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PubMed1999

[Effects of reperfusion and coronary reocclusion on the variability of heart rate in patients with acute myocardial infarction].

The aim of this study was to analyze the very early (first 24 hours) effect of successful or failed thrombolytic therapy on the autonomic nervous system. Thirty consecutive patients with a first acute myocardial infarction were enrolled in the study, and admitted to the Coronary Care Unit within 6 hours of the onset of symptoms and treated with systemic thrombolytic therapy. All patients underwent 24-hour Holter monitoring in order to analyze ST segment variation. The autonomic nervous system was evaluated by frequency-domain heart rate variability: low frequency/high frequency ratio (LF/HF) was measured at the beginning of Holter monitoring (T1), 15 min after reperfusion or 1 hour from the start of thrombolytic therapy (T2) and after 24 hours (T3). Reperfusion status was assessed by a > or = 50% reduction in ST segment elevation within 90 min of thrombolytic therapy, and early CK-MB peak. Early coronary reocclusion was detected by early reduction in ST segment elevation followed by stable ST segment re-elevation. Twenty patients (66%) showed successful thrombolytic therapy (Group 1), 5 patients (17%) had no evidence of successful thrombolytic therapy (Group 2) and 5 patients (17%) showed an early reocclusion (Group 3). LF/HF ratio values at T1 were similar in the three groups (5.66 +/- 1.7 vs 5.65 +/- 1.2 vs 5.51 +/- 0.9, NS). At T2, LF/HF ratio was significantly higher in Group 1 and 3 than Group 2 patients (9.21 +/- 1.7 and 11.1 +/- 1.2 vs 5.58 +/- 1.4, respectively, p < 0.001). In Group 1 LF/HF ratio was significantly lower at T3 when compared with T1 and T2 (1.9 +/- 1 vs 5.66 +/- 1.7 and 9.21 +/- 1.7, respectively, p < 0.001). Conversely, in Group 3 LF/HF ratio at T3 was similar to values measured at T1 (5.59 +/- 1.7 vs 5.51 +/- 0.9, respectively, NS) and significantly higher than those detected in Group 1. In Group 2, LF/HF ratio resulted substantially unchanged at T3 (5.49 +/- 1.7, NS). In conclusion, 1) successful thrombolytic therapy induces early beneficial effects on the autonomic nervous system function, as shown by increased heart rate variability values, when compared with failed thrombolytic therapy; 2) however, during the early period following coronary reperfusion, a transient but dramatic increase in sympathetic activity is observed. This could trigger coronary flow instability, thus facilitating reocclusion, by activating different pathogenetic mechanisms (increased vascular tone, platelet activation, thrombogenic factor prevalence); 3) early coronary vessel reocclusion precludes favorable effects of reperfusion on sympatho-vagal balance observed after the first 24 hours.

Aged↗
PubMed2000

Serial troponin I measurements detect recurrent myocardial infarction after initial acute myocardial infarction.

UNLABELLED: Serial serum troponin I and CK-MB measurements were obtained for 36 patients presenting to the emergency department with a confirmed diagnosis of acute myocardial infarction (AMI). For each patient, the normalized percentage of maximum troponin I concentration (%max TropI) was plotted vs. the time from the maximum value to obtain a kinetic decay plot. The linear correlation plots of the--Log (%max TropI) vs. time were compared. Patients with uncomplicated AMI (n = 31) showed linear correlation coefficients (CC) above 0.97 (mean CC = 0.991). Patients with AMI complicated by recurrent myocardial infarction (n = 5) documented by corroborate clinical findings, electrocardiographic abnormalities and/or abnormal CK-MB results showed linear correlation coefficients (CC) less than 0.97 (mean CC = 0.763). Using a cutoff value of CC = 0.97, both patient groups were completely separated and re-infarction or extension of infarction was predicted with 100% accuracy, sensitivity and specificity. CONCLUSION: Kinetic modeling of troponin I decay in patients with AMI correctly differentiates patients with complicated vs. non-complicated courses.

Creatine Kinase↗
PubMedDate not supplied

Incorporation of an artificial receptor into a native protein: new strategy for the design of semisynthetic enzymes with allosteric properties.

The sugar-facilitated structure and enzymatic activity change of engineered myoglobins bearing a phenylboronic acid moiety, which were semisynthesized by a cofactor reconstitution method, were studied by the denaturation experiment, spectrophotometric titration of the pKa shift of the axial H2O, circular dichloism (CD), and the kinetics of the myoglobin-catalyzed-aniline hydroxylation reaction. Both boronophenylalanine-appended myoglobin [Mb(m-Bphe)2] and phenylboronic acid-appended myoglobin [Mb(PhBOH)2] were stabilized by approximately 2 kcal/mol upon complexation with D-fructose. CD spectral changes and the sugar-induced pKa shift suggested that the microenvironment of the active site of these myoglobins was re-formed from a partially disturbed state to that comparable to the native state upon D-fructose binding. The correlation of pKa with kcat (for the aniline hydroxylase activity) and the delta GDH2O-kcat profile showed that these structural changes of Mb-(m-Bphe)2 and Mb(PhBOH)2 were closely related to their sugar-enhanced aniline hydroxylase activity. Thus, the results established that an incorporation of the artificial receptor molecule can be a valid methodology for the design of stimuli-responsive semiartificial enzymes.

Aniline Hydroxylase↗
PubMed2003

A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2'-deoxycytidine.

Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor alpha (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines. Scriptaid treatment of three ER negative cell lines, MDA-MB-231, MDA-MB-435 and Hs578t, resulted in significant growth inhibition and increased acetylation of H3 and H4 histone tails. Quantitative Real Time PCR showed 2000-20,000-fold increase of ER mRNA transcript in all three cell lines after 48 h of Scriptaid treatment. Further, dose dependent re-expression of an estrogen responsive gene, the progesterone receptor (PR), indicated that induced ER is functional. As seen with TSA and AZA, Scriptaid and AZA co-treatment was more effective in inducing ER than Scriptaid or AZA alone. In vivo analysis using a xenograft mouse model bearing MDA-MB-231 tumors showed decreased tumor growth following Scriptaid or TSA treatment. Our results indicate that the novel HDAC inhibitor, Scriptaid, inhibits tumor growth in vitro and in vivo and, in conjunction with AZA, acts to re-express functional ER. These data suggest that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.

Acetylation↗
PubMed1999

Serum markers of treatment success in leprosy.

UNLABELLED: Intercellular adhesion molecule-1 (ICAM-1) and E-selectin and other variables were evaluated as possible markers of the success of multidrug therapy (MDT) in leprosy. Multibacillary (MB, N = 45) and paucibacillary (PB, N = 29) leprosy patients were examined during MDT, which typically lasted 12 months for MB and 6 months for PB patients. Serum values for total protein, albumin, immunoglobulin gamma (IgG), ICAM-1, and E-selectin (selectin) were recorded, as were lesion type, number, and distribution. Response at the end of therapy was assessed as good, fair, or poor. The bacterial index (BI) of lesions was measured at the beginning and end of therapy. The earlier reported findings of this investigation are herein re-examined. RESULTS: age and lowered serum albumin correlated with the poorer condition of the patients, as did elevated selectin. Albumin was inversely correlated with the BI (p = 0.008) in MB patients, and IgG was positively correlated (p = 0.009). ICAM and E-selectin alone were not useful markers of individual patient condition. A regression combining serum albumin under 41 g/l, age and E-selectin was able to identify 85% of the patients in poorer condition. CONCLUSION: serum albumin was a useful nonspecific marker of both patient condition and infection. Age is an important negative factor in patient response. Albumin and IgG correlate with the BI and with each other (p = 0.011) in MB patients, but not in PB patients.

Adolescent↗
PubMed2004

5-aza-2'-deoxycytidine restores the E-cadherin system in E-cadherin-silenced cancer cells and reduces cancer metastasis.

Down-regulation of the E-cadherin-mediated cell adhesion system is strongly related to cancer invasion and metastasis. Aberrant CpG hypermethylation in the promoter region of the E-cadherin gene has been shown to be responsible for reduction of E-cadherin expression. The present study was designed to test the hypothesis that the demethylating agent 5-aza-2'-deoxycytidine (AZA) can restore the E-cadherin system and reduce the potential for metastasis. AZA treatment modified the methylation status of the 5' CpG island in the E-cadherin promoter, and induced re-expression of E-cadherin in human cancer cells whose E-cadherin expression had been silenced. The re-expressed E-cadherin was correlated with increased in vitro aggregation and reduced motility. After inoculation of cancer cells (MDA-MB-435S) into the mammary fat pads of mice with severe combined immunodeficiency, the mice were treated for nine consecutive weeks with AZA three times per week i.p. The AZA treatment suppressed both growth of the primary tumor and lung metastasis in comparison with untreated controls, suggesting that the suppression of metastasis may be, at least partly, attributable to restoration of E-cadherin expression. Therefore, inhibition of DNA methylation may be useful for preventing cancer metastasis.

Azacitidine↗
PubMed2000

Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes.

The use of somatic cell hybrids has led to an increased understanding of the 'negative' regulation of cellular phenotype. Using somatic cell hybrids constructed between human breast cells that represent differing stages of malignancy but also display differing phenotypes from the same tissue, we present experimental results suggesting that luminal epithelial characteristics are controlled by repressive mechanisms. Fusion of HBL 100 cells, non-tumorigenic and characteristic of the basal cell lineage, with MCF-7 or MDA-MB-468 malignant breast cancer cells, characteristic of the luminal lineage, resulted in hybrid cells that displayed the phenotype of the HBL 100 cells. Using representational difference analysis, a panel of genes whose expression was repressed in the hybrid between HBL 100 and MDA-MB-468 was identified. This analysis revealed markers of luminal epithelial cells to be repressed, including Ep-CAM, cytokeratin 19 and E-cadherin. These markers were found to be coordinately re-expressed in variant hybrid cells indicating that the observed repression is reversible. Integrin (alpha)(v)(beta)(3) expression was found to be in mutual exclusivity to the luminal epithelial markers, thereby revealing a bidirectional 'switch' in the pattern of gene expression in this system. Finally, the expression of Ep-CAM was found to be lost in heterokaryons produced by fusion of HBL 100 and MCF-7 or MDA-MB-468 cells suggesting that the extinction of this gene in hybrid cells is the consequence of a trans-acting factor(s) synthesized by the HBL 100 cells. These data suggest that a number of markers of luminal cell differentiation in the mammary gland can be controlled through negative mechanisms and that such control of phenotype is highly coordinated.

Adenocarcinoma↗
PubMed2002

Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10cM resolution.

Recurrent (two or more episodes), early-onset (first episode at < or = 25 years) major depressive disorder (RE-MDD) is a strongly familial condition (lambda(first-degree relatives) = 8) whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. The goal of this study was to identify candidate susceptibility loci that influence the development of RE-MDD. We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target susceptibility genes for RE-MDD by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. Both groups included equal numbers of Caucasian men and women and were matched as closely as possible for age and ethnicity. Allelic associations with RE-MDD were observed for 19 of the 387 SSTRPs in the CHLC Human Screening Set/Weber Version 9. Sixteen of the 19 candidate susceptibility loci revealed significant allelic associations with RE-MDD in men (n = 7) or women (n = 9), but not in both sexes. Evidence for both risk and protective alleles was detected. Two of the candidate susceptibility loci reside within several Mb of loci previously reported-megabases to be linked to "comorbid alcoholism and depression" in families of individuals with alcoholism and to a broadly defined affected phenotype that included recurrent major depression in the families of patients with bipolar disorder. Although it has been suggested that the genes that influence risk for MDD in the two sexes may not be entirely the same, the results of our study suggest that sex specificity of susceptibility loci for RE-MDD may be the rule rather than the exception. The observed preponderance of sex-specific susceptibility loci for RE-MDD suggests that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli.

Adolescent↗
PubMed2004

[Experimental investigations of the optimal therapy of systemic BCG infection in vivo].

PURPOSE: Hematogenous spread of BCG after intravesical instillation against bladder cancer is rare, but may result in systemic infection and hypersensitivity reaction. We investigated fluoroquinolones and steroids in an animal model to improve the therapeutic options in local and systemic BCG infection. Furthermore, we tested the antitumor effectiveness of intravesical BCG with simultaneous application of fluoroquinolones and/or steroids. METHODS: After systemic BCG infection, experiments were performed with quinolones as antimicrobial agent. Trimethoprim/sulfamethoxazole (TMS) was also tested in comparison to quinolones as a non-specific antimicrobial agent. To evaluate the hyperergic reaction after repeated BCG infection (hypersensitivity model), re-infection was performed seven days after primary infection with accompanying oral antimicrobial therapy with and without steroids. Intravesical tumor therapy was carried out with BCG in orthotopic murine bladder tumor model MB 49 together with simultaneous antimicrobial therapy. RESULTS: After primary infection, quinolones led to a significant prolonged survival independent of steroid administration. Steroids alone after primary BCG infection reduced the survival. In contrast to these experiments, only steroid-treated mice had a significant improvement in survival after a second challenge with BCG. Therapeutic efficacy of BCG was not affected by antibacterial therapy with quinolones. Steroids alone induced a significantly increased death rate during intravesical BCG therapy. CONCLUSION: Quinolones have a positive effect on survival in acute systemic BCG infection in mice. Re-infection with BCG led to severe hyperergic reaction that can only be influenced by steroids. Thus, quinolones can be used in primary systemic BCG infection after topical application as a sufficient alternative to common tuberculostatics. Repeated BCG instillation may lead to hyperergic reaction, making additional administration of steroids essential. In this animal model, therapeutic efficacy of BCG obviously was not affected by additional administration of antimicrobials.

Adrenal Cortex Hormones↗
PubMed2006

Cariporide attenuates myocardial ischaemia, reperfusion injury and apoptosis in isolated rat hearts.

OBJECTIVE: Inhibition of Na+/H+ exchanger (NHE) may protect the ischaemic reperfused myocardium by attenuating sodium overload. This study investigated the time-dependent beneficial effect of the NHEI inhibitor cariporide and the effect on early apoptosis in a rat model of ischaemia and reperfusion. METHODS AND RESULTS: The hearts of rats were perfused in a Langendorff apparatus. In the first part of the experiment, rats were divided into four groups: I/R (cariporide was not given), HOE-Pr+I/R (cariporide was given 15 min before ischaemia), HOE-Is+I/R (cariporide was given shortly before ischaemia), HOE-Re+I/R (cariporide was given during reperfusion). The left ventricular systolic pressure (LVSP), the left ventricular end-diastolic pressure (LVEDP), arrhythmia, coronary flow and myocardial enzymes were measured. In the second part of the experiment, hearts were bathed in the presence or absence of cariporide before ischaemia. Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assays were used to quantify apoptotic cells. Improvement of recovery from ischaemia, defined as increased LVSP, decreased LVEDP, improvement in arrhythmia score, CK-MB and LDH was more significant in the HOE-Pr+I/R group than in the I/R group. Furthermore, cariporide given during ischaemia caused intermediate improvement of ischaemic recovery, while there was no difference between HOE-Re+I/R and I/R hearts. The number of apoptotic cells after ischaemia and reperfusion was 51.8 +/- 15.2 per 1000 cardiomyocytes compared to 11.5 +/- 5.7 (p < 0.05) in hearts pretreated before ischaemia with cariporide. CONCLUSIONS: In conclusion, cariporide decreases the degree of impaired cardiac recovery and early apoptosis after ischaemia/reperfusion injury. The cardioprotective effects of cariporide are more pronounced when the drug is given before ischaemia.

Animals↗
PubMed2006

Retrotranspositions in orthologous regions of closely related grass species.

BACKGROUND: Retrotransposons are commonly occurring eukaryotic transposable elements (TEs). Among these, long terminal repeat (LTR) retrotransposons are the most abundant TEs and can comprise 50-90% of the genome in higher plants. By comparing the orthologous chromosomal regions of closely related species, the effects of TEs on the evolution of plant genomes can be studied in detail. RESULTS: Here, we compared the composition and organization of TEs within five orthologous chromosomal regions among three grass species: maize, sorghum, and rice. We identified a total of 132 full or fragmented LTR retrotransposons in these regions. As a percentage of the total cumulative sequence in each species, LTR retrotransposons occupy 45.1% of the maize, 21.1% of the rice, and 3.7% of the sorghum regions. The most common elements in the maize retrotransposon-rich regions are the copia-like retrotransposons with 39% and the gypsy-like retrotransposons with 37%. Using the contiguous sequence of the orthologous regions, we detected 108 retrotransposons with intact target duplication sites and both LTR termini. Here, we show that 74% of these elements inserted into their host genome less than 1 million years ago and that many retroelements expanded in size by the insertion of other sequences. These inserts were predominantly other retroelements, however, several of them were also fragmented genes. Unforeseen was the finding of intact genes embedded within LTR retrotransposons. CONCLUSION: Although the abundance of retroelements between maize and rice is consistent with their different genome sizes of 2,364 and 389 Mb respectively, the content of retrotransposons in sorghum (790 Mb) is surprisingly low. In all three species, retrotransposition is a very recent activity relative to their speciation. While it was known that genes re-insert into non-orthologous positions of plant genomes, they appear to re-insert also within retrotransposons, potentially providing an important role for retrotransposons in the evolution of gene function.

Evolution, Molecular↗
PubMed2005

Contemporary stent treatment of coronary bifurcations.

Treatment of coronary bifurcation lesions represents a challenging area in interventional cardiology. The introduction of drug-eluting stents (DES) reduced restenosis in the main branch (MB). However, restenosis at the ostium of the side branch (SB) remains a problem. Although stenting the MB with provisional SB stenting seems to be the prevailing approach, in the era of DES various two-stent techniques emerged (crush) or were re-introduced (V or simultaneous kissing stents, crush, T, culottes, Y, skirt) to allow stenting in the SB when needed. This review describes in detail various techniques used for implantation of two stents by intention to treat.

Combined Modality Therapy↗
PubMed2001

Telemedicine in ultrasound: new solutions.

The transport of dynamic ultrasound (US) pictures as video files or streams no longer presents a problem. Despite teleconferencing, this method of transfer provides no active influence on the data sent for the receiving expert. We are evaluating a software-based 3-D US system that provides the new opportunity of an active US re-evaluation of a virtual patient. The 3-D volumes can be reanalyzed, time- and examiner-independent, wherever the device is installed. To test the clinical feasibility of this virtual US investigation, we installed the device in a peripheral hospital and in our US unit. The transfer of the volume (about 10 to 15 MB) could be done with two parallel Integrated Services Digital Network (ISDN) lines with a conduction capacity of 128 KB/s. In this basic assessment, the transmission of US volumes of patients proved to be easy in the acquisition, quick in off-line transmission and reliable in off-line re-evaluation of the data.

Computer Communication Networks↗
PubMed2006

Baseline troponin level: key to understanding the importance of post-PCI troponin elevations.

AIMS: The adverse prognostic significance of biomarker elevations after percutaneous coronary intervention (PCI) is well established. However, often baseline troponin values are not included in the analysis or sensitive criteria are not employed. Accordingly, we assessed the timing and magnitude of post-PCI troponin T (cTnT) levels and their relationships to outcomes in patients with and without pre-PCI baseline cTnT elevations using a sensitive assay and sensitive cut-off values. METHODS AND RESULTS: cTnT was measured at baseline (pre-PCI), 8 and 16 h post-PCI in 2352 patients. A cTnT elevation was defined as > or =0.03 ng/mL. No baseline cTnT elevations were detected in 1619 patients undergoing mostly (97%) non-urgent procedures (cTnT = 0.01 +/- 0.002 ng/mL; mean +/- SD). 733 patients had baseline cTnT elevations. Only the baseline troponin value had prognostic importance. Patients with elevated cTnT baseline levels had a higher overall cumulative 12-month death/MI rate of 11.1% compared with those without elevated baseline levels of 4.7% (P < 0.05). Neither the timing nor the magnitude of the post-procedure cTnT elevations was predictive of long-term death/MI rates when baseline elevations were included in the analysis. Similar findings were observed for baseline creatine kinase-MB (CK-MB) levels. Late increases in cTnT levels (16 h post-PCI) presaged in-hospital events only. CONCLUSION: Long-term prognosis is most often related to the baseline pre-PCI troponin value and not the biomarker response to the PCI. These results support a re-evaluation of the use of biomarker data in relation to PCI.

Aged↗
PubMedDate not supplied

Computer system for four-dimensional transesophageal echocardiographic image reconstruction.

This paper presents a system for reconstructing a four-dimensional (4D) heart-beating image from transesophageal echocardiographic (TEE) data acquired with a rotational approach. The system consists of the necessary processing modules for two-dimensional (2D) echocardiogram reformation and 3D/4D-image reconstruction. These include the modules of image decoding, image re-coordinating, and three-dimensional (3D) volume rendering. The system is implemented under PC platform with Windows 95 operating system (with Intel Pentium-166 CPU, 64 MB RAM on board, and 2.0 GB hard disk capacity). It takes 6 min to reconstruct a 4D echocardiographic data set. The resultant 2D/3D/4D echocardiographic image provide the tools for investigating the phenomenon of heart beating, exploring the heart structure, and reformatting the 2D echocardiograms in an arbitrary plane. The functions provided by the system can be applied for further studies, such as 3D cardiac shape analysis, cardiac function measurement, and so forth.

Computer Systems↗
PubMed2002

Heterochromatic sequences in a Drosophila whole-genome shotgun assembly.

BACKGROUND: Most eukaryotic genomes include a substantial repeat-rich fraction termed heterochromatin, which is concentrated in centric and telomeric regions. The repetitive nature of heterochromatic sequence makes it difficult to assemble and analyze. To better understand the heterochromatic component of the Drosophila melanogaster genome, we characterized and annotated portions of a whole-genome shotgun sequence assembly. RESULTS: WGS3, an improved whole-genome shotgun assembly, includes 20.7 Mb of draft-quality sequence not represented in the Release 3 sequence spanning the euchromatin. We annotated this sequence using the methods employed in the re-annotation of the Release 3 euchromatic sequence. This analysis predicted 297 protein-coding genes and six non-protein-coding genes, including known heterochromatic genes, and regions of similarity to known transposable elements. Bacterial artificial chromosome (BAC)-based fluorescence in situ hybridization analysis was used to correlate the genomic sequence with the cytogenetic map in order to refine the genomic definition of the centric heterochromatin; on the basis of our cytological definition, the annotated Release 3 euchromatic sequence extends into the centric heterochromatin on each chromosome arm. CONCLUSIONS: Whole-genome shotgun assembly produced a reliable draft-quality sequence of a significant part of the Drosophila heterochromatin. Annotation of this sequence defined the intron-exon structures of 30 known protein-coding genes and 267 protein-coding gene models. The cytogenetic mapping suggests that an additional 150 predicted genes are located in heterochromatin at the base of the Release 3 euchromatic sequence. Our analysis suggests strategies for improving the sequence and annotation of the heterochromatic portions of the Drosophila and other complex genomes.

Algorithms↗