael
Published: April 2003

Background/Aim: Irritable bowel syndrome is one of the most common gastrointestinal disorders in Western society, affecting around 15% of the population, especially young adults. The cause(s) of irritable bowel syndrome and effective treatment(s) have remained elusive. This study aimed at exploring the therapeutic value of acupuncture by comparing the responses of irritable bowel syndrome sufferers to true acupuncture versus sham acupuncture in a controlled double-blind study. Methods: Twenty-five patients who fulfilled the Rome criteria (irritable bowel syndrome symptoms persisting for more than 1 year) comprised the final study population. They were recruited through a ‘call for’ bulletin sent to gastroenterologists practicing in the region of our medical center. True acupuncture was performed at LI-4 (colonic meridian, needle only) and sham acupuncture at BL-60 (urinary vesicle meridian, needle only). Patient assignment to one of the two groups was random. Results: The effect of the first true acupuncture on overall symptoms and abdominal pain was a clear and significant improvement (p = 0.05). No comparable effect was seen in the second session. Conclusions: Although the true acupuncture results were consistently better, no difference was found between the two groups in the overall statistical analysis. We could not show a therapeutic benefit of this treatment modality in irritable bowel syndrome.
Changes in the E-Cadherin-Catenin Complex Expression in Early and Advanced Gastric Cancers
Authors: Joo Young-Eun , Rew Jong-Sun , Kim Hyun-Soo , Choi Sung-Kyu , Park Chang-Soo , Kim Sei-Jong
Published: April 2003

Background/Aim: In various human cancers, dysfunction of the E-cadherin-catenin complex is associated with a decrease in cellular and tissue differentiation and with higher invasive and metastatic potentials. Since advanced gastric cancers are thought to evolve from early gastric cancers, we investigated whether differences of the E-cadherin-catenin complex expression can be observed between early and advanced gastric cancers. Methods: We have used an immunohistochemical technique to localize E-cadherin and α-, β-, and γ-catenins in 114 formalin-fixed, paraffin-embedded tissue blocks: 57 from patients with early gastric cancer and 57 from patients with advanced gastric cancer. Results: The immunoreactivity of E-cadherin and α-, β-, and γ-catenins was expressed by normal gastric epithelial cells with strong membranous staining at the intercellular border. Reduced expression of E-cadherin and α-, β-, and γ-catenins occurred in a considerable proportion of both cancer groups. However, no significant difference was seen between early and advanced cancer groups. In the early cancer group, reduced expression of E-cadherin and α-, β-, and γ-catenins correlated with diffuse type of cancer and poor differentiation. However, in the advanced cancer group, reduced expression of the three adhesion molecules, but not β-catenin, correlated with diffuse type of cancer and poor differentiation. The expression of E-cadherin and α-, β-, and γ-catenins did not correlate with depth of invasion or lymph node metastases in both cancer groups. Conclusion: These results suggest that alterations of the E-cadherin-catenin complex may be induced at an early stage of gastric tumorigenesis and may be associated with poorly differentiated and diffuse-type pathways in gastric tumorigenesis.
Medical Treatment of Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
Authors: Holtmeier Julia , Leuschner Ulrich
Published: April 2003

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscropic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.
Mechanisms of Lectin (Phytohemagglutinin)-Induced Growth in Small Intestinal Epithelial Cells
Authors: Otte Jan-Michel , Chen Chunxiao , Brunke Gabriele , Kiehne Karlheinz , Schmitz Frank , Fölsch Ulrich R. , Herzig Karl-Heinz
Published: April 2003

Background/Aims: The lectin phytohemagglutinin is a mitogen for intestinal epithelial cells in vivo. The mechanisms of action are unknown and were therefore analyzed in vitro. Methods: Human (Intestine-407) and rat (IEC-6; IEC-18) intestinal epithelial cell lines were stimulated with phytohemagglutinin. Proliferation was assayed by 3H-thymidine incorporation, activation of mitogen-activated protein kinase (MAPK) by Western blotting, and induction of c-fos mRNA expression by semiquantitative polymerase chain reaction. Control experiments were performed with phenyl-N-acetyl-α-D-galactosaminide or the tyrosine kinase inhibitor tyrphostin A25. Results: Phytohemagglutinin (0.1 µg/ml) significantly stimulated proliferation in all three cell lines after 48–72 h. MAPK activation was detected after 15–30 min, and an induction of c-fos mRNA expression after 15– 30 min of stimulation. Mitogenic effects were blocked by preincubation with phenyl-N-acetyl-α-D-galactosaminide or tyrphostin A25. Conclusion: Phytohemagglutinin stimulated proliferation, MAPK activation and induction of c-fos mRNA expression. The lectin may contribute to intestinal mucosal growth and regeneration thereby preventing gut atrophy.
Cyclooxygenase 2 Expression in Chronic Pancreatitis: Correlation with Stage of the Disease and Diabetes mellitus
Authors: Koliopanos Alexander , Friess Helmut , Kleeff Jörg , Roggo Antoine , Zimmermann Arthur , Büchler Markus W.
Published: April 2003

Background: Fibrotic replacement of the exocrine pancreatic parenchyma and infiltration of inflammatory cells are the main characteristics of chronic pancreatitis (CP). Inflammation involves prostaglandin production in numerous inflammatory and noninflammatory cells, and cyclooxygenase 2 (COX-2) is the dominant regulator of prostaglandin synthesis. Aims: In the present study, we analyzed the expression of COX-2, the key enzyme for prostaglandin synthesis in pancreatic tissues, and evaluated its relation to exocrine and endocrine tissue alterations in CP. Patients and Methods: Pancreatic tissue specimens from 27 patients undergoing pancreatic head resection for CP were included in the study. Pancreatic tissues from 14 organ donors served as controls. The tissue specimens were analyzed histopathologically and for COX-2 immunoreactivity. Results: In normal pancreatic tissue samples, COX-2 immunoreactivity was restricted to islet cells. In contrast, in early-stage CP, islets as well as ductal cells showed intense COX-2 immunoreactivity. In advanced-stage CP, ductal cells were still strongly positive for COX-2, yet islets displayed a variable COX-2 staining pattern which was associated with the distribution of insulin-positive cells and with the clinical diabetes mellitus status of the patient. Thus, patients with normal or latent diabetes mellitus status showed COX-2 immunoreactivity, whereas in diabetic patients the COX-2 immunoreactivity was decreased or absent in pancreatic islets. Conclusion: The presence of COX-2 in ductal cells of early and advanced CP, the relationship between COX-2 and insulin expression in the islets, and the diabetes mellitus status of CP patients suggest that this enzyme plays a role in the pathogenesis of exocrine and endocrine damage in CP.
The Interpretation of Shared Age-Related Variance among Factors in Cross-Sectional Cognitive Aging Studies
Authors: Anstey Kaarin
Published: April 2003

Many cross-sectional correlational studies in cognitive aging have focused on explaining age-related variance. It has been assumed that variables sharing variance with both cognition and age may be the key explanatory variables underlying the cognitive decline in normal aging. Statistical biases intrinsic to this approach have been described by Hofer and Sliwinski and a narrow age cohort design proposed. The present paper aims at explaining how Hofer and Sliwinski’s criticisms apply to a specific type of research design in cognitive aging where the goal is to identify underlying aging processes, but does not apply to more general gerontological research. Methods to estimate bias in cross-sectional studies are required as is greater awareness of this potential bias.
Age Is Not Necessarily Aging: Another Step towards Understanding the ‘Clocks’ That Time Aging
Authors: Li Shu-Chen , Schmiedek Florian
Published: April 2003

Hofer and Sliwinski raise a critical concern regarding a popular practice in aging research of inferring associations among aging changes of different processes from correlations based on cross-sectional age differences. It is shown analytically that cross-sectional information drawn from age-heterogeneous samples is not suitable for answering questions about the interdependence between aging changes. While in general we agree with the problem pointed out by Hofer and Sliwinski, the two aims of this commentary are: (1) to highlight links between the specific concern and two long-standing issues confronting life-span researchers and (2) to introduce alternative approaches that are currently underutilized in gerontological research. We elaborate general issues with respect to challenges in inferring aging changes from age differences and using age as a proxy for aging. We show that several other sources of variance independent of rates of change, such as cohort- and mortality-related selection effects, are confounded in age-heterogeneous designs. We suggest general considerations for developing more explicit theories of cognitive aging in the future. Alternative research methods and paradigms for studying the causes and mechanisms of the aging mind at different time scales and levels are also highlighted. The role of chronological age in aging research is rather ‘superficial’. To understand the underlying processes and mechanisms of cognitive aging, classical process-oriented, rather than solely age-oriented, theoretical conceptions need to be reconsidered and reified with new methodological and empirical advances. Concerted gerontological research endeavors utilizing recent progresses made in statistical analyses of dynamic processes and in cognitive and computational neurosciences that may lead to fruitful breakthroughs.
Uncertainties in the Pharmacotherapy of Parkinson’s Disease and How to Solve Them
Authors: Overstall P.W. , Clarke C.E.
Published: April 2003

The causative relationship between levodopa and the long-term motor complications of therapy, along with the possibility that levodopa may be toxic to dopaminergic neurones in vivo, has led to a move away from its use in early Parkinson’s disease. Alternatives such as amantadine and the anticholinergics suffer from poor efficacy in comparison and a high side effect profile. Selegiline is probably less effective than levodopa and the issue of its safety versus neuroprotective properties remains unresolved. Long-term trials with the old and newer dopamine agonists as monotherapy have shown that as a class they can delay the development of dyskinesia and probably response fluctuations. However, major uncertainties remain about their use as monotherapy in all patients instead of levodopa. No data on their effect on quality of life and health care costs are available. Most of the trials were heavily biased towards younger patients with Parkinson’s disease, so little data in the elderly are available. In later disease when patients have already developed motor complications on levodopa, the choice rests between adjuvant therapy with a dopamine agonist, a catechol-O-methyltransferase inhibitor (COMT; e.g. entacapone), and a monoamine oxidase B inhibitor (MAO B; e.g. selegiline). Trials with the former two classes have confirmed that they can reduce ‘off’ time, reduce levodopa dose, and improve motor impairments and disabilities with acceptable increases in adverse events including dyskinesia. Trials with selegiline as adjuvant therapy were less rigorous but it can allow a reduction in levodopa dose and motor impairments. No studies have compared these three classes of drug as adjuvant therapy so there is no evidence on which to base rational decisions in this type of patient. A large pragmatic trial which includes older patients is needed to clarify which treatment is best for different stages of the disease.
Alterations of Sensory Perceptions in Healthy Elderly Subjects during Fasting and Refeeding
Authors: Mulligan Catherine , Moreau Karine , Brandolini Marion , Livingstone Barbara , Beaufrère Bernard , Boirie Yves
Published: April 2003

Background: Sensory perception losses may contribute to age-related malnutrition by affecting food selection and consumption. Objective: To determine the effects of a 36-hour fast followed by a 6-hour refeeding period on sensory perceptions in 7 healthy elderly subjects (65–80 years of age) and 6 healthy young subjects (18–35 years of age). Methods: Self-perceived hunger and olfactory ratings were recorded on visual analogue scales in response to three different classes of odorant stimuli (salt, sweet and sour). Odorant stimuli were administered three times during the study, twice during the fasting period (12 and 24 h fasted) and once at the end of the re-nutrition period. Results: A significant difference was found between the two groups for the self-perceived hunger ratings in response to the sour stimuli. A significant difference was observed between the two groups for olfactory ratings as regards the salt and sour odorant stimuli. Among the metabolic changes associated with fasting and refeeding, blood glucose was significantly related (r2 = 0.97, p = 0.001) to the perception of hunger in the control group subjects, but no such relationship was found for the elderly subjects (r2 = 0.16, p = NS). Conclusion: (1) Self-perceived hunger and olfactory ratings are specifically affected in healthy elderly. (2) Nutritional status can modulate sensory perceptions in elderly and young during the transition from fasting to refeeding.
Are Stress Resistance and Longevity Really Linked in Normal Living Conditions?
Authors: Le Bourg Éric
Published: April 2003

Background: The existence of a positive relationship between stress resistance and longevity is often accepted, but this conclusion mainly stems from studies putting animals in adverse conditions such as food restriction. Objective: It is argued that a positive correlation between stress resistance and longevity has not been clearly observed at the individual level in animals or humans living in nonstressful conditions. Experiments should verify this point. Conclusions: If experiments would fail to show this correlation, there would be no ground for the proposal that treatments stimulating stress resistance could increase longevity and health.
Surrogate End Points of Antihypertensive Treatment: Left Ventricular Hypertrophy and Structural Alteration of Carotid Arteries
Authors: Kozakova Michaela , Buralli Simona , Palombo Carlo , Salvetti Antonio
Published: April 2003

The present paper provides a critical overview of left ventricular hypertrophy (LVH) and structural changes of carotid arteries as surrogate end points for antihypertensive treatments. LVH is known to be associated with a number of pathophysiologic alterations underlying cardiovascular risk. The quantification of left ventricular mass is feasible and well standardized by echocardiography, even if the reproducibility of measurements is still limited. LVH has been clearly demonstrated to be an independent predictor for cardiovascular morbidity and mortality, and recent data suggest that left ventricular geometric pattern and depressed myocardial function may represent additional risk factors. Although clinical trials have shown that an adequate blood pressure control can be associated with a significant reduction in left ventricular mass, the prognostic impact of LVH regression is still debated. Serial measurements of the carotid artery intima-media complex by B-mode ultrasound have been proposed as an accurate noninvasive approach for the evaluation of progression and regression of the atherosclerotic process over time. The methodology of measurement is not as well standardized as that of LVH, and the reproducibility of measurements is too close to the magnitude of structural changes over time. In addition, sounder data are required concerning the pathophysiologic relationship between carotid lesions and clinical events.
Treatment of Diabetes mellitus by Diet Alone versus Oral Hypoglycemics versus Insulin and Outcome after Successful Percutaneous Coronary Revascularization
Authors: Hasdai David , Rizza Robert A. , Grill Diane E. , Scott Christopher G. , Garratt Kirk N. , Holmes Jr. David R.
Published: April 2003

Objective: To examine whether the outcomes of diabetic patients after successful percutaneous coronary revascularization are influenced by the modality of treatment for hyperglycemia at the time of percutaneous coronary revascularization. Design: Retrospective analysis of the Mayo Clinic PTCA Registry. Material and Methods: We examined whether the modality of treatment of diabetes mellitus (diet alone vs. oral hypoglycemics vs. insulin) impacted on the occurrence of death and death/myocardial infarction among diabetic patients after successful percutaneous coronary revascularization from January 1, 1995 through December 1998. Results: Of the 821 diabetic patients with known treatment status, 129 received diet alone, 370 oral agents, and 322 insulin. The clinical success rates of percutaneous coronary revascularization were similarly high among the groups (>90%). The adjusted risk of suffering either death or death/myocardial infarction after successful percutaneous coronary revascularization was greater for insulin-treated patients (vs. non-insulin): relative risk (95% confidence intervals) of 1.65 (0.99, 2.72) and 1.65 (1.20, 2.27), respectively. Patients treated with oral agents had lower risk of suffering death or death/myocardial infarction than insulin-treated patients (0.59 [0.36, 0.99] and 0.57 [0.38, 0.84], respectively), with a similar trend for patients on diet alone (0.96 [0.48, 1.99] and 0.65 [0.36, 1.16], respectively). Conclusions: Although the clinical success rates of PCR were similar for insulin- and non-insulin-treated diabetic patients, insulin-treated patients had worse long-term outcomes after successful percutaneous coronary revascularization.
Effect of Beta-Blockade on Postexercise Oxygen Uptake Kinetics in Patients with Chronic Heart Failure
Authors: Gianrossi Renato , Myers Jonathan , Wagner Doris , Dziekan Gerald , Bloch Robert , Angern Walter , Erne Paul , Dubach Paul
Published: April 2003

Background: Beta-blocking agents have recently been demonstrated to improve survival in chronic heart failure (CHF), but a debate exists regarding the influence of beta-blockade on exercise capacity in these patients. The time delay for oxygen uptake to return to baseline after exercise (VO2 recovery kinetics) has been shown to be related to the severity of CHF, skeletal muscle metabolic abnormalities and prognosis. We performed the present study to determine the effect of beta-blockade on VO2 recovery kinetics in patients with CHF. Methods: Twenty-five patients with CHF were randomized to 6 months of bisoprolol (n = 10, ejection fraction = 27 ± 6%) or placebo (n = 15, ejection fraction = 25 ± 5%) therapy. Bisoprolol dosage was titrated in accordance with the Cardiac Insufficiency Bisoprolol Study protocol. Before and after the study period, oxygen uptake kinetics in recovery from maximal exercise were calculated and expressed as the slope of a single exponential relation between oxygen uptake and time during the first 3 min of recovery. Results: Resting and maximal heart rates were reduced after bisoprolol therapy, by 17 (p < 0.05) and 14 (p = 0.08) beats/min, respectively. Maximal oxygen uptake was unchanged in the bisoprolol (19.0 ± 4.9 vs. 19.9 ± 4.3 ml/kg/min) and placebo (18.9 ± 3.6 vs. 19.4 ± 3.6 ml/kg/min) groups. The time constants in recovery were reduced by modest and insignificant amounts in both groups (127.2 ± 41 vs. 112.6 ± 27 s for bisoprolol and 119.5 ± 55 vs. 97.3 ± 31 s for placebo). The time constant in recovery was poorly related to peak VO2 (r = –0.10). Conclusion: In patients with CHF, beta-blockade does not influence exercise capacity or oxygen uptake recovery kinetics. While this study confirms the suppression of sympathetic drive which has been shown to have beneficial effects in CHF, these results suggest that beta-blockade has minimal effects on indices of exercise tolerance, including VO2 recovery time.
Dependency on Infarct Size Limits the Clinical Applicability of Non-Invasive Reperfusion Assessment by Biochemical Markers in Acute Myocardial Infarction
Authors: Haastrup Benedikte , Gill Sabine , Haghfelt Torben , Hørder Mogens , Kristensen Søren Risom
Published: April 2003

Background: Thrombolytic therapy often fails to obtain reperfusion in acute myocardial infarction (AMI). To allow further intervention, various methods for non-invasive reperfusion assessment, e.g. release kinetics of biochemical markers and ST segment recovery analysis on the ECG, have been proposed. Methods and Results: In 85 thrombolysed AMI patients <76 years with significant ST elevation on ECG and time delay ≤6 h, blood was drawn and ECGs recorded before and 90 min after the start of treatment. Myoglobin, creatine kinase-MB and troponin I were measured, and slopesand relative increases (RIs) of the markers were calculated. Moreover, the relative decrease in total sum of ST elevation (ST recovery0–90) on the ECG was calculated. A slope0–90 or RI0–90 below previously validated threshold values or an ST recovery <25% was considered indicative of failed reperfusion. Final infarct size was determined as cumulative release of LD1. Patients were followed for 1 year to register deaths, re-infarctions, and coronary revascularisation. The various non-invasive reperfusion indexes showed poor agreement, and no significant prognostic information was obtained. A positive correlation between increase rates and infarct size probably reflected a direct, concentration-dependent enhancement of release of biochemical markers in blood. Thereby, high-risk patients with large, non-reperfused infarcts might have been overlooked while only low-risk patients with small non-reperfused infarcts were recognised. This could readily explain the lack of correlation with long-term outcome. Conclusions: Dependency on infarct size seems to limit the usefulness of biochemical markers for reperfusion assessment. Correction for expected infarct size might improve performance in the future. At present, routine use of biochemical markers for reperfusion assessment is not justified.
Estrogen-Progestin Hormone Replacement Therapy: Evaluation of Epidemiological Studies
Authors: Beckermann Maria J.
Published: April 2003

A systematic review was carried out based on a comprehensive literature search using Medline (years 1980–2000) and the Cochrane Database, covering the topic ‘hormone replacement therapy’ (HRT). Two hundred and forty published trials have been analyzed and evaluated based on their statistical and conceptual strength. Estrogen therapy leads to lower LDL cholesterol and a higher HDL/LDL ratio. Conjugated estrogen taken orally leads to higher triglyceride levels. Progestin, however, reduces the favorable effect of estrogen on serum lipids. Other surrogate parameters such as lipoprotein(a), homocysteine, blood pressure, vessel diameter measurements, Doppler ultrasound assessment, exercise ECG, parameters of carbohydrate metabolism or clotting factors may be favorably influenced by HRT, but they cannot prove a favorable effect on cardiovascular disease in general, as long as there is no proven mortality or morbidity benefit. In 1998, the Heart and Estrogen/progestin Replacement Study showed that women with preexisting cardiovascular disease receive no benefit from long-term (4–5 years) HRT, but have an increased rate of thromboembolism, especially in the first 4 months of treatment. No data exist about the influence of very long-term (>10 years) HRT on cardiovascular disease, either for healthy women or for women with preexisting cardiovascular disease. Very long-term HRT effects might be different from short-term effects. Hence, with regard to the prevention of cardiovascular disease, the following conclusions can be drawn: there are no reliable data to unequivocably prove the benefit of long-term HRT in healthy women. On the contrary, there is a 2- to 3-fold increased risk of thrombosis and embolism in the first months of treatment. Caution should therefore be exercised when using HRT, particularly with regard to the potentially harmful adverse effects.
Cell Adhesion Molecules in Cardiovascular Pathology – A Glance into the Future?
Authors: Goudev Assen , Georgiev Dimiter , Atar Dan , Kehayov Ivan , Kyurkchiev Stanimir
Published: April 2003

Increasing evidence shows that atherosclerosis is a low-grade chronic inflammatory disease. The interaction between the arterial wall and circulating blood cells like monocytes and T lymphocytes is an important step in this inflammatory process. This interaction is mediated via transmembrane glycoprotein receptors known as cellular adhesion molecules (CAM). The expression of these molecules is provoked by a variety of cardiovascular risk factors and is under the control notably of inflammatory cytokines, hemodynamic factors, bacterial endotoxins. Recently, data from large prospective studies have shown that an increased concentration of CAM predicts an increased cardiovascular risk. There is an increasing interest in CAM as a new therapeutic target in atherosclerosis.
Transmyocardial Laser Revascularization: Established Procedure, Acupuncture of the Heart or Placebo Effect?
Authors: Eckstein Friedrich S. , Boss Annette , Frenz Martin , Schaffner Thomas , Walpoth Beat , Meier Bernhard , Carrel Thierry P.
Published: April 2003

Considering the nearly universal skepticism transmyocardial laser revascularization (TMLR) aroused a few years ago, the so-called snake heart procedure has come a long way. The notion that the human heart enjoys significant perfusion from a spongy underlay of microcapillaries and sinusoids has been embraced by hundreds of researchers who have poked away at the coronary bed with external and internal lasers, radiofrequency probes, rotary cutters and saline jets, as well as developing technologies for implanting angiogenic growth factors into and around the resultant channels. TMLR has been described as a therapeutic option for end-stage coronary artery disease when percutaneous transluminal angioplasty and surgical myocardial revascularization are no longer possible and transplantation is not indicated. While debate continues to rage among surgeons and interventionists over the best way to perform transmyocardial laser, a greater question looms over the field: how does it work? No one has been able to explain yet why the procedure works in some patients and utterly fails in others, or to convincingly substantiate the procedure’s contributions to myocardial reperfusion. A few investigators believe that the procedure’s secret lies in creating patent channels. However, mid- and long-term patency of laser-created channels seem not to be required for successful treatment as initially assumed. The development of new vessels within and around the scar following TMLR (a phenomenon called ‘neoangiogenesis’) has moved more and more to the center of attention during the last few years. Some form of angiogenesis or neovascularization around the channels is the most favored explanation now, but nobody knows how TMLR stimulates such processes or how to measure them effectively. Although prospective randomized studies have been able to demonstrate some effectiveness of this treatment, the exact mechanisms of laser revascularization are still not completely elucidated. The notion of mechanisms such as sympathetic myocardial denervation and induction of microinfarctions transforming ischemia into necrotic myocardium has been abandoned. As recently as 1996, the prospect of transmyocardial revascularization becoming a breakthrough therapy seemed exciting enough to the financial market that the stock of PLC Medical Systems, then the front-runner in the field, soared to USD 32 per share. But in only the 2nd year since receiving FDA approval, the company is now trading at around USD 1.5 a share and the laser sales have fallen below expectations. One problem may be that many hospitals do not switch on their TMLR lasers very often once they are installed, with usage estimates as low as one or two procedures per month in some centers.
EARTH: EndothelinA Receptor Antagonist Trial in Heart Failure
Authors: Lüscher Thomas F. , Ruschitzka Frank , Anand Inder , Konstam Marvin A. , McMurray John , Notter Thomas , Cohn Jay N.
Published: April 2003

Endothelin (ET) receptor blockade has been shown to have therapeutic potential in improving hemodynamics in experimental and early clinical studies of heart failure. Whether and to what degree ETA blockade improves left ventricular function and clinical symptoms, however, still remains elusive. As such, the goal of the EARTH study is to evaluate the effects of different dosages of the orally available selective ETA receptor blocker LU 135252 (darusentan) on left ventricular dimensions, mass and function, neurohormone levels and symptoms in patients with advanced chronic heart failure. Patients with chronic heart failure functional class NYHA II–IV were included in the protocol and randomly assigned to receive darusentan (10, 25, 50, 100, 300 mg/day or matching placebo) in a double-blind design. Darusentan was titrated upwards over a 6-week period, starting at 10 or 25 mg/day to a maximum of 300 mg/day with the total treatment period being 24 weeks. The primary outcome was the effect of darusentan on left ventricular function as measured by end-systolic volume using magnetic resonance imaging compared to baseline. Secondary efficacy parameters were changes in left ventricular mass, left ventricular end-diastolic volume, ejection fraction, parameter of neurohumoral activation (plasma norepinephrine, aldosterone, ANP, BNP, ET-1 and big ET-1) and clinical symptoms assessed by a 6-min walk test, quality of life, and changes in NYHA class. The sample size of at least 600 patients (100 for each treatment group) was expected to provide 80% power to detect a difference in improvement of left ventricular end-systolic volume from a baseline of 18 ml with a 5% level of significance. A positive result in the EARTH trial should stimulate the design of a large mortality/morbidity trial of ETA receptor blockers.
Potentiation of Interleukin-1β Adjuvant Effects on the Humoral Immune Response to Antigen in Adrenalectomized Mice
Authors: Kusnecov Alexander W. , Rossi-George Alba
Published: April 2003

Objectives: Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a primary effect of interleukin-1 (IL-1), with elevated glucocorticoids considered a mechanism for negative feedback immunoregulation. However, there is little direct evidence of such a functional relationship between IL-1-mediated immunoregulation and neuroendocrine influences elicited by IL-1. Therefore, the goal of this study was to examine whether the known adjuvant effects of IL-1 are altered in the absence of neuroendocrine feedback due to adrenalectomy. Methods: Male BALB/c mice subjected to adrenalectomy (ADX) or sham surgery were administered with saline or recombinant human IL-1β (rhIL-1β) and at the same time immunized with 100 µg ovalbumin (OVA). In vivo and in vitro measures of antigen-specific IgG antibody production, IL-6 production and spleen cell proliferation were taken 6 and 12 days later. Results: It was demonstrated that administration of rhIL-1β at a dose that activates the HPA axis resulted in a significant augmentation of serum anti- OVA IgG antibody levels. Interestingly, this augmentation was potentiated in ADX animals. In addition, the in vitro spleen cell memory IgG antibody response to OVA was significantly augmented in rhIL-1β-treated animals, and again, further potentiated in ADX animals. Interestingly, while hrIL-1β treatment augmented antigen-stimulated IL-6 production – suggesting an effect of IL-1 on antigen-specific T helper 2 cell memory formation – potentiation was not evident in ADX animals. Conclusions: These results are consistent with the concept of HPA axis-mediated neuroendocrine feedback on excessive immune responsiveness due to IL-1. Such feedback may prevent disturbances to the self-limiting functions of the immune system, which are important to the prevention of autoimmune diseases, some of which involve elevated IL-1 production.
Influence of Reduced Nicotinamide Adenine Dinucleotide on the Production of Interleukin-6 by Peripheral Human Blood Leukocytes
Authors: Nadlinger Karl , Birkmayer Jörg , Gebauer Frank , Kunze Rudolf
Published: April 2003

Objective: Recently, therapy with nicotinamide adenine dinucleotide (NADH) revealed positive effects on neurodegenerative disorders associated with inflammation of the CNS, such as Parkinson’s disease or Alzheimer’s disease. Pathophysiologically, focal CNS inflammation seems to be accompanied by an unbalanced cytokine production, pointing to an involvement of the immune system. Therefore, the aim of our study was to investigate whether NADH could influence cytokine release of peripheral blood leukocytes (PBLs) with special reference to interleukin-6 (IL-6). Methods: PBLs from 18 healthy donors were incubated in vitro with different concentrations of NADH to generate dose-response curves. As a control, mitogen-treated cells and unstimulated cells were included. Results: In PBLs from the 18 healthy donors, NADH significantly stimulated the dose-dependent release of IL-6, ranging from 6.25 to 400 µg/ml, compared to medium-treated cells (p < 0.001). An amount of 1,000 pg/ml IL-6 was induced by NADH concentrations ranging from 3.1 to >25 µg/ml. Conclusions: It is concluded that NADH possesses cytokine-modulating effects on peripheral blood cells. The biological relevance of these data is discussed in the context of the recent use of NADH for the treatment of several neurodegenerative disorders.
Effectiveness of Hemodialysis with High-Flux Polysulfone Membrane in the Treatment of Life-Threatening Methanol Intoxication
Authors: Peces Ramón , Alvarez Rafael
Published: April 2003

Methanol poisoning may result in metabolic acidosis, blindness and death. In this report, we describe a case of life-threatening methanol intoxication in a 44-year-old man who was treated successfully with supportive care, ethanol infusion, folic acid and early hemodialysis with a high-flux polysulfone dialyzer. We conclude that hemodialysis as implemented in this case is a safe and effective approach to the management of methanol poisoning.
β2-Microglobulin Clearance Decreases with Renalin Reuse
Authors: Castro Rui , Morgado Teresa
Published: April 2003

The HEMO study revealed that β2-microglobulin clearance decreases over time with Renalin reuse in the high-flux group. It was suggested that the reuse of polysulfone or cellulose triacetate high-flux dialyzers with Renalin (without bleach) results in degradation of the high-flux capacity. At our haemodialysis unit (Vila Real, Portugal) we reused dialyzers until January 2000 (limited to 10 reuses), with an automatic machine Renatron® (Renal Systems, Minntech®). All of our 31 patients who started with postdilution haemodiafiltration on-line (HDFol) were always dialyzed with F-80 polysulfone (Fresenius®). The reposition rate was 10 litres/session until 1998 and 20 litres/session thereafter. Reuse techniques were abandoned in our country in January 2000 following an EEC directive. Thereafter, we have decided to maintain HDFol with the same dialyzers without reuse. The mean β2-microglobulin predialysis values did not decrease over time until reuse was terminated (1995 with low-flux haemodialysis: 25.4 ± 6.4 µg/l; 1997: 24.7 ± 6.6 µg/l; 1998: 29.2 ± 8.9 µg/l; 1999: 33.7 ± 4.7 µg/l) whereas β2-microglobulin clearances were reasonable with HDFol (1998: 56.4 ± 25.9 ml/min; 1999: 47.9 ± 16.4 ml/min). After stopping reuse we have noticed that predialysis β2-microglobulin values decreased (2000: 23.0 ± 3.9 µg/l) in accordance with β2-microglobulin clearance duplication (2000: 84.1 ± 25.0 ml/min; p < 0.01). It is our opinion that the reuse of polysulfone dialyzers with Renalin should be abandoned in the field of high-flux haemodialysis. It causes deterioration in the β2-microglobulin clearance and probably interferes with the high-flux haemodialysis benefits, namely the reduction of dialysis-related amyloidosis.
Can HLA Typing Predict the Outcome of Grass Pollen Immunotherapy?
Authors: Fleva A. , Daniilidis M. , Sidiropoulos J. , Adam K. , Tourkantonis A. , Daniilidis J. , Hadzipetrou L.
Published: April 2003

Objective: The aim of this study was to investigate the relationship between HLA molecules and the positive or negative response of atopic patients to specific immunotherapy (SIT). Methods: We studied 42 atopic multisensitive patients undergoing grass pollen immunotherapy, 42 parents of patients (30 mothers and 12 fathers) and 173 control individuals. HLA class I and class II antigens were typed by a microlymphocytotoxicity test. The typing of DRB1* alleles for atopic patients and their parents was based on the reverse hybridization principle, while for the control group, DNA-RFLP and PCR-SSP methods were used. Results: The frequency of B14 and DRB1*1101-4 antigens/alleles, as well as the A2B5DR11 haplotype, showed a statistically significant difference in those patients who responded to immunotherapy. On the other hand, HLA-A28, B8 and DRB1*0301 antigens/alleles, as well as the frequency of the A1B8 and A1B8DR3 haplotypes, were found to be significantly higher in patients who responded poorly to SIT. Discussion: Our findings support the hypothesis that treatment responsiveness may show an association to HLA molecules, which could thus play a role in the immunological selection and monitoring of atopic patient candidacy for SIT.
How to Measure the Effects of Fluoride Treatments in Clinical Trials?
Authors: Reich Elmar
Published: April 2003

Many products that claim to have caries-preventive effects are available to the general public. Different and sometimes even contradictory claims of effectiveness are given in advertisements. Dentists would like to give good information and advice to their patients and the public with respect to the efficacy of different products. In medicine and dentistry there are guidelines which consider the ethics, design, conduct as well as the recording and reporting of clinical studies. The effects of clinical trials in subjects with a high risk for caries or in a population with a high caries prevalence are not comparable to the situation in most industrialized countries today. The sample should, therefore, include subjects with a range of prevalences and of risks for a valid assumption of efficacy. Reliable data can be obtained if a strict control of the design and management of the clinical trials is maintained over the duration of the experiment. New diagnostic methods used in the study must be validated and could lead to trials of a shorter duration. For a new fluoride product the bioavailability of the ion should be demonstrated. The results must have the necessary characteristics to be included in a meta-analysis. Thesis: The caries-preventive effect of a fluoride product cannot be accurately measured in populations with a variety of preventive products in use. On the other hand, the measured effect in populations with caries prevalence higher than those of the country where it will be used is not comparable to the real situation.
A Benefit/Risk Analysis of the Prevention of Brain Ischaemia with Anticoagulant Drugs: When, How and Whom to Treat?
Authors: Algra Ale
Published: April 2003

This paper summarises the benefits and risks of anticoagulant treatment in patients who have had cerebral ischaemia. In patients with a cardiac source of embolism (in most studies atrial fibrillation), anticoagulation with a target intensity of an INR of 2.0–3.0 is the therapy of first choice. In the case of a contraindication to such treatment, aspirin and ibuprofen are safe, but less effective alternatives. In patients with cerebral ischaemia of presumed arterial origin, anticoagulation with an achieved intensity of 3.0–4.5 proved not to be safe. Results from trials with more moderate anticoagulation regimes are awaited.