bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Plasticity and Information Processing by Transcription Coregulators
Authors: Benecke Arndt
Published: May 2003

Functional genomics in higher eukaryotes faces major challenges attributable to the ever-increasing complexity of the regulatory circuitry and its biological manifestation. The genomic regulon remains largely inaccessible to bioinformatics tools due to a degree of apparent functional redundancy (degeneration) of the underlying code and nonlinearities of its cellular interpretation. Based on recent biochemical work on transcription coregulators and their crosstalk with other genome maintenance and regulation pathways, a model is developed that offers an explanation how the cellular transcription machinery interprets the gene regulatory code. The experimental evidence suggests a secondary layer of coding by the chromatin structure of the genome producing hypercycles of repressed and open nucleosomal sites in euchromatin. The code is read out by coregulators analog and prior to the reading out of the primary coding (the nucleotide sequence) by transcriptionfactors. The coregulator model of transcription thus promises not only to enhance our comprehension of the biological phenomena leading to faithful gene regulation in higher eukaryotes, but also to overcome some of the above-described impediments to bioinformatic analysis, and it may lead to the systematic description of gene regulatory networks and their dynamics. The implications of a coregulator-based view of transcription for the development of tools analyzing genomes of higher eukaryotes for complex, composite nucleotide patterns derived from above molecular understanding are significant. Furthermore, the recent generation of systematic gene expression information in response to specific cellular signals can be utilized, within limits, as training data in multiple-round feed-back optimization of these complex search expressions.
The Search for Homology: A Paradigm for Molecular Interactions?
Authors: Dutreix Marie , Fulconis Renaud , Viovy Jean-Louis
Published: May 2003

Homologous recombination relies on specific interactions between two homologous DNA molecules. How a DNA sequence finds its homologous target in the complexity of a genome remains a thermo-dynamical challenge. The initial recognition step involves insertion of a single-stranded DNA region into the minor groove of a duplex DNA. It requires a local melting of the double helix for specific base pairing and recognition. A family of recombination proteins, such as the RecA protein of Escherichia coli, stimulates this reaction. The kinetic mechanism of DNA pairing is surprisingly poorly understood. The homologous alignment can occur anywhere along the length of either DNA substrate and is generally completed within a few minutes. We will review different experiments suggesting that the speed and the efficiency of the pairing reaction cannot be simply explained by Brownian movement or molecule sliding, but probably involves more complex mechanisms such as ‘molecular translocations and ‘inchworm local movements.
Th2 Immune Responses in GATA-3-Transgenic Mice Infected with Heligmosomoides polygyrus
Authors: Watanabe Naohiro , Tamauchi Hidekazu , Ozawa Hideyuki , Ito Mamoru , Ovary Zoltan , Habu Sonoko
Published: May 2003

To examine the participation of transcription factor GATA-3 in Th2 immune responses in vivo, we generated transgenic mice having several copies of GATA-3 with lck promotor. Mice were infected with the intestinal nematode Heligmosomoides polygyrus to induce Th2 immune responses. Upon antigen stimulation, IL-5 and IL-13 production of mesenteric lymph node cells from H. polygyrus-infected mice, was significantly enhanced in GATA-3-transgenic mice compared with nontransgenic control mice. However, IL-4 production was the same in GATA-3-transgenic and control mice. H. polygurus-infected GATA-3-transgenic mice exhibited significantly more peripheral blood eosinophils and total IgE levels compared with control mice. These results suggest that GATA-3 promotes IL-5 and IL-13 production, and that the function of these cytokines results in eosinophilia and hyper-IgE, respectively.
Interaction with Monocytes Enhances IL-5 Gene Transcription in Peripheral T Cells of Asthmatic Patients
Authors: Ogawa Koji , Kaminuma Osamu , Kikkawa Hideo , Akiyama Kazuo , Mori Akio
Published: May 2003

Background: The regulatory mechanisms of IL-5 gene transcription in human peripheral T cells are unclear because the transfection efficiency of plasmid constructs into nontransformed T cells is very low. Methods: Concanavalin A (ConA)-stimulated blastocytes derived from peripheral blood lymphocytes of asthmatic subjects were transiently transfected with the human IL-5 gene promoter/enhancer-luciferase gene construct, pIL-5 (–511)Luc, and cultured with THP-1 cells (human monocytoid cells) and anti-CD3 monoclonal antibody (mAb). IL-5 level in the culture medium was determined by an enzyme-linked immunosorbent assay. Transcriptional activity of the IL-5 gene was measured by luciferase reporter analysis. Results: ConA-blast lymphocytes of asthmatic patients produced a significant amount of IL-5 upon combined stimulation with anti-CD3 mAb and THP-1 cells, but not with anti-CD3 mAb alone. Costimulation with anti-CD28 mAb also enhanced the anti-CD3 mAb- induced IL-5 production. Accordingly, luciferase activity induced by anti-CD3 mAb stimulation in pIL-5(–511)Luc-transfected ConA-blast lymphocytes was increased 1.9- and 3.4-fold by the addition of anti-CD28 mAb and THP-1 cells, respectively. Serial 5′ deletion analysis of the reporter gene demonstrated that the cis-regulatory element located at –119 to –80 is critical for anti-CD3 mAb-induced IL-5 gene transcription. Conclusions: Our present findings provide a useful model reflecting IL-5 gene transcription in human peripheral T cells in vivo, and clearly demonstrate that an interaction with monocytes enhances IL-5 gene transcription.
Theophylline Attenuates the Adhesion of Eosinophils to Endothelial Cells
Authors: Choo Jae Hong , Nagata Makoto , Sutani Akihisa , Kikuchi Izumi , Sakamoto Yoshio
Published: May 2003

Background: Bronchial asthma is characterized by infiltration of eosinophils and other inflammatory cells into the airways. Binding to adhesion molecules expressed on endothelial cells is an initial step of eosinophil accumulation in the airways of asthmatic patients. Theophylline has been widely used in the treatment of bronchial asthma mainly due to its bronchodilating effect. It has recently been suggested that theophylline induces modulating effects on the survival or functional status of eosinophils. The objective of this study was to determine whether theophylline modifies the adhesive interaction between eosinophils and endothelial cells. Methods: Eosinophils were isolated from blood of patients with mild asthma. The effects of theophylline on eosinophil adhesion to human umbilical vein endothelial cells (HUVEC) or recombinant adhesion proteins were evaluated. The effect of theophylline on the expression of adhesion molecules on HUVEC was also examined. Results: Theophylline significantly inhibited the eosinophil adhesion induced by formyl-methionyl-leucil-phenylalanine (FMLP) or interleukine-5 (IL-5) at a concentration within the therapeutic range. The effect of theophylline on eosinophil adhesion was mimicked by rolipram, a selective phosphodiesterase inhibitor, and N6,2′-O-dibutyladenosine 3′5′-cyclic monophosphate (Db-cAMP; cAMP analogue). Finally, theophylline inhibited the expression of ICAM-1 and VCAM-1 on HUVEC stimulated with IL-4 plus TNF-α. Conclusion: Theophylline showed inhibitory effects on both the adhesive property of eosinophils and the expression of adhesion molecules on endothelial cells, thus suggesting that theophylline attenuates the adhesive interaction between eosinophils and endothelial cells.
The Study of Cytosolic Phospholipase A2 Gene Polymorphism in Schizophrenia Using Eye Movement Disturbances as an Endophenotypic Marker
Authors: Rybakowski Janusz K. , Borkowska Alina , Czerski Piotr M. , Dmitrzak-Węglarz Monika , Hauser Joanna
Published: May 2003

Phospholipase A2 (PLA2) is a key enzyme of the phospholipid metabolism which shows alteration in schizophrenia. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives, and they have been suggested as an endophenotypic marker in genetic studies of this illness. Here we report an association between the Ban I polymorphism of the cytosolic PLA2 gene (single nucleotide polymorphism in the first intron of the gene) and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 126 schizophrenic patients. The mean intensity of both kinds of eye movement disturbances was significantly higher in individuals homozygous for the A2 genotype compared with the remaining phenotypes. There was also a trend for greater A2 allele frequency in schizophrenic patients with a higher degree of eye movement disturbances. The relative frequency of the A2/A2 genotype was higher in patients with a greater degree of eye movement disturbances occurring during both fixation and smooth pursuit tests. Our results correspond to the other studies showing an association between the cPLA2 polymorphism and schizophrenia (predominance of the A2 allele in schizophrenic subjects).
Depressed Patients Have Higher Body Temperature: 5-HT Transporter Long Promoter Region Effects
Authors: Rausch J.L. , Johnson M.E. , Corley K.M. , Hobby H.M. , Shendarkar N. , Fei Y. , Ganapathy V. , Leibach F.H.
Published: May 2003

Background: Depression has been associated with a decrease in intracellular serotonin (5-HT) reuptake through its transporter, SERT. The 5-HT transporter long promoter region (5-HTTLPR) deletion in the SERT gene has also been associated with a decrease in 5-HT reuptake. Conversely, increases in extracellular 5-HT have been associated with increased temperature. It has not been established, however, whether body temperature in depressed patients is different from controls. Here, we hypothesized that temperature would be increased in depressed patients as well as in those with the 5-HTTLPR deletion. Methods: A strict oral temperature protocol employed single, cross-sectional, naturalistic time-of-day temperature measures in 125 subjects (46 normal controls, 79 outpatients with major depression). Controls and depressed patients were free of psychotropic medication and classified by the Structured Clinical Interview for Psychiatric Diagnoses. Eighty-one of the subjects (68 depressed, 13 normal) were additionally genotyped for 5-HTTLPR polymorphisms. Results: Depressed patients had a significantly higher uncorrected body temperature (mean ± SD 98.38 ± 0.61°F) than controls (mean ± SD 98.13 ± 0.59°F; F = 4.8, p = 0.03). An age (F = 14.09, p < 0.001) and time-of-day (11.4, p = 0.001) correction revealed a more robust (F = 14.02, p < 0.001) difference between depressed patients (mean ± SD 98.44 ± 0.55°F) and controls (mean ± SD 98.02 ± 0.56°F). When normalized for age and circadian differences between subjects, random, outpatient oral temperatures had a sensitivity of 63% and a specificity of 76% in identifying the depressed subjects from the controls. Independent of depression, subjects with the 5-HTTLPR deletion (short SERT allele) were warmer (mean ± SD 98.33 ± 0.65°F) than those lacking the short allele on either chromosome (mean ± SD 97.91 ± 0.69°F; F = 7.0, p = 0.01). However, the genotype did not explain the temperature differences between controls and depressed patients. Conclusion: This is the first demonstration of an increased daytime body temperature in cases with major depression. Subjects with a corrected temperature above 98.3°F were 2.6-fold more likely to be depressed. The results may strengthen the hypothesis of an inflammatory component of depression. In addition, the findings suggest a potential link between genetic differences in 5-HT transport and body temperature.
Association Analysis for Neuronal Nitric Oxide Synthase Gene Polymorphism with Major Depression and Fluoxetine Response
Authors: Yu Younger W.-Y. , Chen Tai-Jui , Wang Ying-Chieh , Liou Ying-Jay , Hong Chen-Jee , Tsai Shih-Jen
Published: May 2003

Nitric oxide (NO) is produced from its precursor L-arginine by the enzyme NO synthase (NOS), which includes at least three distinct isoforms – neuronal (nNOS), endothelial, and inducible NOS. Recent studies have implicated NOS in the mechanism that underlies the therapeutic efficacy of antidepressant medication. In addition, major depressive disorder (MDD) patients were found to have significantly higher plasma nitrate concentrations than normal subjects, an index of NO production, in comparison to normal subjects. In a population-based association study, we tested the hypothesis that the nNOS C276T polymorphism confers susceptibility to MDD. We also examined the association between this polymorphism and therapeutic fluoxetine response in 114 MDD patients who underwent a 4-week fluoxetine treatment. The results demonstrate that the nNOS variants are found at similar frequencies in MDD patients and healthy control subjects. Further, we did not discover any genetic variants that influenced the fluoxetine response in MDD patients treated with fluoxetine. Our findings suggest that this nNOS C276T polymorphism does not play a major role in the susceptibility to, or fluoxetine response in, MDD. However, the association between other NOS variants and MDD or antidepressant response, including sexual dysfunction, may warrant further investigation.
A Comprehensive Method for Genome Scans
Authors: Malley James D. , Naiman Daniel Q. , Bailey-Wilson Joan E.
Published: May 2003

In applications involving the use of genome scans the problem of correcting for multiple testing figures prominently. A frequently used approach is the Bonferroni adjustment, but this is known to be often severely conservative. As an alternative we use the method of importance sampling to accurately and efficiently obtain required exceedance probabilities. This method is comprehensive in the sense that it has application to exceedance probabilities for other classes of test statistics, such as those for linkage disequilibrium or Hardy-Weinberg equilibrium at multiple loci. We illustrate the importance sampling technique by focusing on affected sib pair tests done at a large number of fully informative markers. We demonstrate how our approach can be used to obtain exceedance probabilities for arbitrary marker spacings, and we compare our approach with that of Feingold et al. [1993], which uses the method of large deviations and does not provide the means for adjusting for unequal marker spacing.
Entropy as a Measure for Linkage Disequilibrium over Multilocus Haplotype Blocks
Authors: Nothnagel M. , Fürst R. , Rohde K.
Published: May 2003

Objective: The presence of linkage disequilibrium (LD) forms the basis for a range of uses, including the fine-mapping of diseases and studies on human genealogy. Recent findings indicate that single nucleotide polymorphisms (SNP) can occur in blocks of limited haplotypic diversity with high degrees of LD. Commonly used measures for LD, such as r2 and D′, consider only two loci and might miss information to appropriately describe LD in larger haplotypic structures. Methods: We introduce the Normalized Entropy Difference, Ε, as a new multilocus measure for LD. A related quantity, ΔS, provides an approximate χ2 test for the significance of LD. The ability of the measure to detect haplotype blocks is investigated using simulated data sets as well as a real data set previously analyzed by Daly et al. (2001). Results: Ε allows for arbitrary numbers of loci, describes LD with regard to the loci sequence, and can be interpreted as a multilocus extension of r2. The application of Ε to the data sets demonstrated the measure’s ability to appropriately describe simultaneous multilocus LD and to detect haplotype blocks. Conclusions: Ε is a reasonable multilocus LD measure and might be of potential use in the construction of the human haplotype map.
Confidence Intervals for Genotype Relative Risks and Allele Frequencies from the Case Parent Trio Design for Candidate-Gene Studies
Authors: Scherag André , Dempfle Astrid , Hinney Anke , Hebebrand Johannes , Schäfer Helmut
Published: May 2003

Objectives: Confidence intervals for genotype relative risks, for allele frequencies and for the attributable risk in the case parent trio design for candidate-gene studiesare proposed which can be easily calculated from the observed familial genotype frequencies. Methods: Likelihood theory and the delta method were used to derive point estimates and confidence internals. We used Monte Carlo simulations to show the validity of the formulae for a variety of given modes of inheritance and allele frequencies and illustrated their usefulness by applying them to real data. Results: Generally these formulae were found to be valid for ‘sufficiently large’ sample sizes. For smaller sample sizes the estimators for genotype relative risks tended to be conservative whereas the estimator for attributable risk was found to be anti-conservative for moderate to high allele frequencies. Conclusions: Since the proposed formulae provide quantitative information on the individual and epidemiological relevance of a genetic variant they might be a useful addition to the traditional statistical significance level of TDT results.
An Automatic Method to Quantify the Vibration Properties of Human Vocal Folds via Videokymography
Authors: Qiu Qingjun , Schutte H.K. , Gu Lide , Yu Qilian
Published: May 2003

The study offers an automatical quantitative method to obtain vibration properties of human vocal folds via videokymography. The presented method is based on image processing, which combines an active contour model with a genetic algorithm to improve detecting precision and processing speed, can accurately extract the vibration wave in videokymograms and quantify the vibration properties in terms of eight typical parameters automatically. To verify the precision of the proposed algorithm, an indirect simulation setup of vocal folds has been performed. The verification result shows that the relative error of the entire simulation system is less than 5%. Applying the method to analyzing hundreds of videokymograms from 12 subjects, the result indicates that the vibration characteristics of vocal folds can be recognized more exactly, and diseases of the vocal folds can be diagnosed quantitatively.
Animal Models for Asthma: Controversial Aspects and Unsolved Problems
Authors: Pabst R.
Published: May 2003

The incidence of asthma in children and adults is continuously increasing in the developed countries. Its pathophysiology is still not yet clarified in sufficient detail. Despite a large number of animal models for asthma (mainly rodents), these only partly mimic the situation in humans. Some examples of limitations of using the mouse as an animal model for asthma will be discussed and directions of future research outlined.
Recruitment of Lymphocytes and Dendritic Cells from the Blood to the Bronchoalveolar Space and the Draining Lymph Nodes after a Single Intrabronchial Application of the Lipopeptide MALP-2
Authors: Tschernig T. , Lührmann A. , Pabst R.
Published: May 2003

Objective: It has been shown previously that the synthetic macrophage-activating lipopeptide, MALP-2, is a potent stimulator of the respiratory immune system and an effective adjuvant in the induction of mucosal immune responses. In this study, the migration route of leukocytes from the blood to the bronchoalveolar space and then to the draining lymph nodes was investigated. Methods: MALP-2 was intratracheally instilled into lungs of Lewis rats. Bronchoalveolar lavage cells as well as cell preparations of other lung compartments such as the marginal vascular pool, the interstitial pool and also the draining lymph nodes were examined 3 days later. Results: The application of MALP-2 induced a pronounced leukocyte accumulation in the bronchoalveolar space and the lung interstitium but not in the marginal vascular pool. A tendency to increased lymphocyte and dendritic cell numbers was observed in the draining lymph nodes. Conclusion: Our data indicate the migration of blood cells into the lung interstitium and the bronchoalveolar space in response to MALP-2. Thus, the immune reaction induced by MALP-2 might be of relevance as an adjuvant treatment in inhalant vaccination strategies in the lung.
Stimulation of Bronchus-Associated Lymphoid Tissue in Rats by Repeated Inhalation of Aerosolized Lipopeptide MALP-2
Authors: Lührmann A. , Tschernig T. , Pabst R.
Published: May 2003

Objective: Bronchus-associated lymphoid tissue (BALT) is a part of the integrated mucosal immune system. It may play an important functional role for antigen uptake and induction of specific immune reactions. The aim of this study was to investigate whether it is possible to induce or modulate BALT by the repetitive inhalation of the synthetic lipopeptide MALP-2. Methods: Female Lewis rats (245 ± 19 g) inhaled 25 µg of MALP-2 six times at intervals of 1 week. One week after the last inhalation, they were sacrificed. Cells of the bronchoalveolar lavage and the left lung were investigated by flow cytometry. The middle lobe of the right lung was embedded in paraffin. BALT was semiquantitatively measured in 15 serial cross sections per animal. Results: After repetitive inhalation of the diluent as well as MALP-2, BALT was found. The total area was increased after repetitive treatment with MALP-2. In addition, the preferential incidence of BALT was higher after MALP-2 application, in association with a bronchial diameter of 0.6–1 mm. The cellular analysis revealed no differences in the number of leukocyte subsets between the control and MALP-2 group. Conclusion: MALP-2 is a potent local stimulator and can be used to modulate BALT by repetitive inhalant treatment. The functional significance of enlarged or activated BALT has to be elucidated in future studies.
Long-Term NO2 Exposure Induces Pulmonary Inflammation and Progressive Development of Airflow Obstruction in C57BL/6 Mice: A Mouse Model for Chronic Obstructive Pulmonary Disease?
Authors: Wegmann M. , Renz H. , Herz U.
Published: May 2003

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, development of emphysema and irreversible airway obstruction. Macrophages, neutrophils and CD8+ T cells and their products have been shown to play an important role in the initiation and maintenance of these processes. In contrast, the mechanisms underlying COPD pathogenesis still remain uncertain. This article focuses on the generation of an animal model that mirrors some features of human COPD in association with a progredient airflow limitation.
Surfactant Proteins SP-A and SP-D as Modulators of the Allergic Inflammation in Asthma
Authors: Hohlfeld J.M. , Erpenbeck V.J. , Krug N.
Published: May 2003

Surfactant proteins A and D (SP-A and SP-D) are members of the collectin family and bind to various motifs of microorganisms, particles and allergens. They play an important role in the first-line defense within the lung. Recent research has highlighted that these proteins not only augment innate immune responses to invading microorganisms but also act on adaptive immune functions like dendritic cell maturation and T cell proliferation. Both SP-A and SP-D downregulate the eosinophilic inflammation in murine asthma models and shift the cytokine profile towards a T helper cell type 1 response. In addition, they are effective at alleviating bronchial hyperresponsiveness. Although our knowledge about surfactant proteins as modulators of the allergic inflammatory reaction in asthma is still limited, the idea that surfactant proteins play a role in asthma has attracted increasing attention. In this review, the impact of the lung collectins SP-A and SP-D on asthmatic allergic inflammation and vice versa will be discussed.
Acceptability for the Use of Postpartum Intrauterine Contraceptive Devices: Assiut Experience
Authors: Mohamed Safwat A. , Kamel Momen A. , Shaaban Omar M. , Salem Hossam T.
Published: May 2003

Objectives: To evaluate the acceptance of postpartum intrauterine contraceptive devices (PPIUCD) among the inhabitants of Assiut governorate, Egypt and to study the factors that influence this acceptance. Subjects and Methods: Contraceptive counseling was given to 3,541 clients: 1,880 and 1,661 during the antenatal visits and postpartum hospitalization, respectively. Acceptors during antenatal counseling were to receive IUCDs via postplacental insertion in the case of vaginal delivery or transcesarean insertion in case of abdominal delivery. The clients who refused PPIUCD and chose interval IUCD insertion were referred to the Family Planning Clinic after the end of puerperium. Among postpartum counselees, PPIUCD acceptors received predischarge insertion within 48 h of delivery and the interval IUCD were referred to have IUCD inserted after the end of puerperium. The acceptance rate of both PPIUCD and interval IUCD and the percentage of actual insertions were recorded. The causes of both acceptance and refusal were also recorded. Results: Of the 3,541 clients, 1,024 (28.9%) accepted the use of IUCD after delivery. Acceptance was approximately the same during antenal and postpartum counseling: 26.4 and 31.8%, respectively. Verbal acceptance was higher among women with formal education than among illiterate women. Planning another pregnancy in the near future, preference for another contraceptive method, namely lactational infertility, and complications from previous use of IUCD were the most common reasons for refusing the use of IUCD. Of the 1,024 verbal acceptors, only 243 (23.7%) had the actual insertion of IUCD. Conclusion: Both the acceptance and actual insertion of IUCD were low probably because the use of IUCD is a new concept in the community. For these women, the only opportunity to receive information about contraceptives is during childbirth when they are in contact with medical personnel. Hence, it is suggested that family planning should be integrated with maternal and child-care services in order to effectively promote the use of contraceptive devices in these women who otherwise would not seek the use of such a device.
Pain during Mammography: Impact of Breast Pathologies and Demographic Factors
Authors: Gupta R. , Nayak M. , Khoursheed M. , Roy S. , Behbehani A.I.
Published: May 2003

Objectives: The aim of this study was to systematically assess the pain experienced by patients undergoing mammography for various clinical presentations. Subjects and Methods: Two hundred and twenty-five patients aged 25–85 years (45.43 ± 8.25 years) presenting for mammography were included in the study. Presenting symptoms and clinical diagnosis were provided by the referring physicians and demographic information was obtained from self-reported questionnaires. Mammography results were recorded by the radiologist. Two different but reliable and valid measures of pain – Visual Analog Scale (VAS) and Pain/Discomfort Rating Scale (DRS) – were used to assess pain during mammography and data were statistically analyzed to examine the possible predictors of pain. Results: Forty-nine percent of the patients reported pain during mammography when cut-off level of VAS score was 40; however, when the cut-off level was raised to 60 (considering the preexisting pain as presenting symptom in some patients) only 23% reported pain. With DRS, 7% reported pain, 27% discomfort and 66% neither pain nor discomfort. Biserial correlation between the VAS and DRS scores suggested strong positive agreement between the two measures of pain (r = 0.56, d.f. = 90, p < 0.01). Patients presenting with coexisting breast lumps and preexisting breast pain and those diagnosed with inflammatory conditions of the breast and fibrocystic changes experienced more pain during mammography. Conclusion: Preexisting breast pathologies and demographic factors such as age and educational level of the patient were important in reporting pain during mammography. This finding indicates that proper assessment of pain using standard measures and its association with breast pathologies and demographic factors is important for planning pain management in women undergoing mammography.
Influence of Vitamin A Consumption on Resting Metabolic Rate and Fasting Respiratory Quotient in Severely Obese Subjects
Authors: Mikulová-Braunerová Radka , Hainer Vojtěch , Kunešová Marie , Paĕízková Jana , Slabá Šárka , Wagenknecht Martin
Published: May 2003

Objective: To study whether or not the amount of vitamin A consumed affects the resting metabolic rate (RMR) and fat oxidation at rest in severely obese subjects. Materials and Methods: In 239 obese subjects, RMR and fasting respiratory quotient (RQ) were determined by indirect calorimetry. Vitamin A consumption was calculated by the Czech PC program ‘Nutrition’. The relation between the intake of vitamin A and RMR and RQ was tested by simple regression. High and low vitamin A consumers were defined by an upper and a lower quintile of vitamin A intake (>842 vs. <382 IU/day). Results: The RMR for high and low vitamin A consumers were 7,693.5 ± 1,557 and 7,479.8 ± 1,708 kJ/day, respectively, while the corresponding values for fasting RQ were 0.800 ± 0.077 and 0.809 ± 0.049, respectively. No significant correlation was found between vitamin A consumption and both RMR and RQ. Similarly, there was no significant difference in RMR and RQ, as well as weight, body mass index, body fat, waist girth and food quotient between the two groups characterized by high and low consumption of vitamin A. However, the energy intake of high vitamin A consumers was significantly higher than that of low vitamin A consumers, due to higher carbohydrate and protein intake. Conclusion: There was no significant correlation between the vitamin A intake and RMR or RQ in obese subjects determined in this study.
Rationale for the Use of Blood Volume and Temperature Control Devices during Hemodialysis
Authors: Donauer Johannes , Böhler Joachim
Published: May 2003

Despite substantial progress in blood purification techniques over the last three decades, treatment-related hypotensive episodes remain one of the major problems in hemodialysis therapy. There are two main reasons for hypotension occurring during dialysis treatments. First, hypovolemia is frequently induced by rapid fluid removal from the blood compartment which is in excess of refilling of fluids from the interstitial space. Second, many patients fail to support blood pressure by adequate vasoconstriction or increased heart rate as a response to hypovolemia. The capacity to respond adequately to volume contraction may be reduced due to patient- or treatment-related factors, among which heat accumulation within the body plays a major role. Recently, two newer technical developments became commercially available for use in hemodialysis therapy: devices for blood volume and blood temperature control were designed to reduce the incidence of intradialytic hypotension. Although blood volume and temperature measurements are easy to perform today, there is some uncertainty in the dialysis community how and when their use may be helpful and in which patients it is indicated. This review critically discusses the application of blood volume- and temperature-measuring devices with regard to their usefulness in the clinical setting.
Experience with the GENIUS® Hemodialysis System
Authors: Fassbinder Winfried
Published: May 2003

The late B. Tersteegen devised a clever way to combine the advantages of a closed tank hemodialysis system with the efficacy and bacteriological safety of a single-pass system. The Teerstegen equipment is now marketed as the GENIUS® hemodialysis system. For each treatment, fresh dialysis fluid is prepared according to the physician’s prescription by mixing sterile ingredients (electrolytes and glucose) with preheated ultrapure water. The total amount of dialysis fluid is put into a thermally insulated glass tank (volume 75 l) of the hemodialysis machine. The filling and emptying process is completely automated. An UV radiator is used for desinfection. Due to a consequent hygienic concept, the system operates with an almost sterile and usually pyrogen-free dialysis fluid. During treatment, fresh dialysis fluid is taken from the top of the system, and the used dialysate is returned to the bottom. There is a sharp interface between the fresh and used dialysis fluids because of a small difference in temperature (1°C). True volumetric ultrafiltration control is simply achieved; ultrafiltration rates between 100 and 1,000 ml/h can be selected as considered appropriate by the physician. Microbiological examination: We cultured more than 2,000 dialysate specimens to examine bacterial contamination, and found either no bacterial growth at all (in the vast majority of the cases) or less than 1 CFU/ml dialysate. Clinical experience: We have utilized the GENIUS® system since 1994. Meanwhile, more than 40,000 treatments have been performed in our center. Biochemical results of the first 19 stable hemodialysis patients (mean age 66 years, range 45–82), who had been treated with conventional hemodialysis systems for at least 6 months (range 6–157) before changing to GENIUS®, were evaluated. We observed an increase of mean serum albumin concentration from 4.1 (±0.4 SD) g/dl to 4.8 (±0.3) g/dl (p < 0.01) within 6 months. Most patients reported improved well-being. Of these 19 patients, 18 preferred further treatment with the GENIUS® system in comparison to conventional hemodialysis machines. Conclusion: The GENIUS® hemodialysis system permits an individualized therapy of high quality; most patients prefer this system to conventional hemodialysis machines. Serum albumin levels increased significantly from normal to high normal values after change from conventional hemodialysis machines to GENIUS®, probably due to less catabolic stress during the hemodialysis sessions.
Angiogenin: A Novel Inhibitor of Neutrophil Lactoferrin Release during Extracorporeal Circulation
Authors: Schmaldienst Sabine , Oberpichler André , Tschesche Harald , Hörl Walter H.
Published: May 2003

Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (≤8%) of plasma angiogenin levels within 2 h of dialysis treatment associated with a 1.6-fold lactoferrin release from PMNL. Hemodialysis therapy with high-flux membranes (e.g. cellulose triacetate, polymethylmethacrylate) or hemodiafiltration resulted in a reduction of plasma angiogenin levels by 20–40% after 2 h associated with a nearly 4-fold PMNL lactoferrin release. The release of PMNL elastase was not affected by the different treatment modalities used. We conclude that high angiogenin plasma levels protect against lactoferrin release from PMNL during extracorporeal circulation in chronically uremic patients. A decrease of plasma angiogenin between 20 and 40% during extracorporeal circulation, however, results in marked PMNL lactoferrin release. This novel mechanism may explain, at least in part, PMNL degranulation also in non complement activating high-flux membranes.
Glucose Degradation Products in Peritoneal Dialysis: From Bench to Bedside
Authors: Jörres Achim
Published: May 2003

In continuous ambulatory peritoneal dialysis patients, treatment success is inextricably linked to the functional and morphological integrity of the peritoneal membrane. This membrane, however, is repeatedly exposed to peritoneal dialysis fluids (PDFs) with unphysiological composition (e.g., acidic pH, high glucose content, hyperosmolarity). More recently, attention of researchers and clinicians has been focused on the presence of glucose degradation products (GDPs) that are generated during heat sterilization of PDF. These GDPs were found to adversely affect peritoneal cell function both acutely and chronically. Recently, a new family of multi-chambered PDFs has been introduced into clinical practice. By keeping the glucose in a separate compartment at very low pH, the generation of GDPs during heat sterilization is markedly reduced. Initial clinical studies indicate that treatment with these novel PDFs may lead to improved clinical outcomes. The current article reviews recent experimental and clinical experience with both conventional and multi-chambered PDFs.
Minimally Invasive Retroperitoneal Pancreatic Necrosectomy
Authors: Connor S. , Ghaneh P. , Raraty M. , Sutton R. , Rosso E. , Garvey C.J. , Hughes M.L. , Evans J.C. , Rowlands P. , Neoptolemos J.P.
Published: May 2003

Introduction: Open surgery for pancreatic necrosis is associated with considerable morbidity and mortality. We report the results of a recently developed minimally invasive technique that we adopted in 1998. Methods: A descriptive explanation of the approach is given together with the results of a retrospective analysis of patients who underwent a minimally invasive retroperitoneal pancreatic necrosectomy (MIRP) between August 1998 and April 2002. Patients: There were 24 patients with a median (range) age of 61 (29–75) years. The initial median (range) APACHE II score was 8 (2–21). All patients had infected pancreatic necrosis with at least 50% pancreatic necrosis. In three patients it was not possible to complete the first MIRP because of technical reasons. Results: A total of 88 procedures were performed with a median (range) of 4 (0–8) per patient. Twenty-one (88%) patients developed 36 complications during the course of their illness. Five patients required an additional open procedure: 2 for subsequent distant collections, 2 for bleeding and 1 for persisting sepsis and a distant abscess. Six (25%) patients who had MIRP died. The median (range) post-operative hospital stay was 51 (5–200) days. Conclusions: MIRP is a new technique that has shown promising results, and could be preferable to open pancreatic necrosectomy in selected patients. However, unresolved issues remain to be overcome and the exact role of MIRP in the management of pancreatic necrosis has yet to be defined.
Routine Replacement of Tunneled, Cuffed, Hemodialysis Catheters Eliminates Paraspinal/Vertebral Infections in Patients with Catheter-Associated Bacteremia
Authors: Philipneri Marie , Al Aly Ziyad , Amin Kamal , Gellens Mary E. , Bastani Bahar
Published: May 2003

Background: Management of tunneled, cuffed, central venous catheters in hemodialysis (HD) patients with bacteremia remains a challenge. Attempts to salvage the catheter with systemic antibiotics alone have been associated with increased risk of metastatic infectious complications. Methods: Retrospective case series of patients with infectious complications in a chronic dialysis unit, affiliated with a tertiary care university hospital. Results: Between 1996 and 1999, when we treated HD catheter-associated bacteremia with systemic antibiotics alone, we encountered a clustering of 8 cases of paraspinal/vertebral infections in a population of 162 patients. After changing our protocol, i.e., routine catheter exchange over a guide wire at ∼48 h, while on systemic antibiotic therapy, we did not encounter any new cases of paraspinal/vertebral infections over a 15-month period. Conclusion: Our experience suggests that routine exchange of tunneled, cuffed catheters over a guide wire in HD patients presenting with bacteremia may significantly reduce serious infectious complications, e.g., epidural abscess/vertebral osteomyelitis.
Direct Contact between Human Peripheral Blood Mononuclear Cells and Renal Fibroblasts Facilitates the Expression of Monocyte Chemoattractant Protein-1
Authors: Hao Lirong , Okada Hirokazu , Kanno Yoshihiko , Inoue Tsutomu , Kobayashi Tatsuya , Watanabe Yusuke , Strutz Frank , Müller Gerhard A. , Suzuki Hiromichi
Published: May 2003

Background: Cell-to-cell interaction is thought to be an important feature of a variety of biological processes. As far as the proinflammatory process is concerned, the interaction between mesangial cells and monocytes/macrophages induces the expression of monocyte chemoattractant protein-1 (MCP-1), and this may play a role in glomerulonephritis. In this study, we investigated whether the cell-to-cell interaction between immune cells and renal fibroblasts induces MCP-1 gene expression, which may be involved in interstitial inflammation in the kidney. Methods: Human renal fibroblast cell lines, tNKF (from a normal kidney) and tFKIF (from a kidney with fibrosis), and peripheral blood mononuclear cells (PBMC) were used to assess the effect of cell-to-cell contact on the expression of MCP-1 mRNA in the fibroblasts. The expression of the MCP-1 gene in the fibroblasts was also examined after stimulation with tumor necrosis factor-α (TNF-α) and the culture supernatant from PBMC. RT-PCR was used to detect MCP-1 mRNA expression. Neutralizing antibodies to intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1) were used to block the cell-to-cell contact between the fibroblasts and PBMC. Results: TNF-α and the culture supernatant from PBMC increased MCP-1 gene expression in tNKF cells. Contact culture with PBMC also significantly increased MCP-1 gene expression in tNKF cells. Although the basal level of MCP-1 mRNA was higher in tFKIF than tNKF cells, tFKIF cells did not respond significantly to any stimulation in this study. Following pretreatment with anti-ICAM-1 antibody, MCP-1 gene expression in tNKF cells was significantly suppressed in contact culture with PBMC. Anti-VCAM-1 antibody treatment had no effects. Conclusion: It is suggested that the interaction between renal fibroblasts and PBMC was mediated through direct contact and by secreted humoral factors. ICAM-1 on renal fibroblasts may be involved in the direct cell-to-cell interaction inducing MCP-1 gene expression, which seems to be involved in renal interstitial inflammation.
Activation of CR3-mediated phagocytosis by MSP requires the RON receptor, tyrosine kinase activity, phosphatidylinositol 3-kinase, and protein kinase C ζ
Authors: Lutz Michael A , Correll Pamela H
Published: May 2003

Macrophage-stimulating protein (MSP) promotes the phagocytosis of C3bi-coated erythrocytes by resident peritoneal macrophages, although the mechanism by which this occurs is largely unknown. We show that MSP-induced complement-mediated phagocytosis requires the RON receptor tyrosine kinase and the αMβ2 integrin, as evidenced by the inability of RON−/− and αM−/− peritoneal macrophages to augment phagocytosis of complement-coated sheep erythrocytes in response to MSP. MSP stimulation of macrophages results in tyrosine phosphorylation and AKT activation, and inhibitor studies demonstrate a phagocytic requirement for tyrosine kinase and phosphatidylinositol 3-kinase (PI-3K) activity as well as activity of the atypical protein kinase C (PKC) isoform ζ, which localizes to MSP-induced phagosomes containing complement-coated beads. Additionally, MSP augments the ability of peritoneal macrophages to bind to intercellular adhesion molecule-1 (ICAM-1) via the αMβ2 integrin. MSP-induced ICAM-1 adhesion is also dependent on tyrosine kinase activity, PI-3K, and PKC ζ, indicating that these signaling requirements are upstream of complement receptor 3 activation.
Up-regulated expression of MICA on activated T lymphocytes involves Lck and Fyn kinases and signaling through MEK1/ERK, p38 MAP kinase, and calcineurin
Authors: Molinero Luciana L , Fuertes Mercedes B , Fainboim Leonardo , Rabinovich Gabriel A , Zwirner Norberto W
Published: May 2003

Major histocompatibility complex class I-related chain (MICA) is a cell stress-regulated molecule recognized by cytotoxic cells expressing the NKG2D molecule. MICA can be induced on T cells after CD3 or CD28 engagement. Here, we investigated the intracellular pathways leading to activation-induced expression of MICA. The Src kinase inhibitor PP1 inhibited up-regulated expression of MICA on anti-CD3-stimulated T cells. Downstream signaling routes involved mitogen-activated protein kinase (MAPK) kinase (MEK)1/extracellular signal-regulated kinase (ERK), p38 MAPK, and calcineurin, as MICA expression was prevented by U0126, SB202190, cyclosporin A, and FK506. Also, Lck and Fyn as well as MEK1/ERK and p38 MAPK were found to regulate MICA expression in anti-CD28/phorbol 12-myristate 13-acetate-stimulated T cells. Expression of MICA on activated T cells involved interleukin-2-dependent signaling routes triggered by Janus tyrosine kinases/signal transducer and activators of transcription and p70S6 kinase, as it could be inhibited by AG490 and rapamycin. This is the first demonstration of the intracellular pathways involved in activation-induced expression of MICA, which may reveal potential targets for immune intervention to modulate MICA expression in pathological disorders.
Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice
Authors: Lin Zi-Qing , Kondo Toshikazu , Ishida Yuko , Takayasu Tatsunori , Mukaida Naofumi
Published: May 2003

To clarify interleukin (IL)-6 roles in wound healing, we prepared skin excisions in wild-type (WT) and IL-6-deficient BALB/c [knockout (KO)] mice. In WT mice, the wound area was reduced to 50% of original size at 6 days after injury. Microscopically, leukocyte infiltration was evident at wound sites. Furthermore, the re-epithelialization rate was ∼80% at 6 days after injury with increases in angiogenesis and hydroxyproline contents. The gene expression of IL-1, chemokines, adhesion molecules, transforming growth factor-β1, and vascular endothelial growth factor was enhanced at the wound sites. In contrast, the enhanced expression of these genes was significantly reduced in KO mice. Moreover, in KO mice, the reduction of wound area was delayed with attenuated leukocyte infiltration, re-epithelialization, angiogenesis, and collagen accumulation. Finally, the administration of a neutralizing anti-IL-6 monoclonal antibody significantly delayed wound closure in WT mice. These observations suggest that IL-6 has crucial roles in wound healing, probably by regulating leukocyte infiltration, angiogenesis, and collagen accumulation.
Ly49E expression points toward overlapping, but distinct, natural killer (NK) cell differentiation kinetics and potential of fetal versus adult lymphoid progenitors
Authors: Stevenaert Frederik , Van Beneden Katrien , De Creus An , Debacker Veronique , Plum Jean , Leclercq Georges
Published: May 2003

Using a new antibody, we found previously that contrary to adult natural killer (NK) cells, fetal NK cells have a unique phenotype, as they exclusively express Ly49E. This can be explained by an intrinsic different NK differentiation potential of fetal versus adult lymphoid progenitors, by immaturity of fetal NK cells or by instability of Ly49E expression. Here, we show that adult progenitor cells were still capable of differentiating into Ly49E-expressing NK cells but at a much lower frequency. Surprisingly, Ly49E expression in vitro did not require stromal cells. Kinetic analysis in vivo showed that Ly49E was expressed early, together with CD94/NKG2 and Ly49G2, followed by Ly49C, and finally Ly49D. Transfer of sorted Ly49E-positive fetal NK cells showed stable Ly49E expression, and later, part of these cells up-regulated other Ly49 members. These data indicate that although there are intrinsic differences, there is no strict fetal and adult wave of NK cell differentiation.