Apoptosis pathways and osteoporosis: An approach to genomic analysis.

BACKGROUND: Osteoporosis is a disease of the bone system that causes a decrease in skeletal density and degrades skeletal tissue. Decreased bone quality, so that bones are easily broken, damaged and fractured, is an important public health problem. Previous studies have shown that the maintenance of adult bone mass is not only due to changes in bone marrow and bone cells. By regulating apoptosis, they change the lifespan of each individual. This study influences understanding of the function of apoptosis in the pathogenesis of osteoporosis and the importance of controlling the mechanisms of osteoporosis. METHODS: On the National Institute of Biotechnology Information website, Gene Expression Omnibus (GEO) microarray data and GSE551495 GEO profiles were collected. The gene set enrichment analysis tool was used to confirm the enrichment of genetic sets in relation to the gene set. The collection of C2 gene sets is compiled from the KEGG (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://www.kegg.jp/kegg/) online database and REACTOME (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://reactome.org/) pathway analysis. The Search Tool for the Retrieval of Interaction Genes (STRING) website was used to construct and select proteins and genes. The comparative toxicological genomic database (CTD) tools can be used to predict the relationship between apoptosis, osteoporosis-related genes and interactions between central genes and osteoporosis. RESULTS: These results generally expand our understanding of the path of apoptosis in osteoporosis. We have discovered genes CASP9, CASP8, CASP3, BAX and TP53 associated with osteoporosis. In activation of KEGG apoptosis and REACTOME, caspase activation through the extrinsic apoptotic signaling pathway is characterized by the identification of a subcollection of C2. Other STRINGs show the formation of protein networks and central gene selection, and CTD can accurately predict the relationship between these apoptosis pathways and central genes. CONCLUSIONS: Our research has highlighted the importance of the osteoporosis pathway associated with osteoporosis apoptosis with several analytical approaches. These results have broadened our understanding of the pathways of osteoporosis apoptosis. It is particularly possible to predict the sensitivity and vulnerability to osteoporosis.

Mass spectrometry-based plasma peptide profiling of acute exacerbation in HBeAg-positive chronic hepatitis B.

BACKGROUND: Acute exacerbations (AE) of serum alanine aminotransferase activities that are 5 times above the normal upper limit frequently occur during the immune clearance phase of hepatitis Be antigen (HBeAg)-positive chronic hepatitis B (CHB). It is unclear how the varying clinical severities of AE reflect differences in the underlying immune responses against the hepatitis B virus. METHODS: We utilized magnetic bead-based purification methods coupled with MALDI-TOF mass spectrometry to generate plasma peptide profiles from HBeAg-positive CHB patients experiencing AE without and with clinical decompensation. RESULTS: Hydrophobic interaction chromatography (HIC C18) provided a more discriminatory spectral profile than immobilized Cu(2+) metal ion affinity chromatography did for diagnosis of a clinical spectrum of AEs. Using the sorting algorithm, Support Vector Machine, a classification model consisting of 5 classifiers was determined to give a sensitivity of 94.7% and a specificity of 75% for differentiating patients with and without decompensation. Classifiers identified as fragments derived from transthyretin and apolipoprotein A-IV were significantly decreased and increased in patients with decompensation, respectively. CONCLUSIONS: Our study demonstrated that HIC C18 fractionation coupled with MALDI-TOF mass spectrometry can be used for differentiating AE with and without decompensation in patients with HBeAg-positive CHB.

Direct tissue analysis by MALDI-TOF mass spectrometry in human hepatocellular carcinoma.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) relies mainly on histopathological imaging examinations after surgical removal of the tumor. However, the rate of tumor recurrence is still high. Defining molecular signatures comprised of a number of distinct peptide ions specific for various tumor regions may improve the classification and prognosis of HCC patients. METHODS: MALDI imaging technology, cluster analysis and classification software were applied to investigate patients with hepatitis B virus (HBV)-related HCC to obtain differences in protein abundance and distribution from non-tumor to tumor regions. RESULTS: A number of mass spectra obtained from non-tumor and HCC tumor sections were readily distinguishable. Progressive change was found in a distance-dependent manner from non-tumor to tumor regions within the junction section of HCC. Fourteen of the peaks were determined from non-tumor and tumor sections as classifiers to classify various non-tumor and tumor regions of the junction section of HCC. The performance of the classification test for the tumor region with a coefficient of variation (CV) of 0.16 was better than the non-tumor region, which reached a CV of 0.53. CONCLUSIONS: Our findings provide peptide information pertaining to the classification of various tumor regions to supplement current histopathological analysis in tumor margins.

Protective effects of Danshen (Salvia miltiorrhiza) on adriamycin-induced cardiac and hepatic toxicity in rats.

The present study was carried out to investigate the protective effects of Danshen (DS, Salvia miltiorrhiza) on adriamycin (ADR)-induced cardiac and hepatic toxicity. Wistar rats were divided into six groups: control group, 10 animals received saline (i.p.); 15 animals received ADR (3 mg/kg, i.p.) three times weekly, for 2 weeks; 10 animals each received DS(1) (20 mg/kg, oral) and DS(2) (100 mg/kg, oral) for 30 days; 15 animals each received DS(1) + ADR and DS(2) + ADR. The ADR-induced cardiac and hepatic toxicity and protective action of DS were determined and quantitated with the use of hemodynamic measurements, biochemical analyses of serum, synthesis rates of DNA, RNA and protein, myocardial antioxidants, lipid peroxidation and histopathological procedure. Liver function was damaged. Nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity and superoxide dismutase activities (SOD) were decreased and histopathology revealed myocardial lesions indicative of ADR-induced cardiac and hepatic toxicity. In contrast, administration of DS before and concurrent with ADR significantly attenuated these effects. In conclusion, DS is potentially protective against ADR-induced cardiac and hepatic toxicity.

Comparative proteomic studies on the pathogenesis of human ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the colon mucosa. Its etiology and pathogenesis remain unclear. We used 2-DE and MS to identify differentially expressed proteins among the UC active, UC inactive, nonspecific colitis, and normal colon mucosa. Thirteen down-regulated and six up-regulated proteins were identified. Of the down-expressed proteins, eight (heat-shock protein 90 (HSPA9B), heat-shock protein 60 (HSPD1), H+-transporting two-sector ATPase (ATP5B), prohibitin (PHB), mitochondrial malate dehydrogenase (MDH2), voltage-dependent anion-selective channel protein 1 (VDAC1), thioredoxin peroxidase (PRDX1), and thiol-specific antioxidant (PRDX2)) were mitochondrial proteins, three (ATP5B, MDH2, triosephosphate isomerase) were involved in energy generation, three (PRDX1, PRDX2, SELENBP1) were cellular antioxidants, and six (HSPD1, HSPA9B, PRDX1, PRDX2, PHB, VDAC1) were stress-response proteins. Transmission electron microscopy revealed pathological alterations of mitochondrial ultrastructures even before the global colonocyte changes in the UC colon mucosa. PHB, an essential mitochondrial component protein, was down-expressed in the disease active as well as inactive colon mucosa from the patients of UC, indicative of an early event of mitochondrial changes during UC development. In contrast, aberrant activation of NFAT and ectopic expression of potential immunogenic proteins (tumor rejection antigen 1 and poliovirus receptor related protein 1) were found in the UC-diseased colon mucosa. Our findings suggest the implications of colonocyte mitochondrial dysfunction and perturbed mucosa immune regulation in the pathogenesis of UC and provide potential targets for the development of a new therapy.

Sheng-mai-san reduces adriamycin-induced cardiomyopathy in rats.

The traditional Chinese medicine prescription "sheng-mai-san (SMS)" has been used for treating patients with coronary heart disease for a long time and was found to have antioxidative effects. Here, we applied adriamycin (doxorubicin, ADR), a highly effective anticancer agent, as an inducer to establish the animal model of dose-related cardiomyopathy due to inhibition of nucleic acid as well as protein synthesis, formation of free radicals, and lipid peroxidation. The objective of this study was to investigate the protective effects of SMS on adriamycin-induced cardiomyopathy. Wistar rats were divided into four groups: CONT (control), ADR, SMS, and ADR + SMS. ADR (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks and SMS was administered via a feeding tube throughout the mouth once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5-week post-treatment period, the hearts of the rats were surgically removed for the study of synthesis rates of DNA, RNA and proteins. Besides myocardial antioxidants, lipid peroxidation and morphological ultrastructure were also evaluated. Three weeks after the treatment, cardiomyopathy and congestive heart failure were characterized according to assessment in ascites, congested liver, depressed cardiac function and myocardial cell damage. The results demonstrated that nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity was decreased and electron microscopic examination revealed myocardial lesion indicative of ADR-induced cardiomyopathy. In contrast, administration of SMS before and concurrent with ADR significantly attenuated the myocardial effects. It also lowered mortality as well as the amount of ascites. In addition, indexes in myocardial GSHPx, macromolecular biosynthesis and superoxide dismutase activities were increasing, with a concomitant decrease in lipid peroxidation and preserved myocardial ultrastructure. These results indicated that SMS may be partially protective against ADR-induced cardiomyopathy.

Genetic variations of apolipoprotein A5 gene is associated with the risk of coronary artery disease among Chinese in Taiwan.

Recently, a T/C polymorphism of the promoter region of the APOA5 gene at position -1131 and a G/T polymorphism at position 553 were found to be associated with increased levels of plasma triglyceride. Triglyceride plays a role in coronary artery disease (CAD), so this case-control study tested for a possible link between these two APOA5 polymorphisms, their common haplotypes and the risk of CAD. The subjects included 211 CAD patients and 677 unrelated controls. A significantly higher level of triglycerides and a lower level of high-density lipoprotein cholesterol (HDL-C) were noted for carriers with -1131C than for non-carriers (P<0.001 and 0.013, respectively) among controls. Plasma triglyceride levels were significantly higher (P=0.014) in controls with genotypes that contained the c.553T allele than in homozygotes for the G allele. Subjects homozygous for the wild-type haplotype had significantly lower triglyceride levels and higher HDL-C levels than subjects with all other haplotype pairs. The -1131C homozygous carriers and c.553T heterozygous carriers were found more frequently in 211 patients with CAD than in the 317 age/sex-matched controls (P=0.008 and 0.023, respectively) in univariate analysis. The significant association between c.553T allele carriers with CAD remained in multivariate regression analysis (OR, 1.79; CI, 1.07-3.00; P=0.028), after adjustments were made for other risk factors. Notably, haplotype analysis further verified that the APOA5 -1131C and c.553T bi-loci haplotype was significantly overpresented in CAD, as compared to the controls. These results indicate that the variants of APOA5 gene modulate plasma triglyceride and may use them to predict CAD susceptibility in Taiwanese Chinese.

Multiple cellular electrophysiological effects of a novel antiarrhythmic furoquinoline derivative HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione] in guinea pig cardiac preparations.

We studied the electrophysiological and antiarrhythmic actions of HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione], a furoquinoline alkaloid derivative, in guinea pig heart preparations. In the perfused whole heart model, HA-7 caused a prolongation in the basic cycle length, ventricular repolarization time, and the atrioventricular (AV) nodal Wenckebach cycle length and prolonged the refractory period of the atrium, AV node, and His-Purkinje system. The atrioventricular conduction interval was also prolonged in a frequency-dependent manner. In isolated hearts, HA-7 significantly raised the threshold for experimental atrial fibrillation and reduced the occurrence of reperfusion-induced ventricular fibrillation. Conventional microelectrode-recording study shows that HA-7, but not d-sotalol, prolonged the action potential duration (APD) and decreased the maximum rate of depolarization in isolated atrial strips. In ventricular papillary muscles, higher concentrations of HA-7 caused a prolongation of APD(90) in a frequency-independent manner, whereas d-sotalol exerted a reverse frequency-dependent action on this parameter. Whole-cell patch clamp results on ventricular myocytes indicate that HA-7 decreased both the slow (I(Ks)) (IC(50) = 4.8 muM) and fast component (I(Kr)) (IC(50) = 1.1 muM) of the delayed rectifier K(+) currents. Similar results could also be observed in atrial myocytes. The inward rectifier K(+) current (I(K1)) was also reduced somewhat by HA-7. HA-7 also suppressed the Na(+) inward current (I(Na)) (IC(50) = 2.9 muM) and inhibited the L-type Ca(2+) current (I(Ca)) (IC(50) = 4.0 muM, maximal inhibition = 69%) to a lesser extent. We conclude that HA-7 blocks multiple ionic currents and that these changes affect the electrophysiological properties of the conduction system as well as the myocardial tissues and may contribute to its antiarrhythmic efficacy.

Functional polymorphisms of FGA, encoding alpha fibrinogen, are associated with susceptibility to venous thromboembolism in a Taiwanese population.

To determine the genetic risk factors for venous thromboembolism (VTE), this study examined 14 genetic variants from 10 hemostatic genes in 186 Taiwanese VTE patients and the same number of matched controls, which demonstrated FGA (encoding alpha fibrinogen) Thr312Ala polymorphism was the only variant significantly associated with VTE. Nine genetic polymorphisms on the fibrinogen cluster region of chromosome 4q28 were further studied, in which four FGA polymorphisms were found in strong linkage disequilibrium and were significantly associated with VTE by genotype and allele frequency analyses. Haplotype analysis showed significantly different FGA haplotype frequencies between VTE patients and controls with the haplotype F1, containing -1051G, -3A, 312Ala and TaqI duplication alleles, significantly associated with susceptibility to VTE (P = 0.001). Haplotype-pair analysis results also indicated a strong association of the haplotype-pair F1F1 with VTE in various VTE patient subgroups. In vitro functional analysis indicated that FGA -1051G, -3A and TaqI duplication alleles enhanced significantly the transcription level of FGA; however, control subjects with FGA genotypes containing these alleles had no elevated plasma fibrinogen levels. In conclusion, our experimental data indicated that functional genetic variants in FGA are risk factors for VTE in Taiwanese populations. Determination of FGA genotypes will likely contribute to primary prevention of this condition.

Molecular signature of clinical severity in recovering patients with severe acute respiratory syndrome coronavirus (SARS-CoV).

BACKGROUND: Severe acute respiratory syndrome (SARS), a recent epidemic human disease, is caused by a novel coronavirus (SARS-CoV). First reported in Asia, SARS quickly spread worldwide through international travelling. As of July 2003, the World Health Organization reported a total of 8,437 people afflicted with SARS with a 9.6% mortality rate. Although immunopathological damages may account for the severity of respiratory distress, little is known about how the genome-wide gene expression of the host changes under the attack of SARS-CoV. RESULTS: Based on changes in gene expression of peripheral blood, we identified 52 signature genes that accurately discriminated acute SARS patients from non-SARS controls. While a general suppression of gene expression predominated in SARS-infected blood, several genes including those involved in innate immunity, such as defensins and eosinophil-derived neurotoxin, were upregulated. Instead of employing clustering methods, we ranked the severity of recovering SARS patients by generalized associate plots (GAP) according to the expression profiles of 52 signature genes. Through this method, we discovered a smooth transition pattern of severity from normal controls to acute SARS patients. The rank of SARS severity was significantly correlated with the recovery period (in days) and with the clinical pulmonary infection score. CONCLUSION: The use of the GAP approach has proved useful in analyzing the complexity and continuity of biological systems. The severity rank derived from the global expression profile of significantly regulated genes in patients may be useful for further elucidating the pathophysiology of their disease.

The genome sequence of Salmonella enterica serovar Choleraesuis, a highly invasive and resistant zoonotic pathogen.

Salmonella enterica serovar Choleraesuis (S. Choleraesuis), a highly invasive serovar among non-typhoidal Salmonella, usually causes sepsis or extra-intestinal focal infections in humans. S. Choleraesuis infections have now become particularly difficult to treat because of the emergence of resistance to multiple antimicrobial agents. The 4.7 Mb genome sequence of a multidrug-resistant S. Choleraesuis strain SC-B67 was determined. Genome wide comparison of three sequenced Salmonella genomes revealed that more deletion events occurred in S. Choleraesuis SC-B67 and S.Typhi CT18 relative to S. Typhimurium LT2. S. Choleraesuis has 151 pseudogenes, which, among the three Salmonella genomes, include the highest percentage of pseudogenes arising from the genes involved in bacterial chemotaxis signal-transduction pathways. Mutations in these genes may increase smooth swimming of the bacteria, potentially allowing more effective interactions with and invasion of host cells to occur. A key regulatory gene of TetR/AcrR family, acrR, was inactivated through the introduction of an internal stop codon resulting in overexpression of AcrAB that appears to be associated with ciprofloxacin resistance. While lateral gene transfer providing basic functions to allow niche expansion in the host and environment is maintained during the evolution of different serovars of Salmonella, genes providing little overall selective benefit may be lost rapidly. Our findings suggest that the formation of pseudogenes may provide a simple evolutionary pathway that complements gene acquisition to enhance virulence and antimicrobial resistance in S. Choleraesuis.

Unusual cardiac papillary fibroelastoma in the right ventricular outflow tract.

Cardiac papillary fibroelastoma (CPF) is the second most common benign neoplasm of the heart. This study describes the case of an 81-year-old man who was admitted to the hospital for severe vertigo and in whom a tumor at the right ventricular outflow tract (RVOT) was identified incidentally during echocardiography. The CPF was excised smoothly following the confirmation of its position by computed tomography. The comprehensive pathologic findings of CPF were reviewed. Detailed immunohistochemical analyses of CD34 and factor VIII-related antigen were performed on the covering endocardial cells. The unique chondroid metaplasia of fibrous tissue in this CPF has never been reported. This work is the first to present an unusual CPF at the RVOT with reactive process of fibrous connective tissue.

Electrophysiological characteristics of accessory pathways with prolonged retrograde conduction.

Electrophysiological characteristics of an accessory pathway (AP) with a long ventriculoatrial (VA) interval (arbitrarily defined as > or = 50 ms and absence of continuous electrical activity) and no retrograde decremental property are described in this study. Fifteen patients (group 1) were compared with 171 patients with normal VA conduction (group 2). Mean VA conduction time was 77 +/- 24 versus 34 +/- 12 ms in group 1 versus group 2, respectively. Group 1 patients were older (55 +/- 14 vs 40 +/- 14 years), the male to female ratio was higher (2.8 vs 1.6), and APs were more prevalent on the right (60%) but manifest APs were lower (20% vs 54%) compared to group 2 patients (P < 0.05 in all cases). QRS morphology during induced atrioventricular reciprocating tachycardia was identical in both groups but the tachycardia cycle length was longer in group 1 (373 +/- 29 vs 344 +/- 50 ms, P < 0.05). Retrograde AP block cycle length and effective refractory period were greater in group 1 (362 +/- 59 vs 293 +/- 57 ms; 330 +/- 58 vs 273 +/- 55 ms, both P < 0.05). Adenosine (up to 18 mg) and verapamil (5-10 mg) failed to block the VA conduction via AP during ventricular pacing. In group 1 the number of radiofrequency lesions for a successful ablation were significantly less (3 +/- 2 vs 6 +/- 5, P < 0.05). In conclusion, APs with a long VA interval and no decremental retrograde conduction have electrophysiological characteristics that are different from those with a short VA interval. Role of aging deserves further exploration.

Evidence that high-dose L-arginine may be inappropriate for use by diabetic patients as a prophylactic blocker of methylglyoxal glycation.

Previous reports have suggested that high-dose L-arginine could be used in diabetic patients as a prophylactic blocker for the initial glycation reaction of proteins by methylglyoxal (MG), a reactive dicarbonyl compound of glucose metabolism. Here, we present several lines of evidence to substantiate that this prophylactic intervention may be inappropriate and should be used with care. First, we demonstrated that when various concentrations of L-arginine (2.0-8.0 mM) were added to a fixed concentration of MG (1.56 microM) in a buffered lucigenin solution, dose-dependent generation of superoxide anion (O(-)(2))-mediated ultraweak chemiluminescence (uwCL) occurs. The suppression of uwCL generation by exogenously added superoxide dismutase further substantiated that the interaction between MG and L-arginine generated O(-)(2). This phenomenon can also be demonstrated in a serum-based system. Furthermore, when a fixed concentration of L-arginine (8.0 mM) was added exogenously to a group of sera obtained from either diabetic patients (n = 10) or their matched nondiabetic controls (n = 10), a marked discrepancy in the generation of O(-)(2)-mediated uwCL could be demonstrated (12,534 +/- 3,147 vs. 950 +/- 350 counts; p < 0.001). Taken together, this evidence demonstrates that the appropriateness of using high-dose L-arginine for prophylactic measures in diabetic patients may be questioned, because the inhibition of the glycation reaction between MG and proteins by high-dose L-arginine unexpectedly produces plethoric O(-)(2) as a by-product, which may subsequently aggravate the preexisting oxidative stress status of diabetic patients.

Establishment of cDNA microarray analysis at the Genomic Medicine Research Core Laboratory (GMRCL) of Chang Gung Memorial Hospital.

BACKGROUND: Advances in molecular and computational biology have led to the development of powerful, high-throughput methods for analysis of differential gene expression, which are opening up new opportunities in genomic medicine. DNA microarray technology has been enthusiastically integrated into basic biomedical research and will eventually become a molecular monitoring tool for various clinical courses. METHODS: As a core research facility of Chang Gung University (CGU) and Chang Gung Memorial Hospital (CGMH), the Genomic Medicine Research Core Laboratory (GMRCL) welcomes investigators from every discipline to employ DNA microarray technology in the quest for knowledge of genomic medicine. The first tasks for GMRCL are to optimize the standard operating procedures (SOP) for each instrument and to assure the quality of every procedure. RESULTS: During the first year after the establishment of the GMRCL at the CGMH, we tested and adopted procedures that were satisfactory for our purposes. These procedures included: replication of bacterial stocks, amplification of human DNA clones, annotation of each DNA clone, production of cDNA microarrays, validation of RNA quality and quantity, labeling of target specimens, competitive hybridization, scanning of slides, data analysis, and post-microarray validation of results. We present a summarization of the materials and procedures used at the GMRCL and discuss the reasons for using them. CONCLUSIONS: The information about the cDNA microarray analysis system at the GMRCL is compliant with the minimal information about a microarray experiment (MIAME) format. The information may be useful to both the investigators who are using this core facility and researchers at other institutes, who will establish their own in-house cDNA microarray systems.

Irregular connexin43 expressed in a rare cardiac hamartoma containing adipose tissue in the crista terminalis.

Cardiac hamartomas are very rare and are demarcated masses of enlarged, hypertrophied, mature myocytes and collagen tissue. Cardiac hamartomas are generally circumscribed in the right ventricle or atrium, but not reported in the crista terminalis (CRT). The CRT is crucial in electrophysiology, is related to arrhythmogenesis, and is targeted by radiofrequency catheter procedures. Previous works only described the benign natures of prominent CRT using non-invasive methods. This study describes an unusual cardiac hamartoma originating from the CRT and extending toward the tricuspid valve. Microscopically, this hamartoma comprised dense collagen and adipose tissue, mixed with hypertrophy, but with disarrayed cardiomyocytes. An irregular gap junction, connexin43, was demonstrated in this cardiac hamartoma.

Three-dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data.

BACKGROUND: The 3D structure of the atrioventricular conduction axis incorporating detailed cellular and molecular composition, especially that relating to gap-junctional proteins, is still unclear, impeding mechanistic understanding of cardiac rhythmic disorders. METHODS AND RESULTS: A 3D model of the rabbit atrioventricular conduction axis was reconstructed by combining histological and immunofluorescence staining on serial sections. The exact cellular boundaries, especially those between transitional cells and atrial myocardium, were demarcated by a dense and irregular desmin-labeling pattern in conductive myocardium. The model demonstrates that the atrioventricular conduction axis is segregated into 2 connecting compartments, 1 predominantly expressing connexin45 (compact node and transitional cells) and the other predominantly coexpressing connexin43 and connexin45 (His bundle, lower nodal cells, and posterior nodal extension). The transitional zone shows unique features of spatial complexity, including a bridging bilayer structure (a deep transitional zone connecting with a superficial atrial-transitional overlay) and asymmetrical continuity (wider atrial-transitional interfaces and shorter atrial-axial distances in the hisian portion than in the ostial portion). In the latter compartment, the His bundle, lower nodal cells, and posterior nodal extension form a continual axis and longitudinal transitional-axial interface. CONCLUSIONS: Key findings of the present study are the demonstration of a distinct anatomical border between transitional and atrial cells, connection between transitional cells and both lower nodal cells and posterior nodal extension, and distinctive connexin expression patterns in different compartments of the rabbit atrioventricular conduction axis. These features, synthesized in a novel 3D model, provide a structural framework for the interpretation of nodal function.

The interactive effects of hepatic lipase gene promoter polymorphisms with sex and obesity on high-density-lipoprotein cholesterol levels in Taiwanese-Chinese.

OBJECTIVES: Hepatic lipase (HL) is involved in the metabolism of several lipoproteins and plays a key role in reverse cholesterol transport. The aim of the current study was to test the statistical association between two HL gene promoter polymorphisms (HL-514C/T and HL-250G/A) and lipoprotein profiles in a Taiwanese-Chinese population. METHODS: A sample population of 716 Taiwanese-Chinese individuals was analyzed. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction enzyme digestion, and agarose gel electrophoresis. RESULTS: Analysis of the data revealed that these two polymorphisms are in strong linkage disequilibrium (D/D(max)=0.97, P<0.001). A significantly lower total cholesterol/HDL-C ratio was noted for carriers with the -514T and -250A alleles compared to non-carriers (P=0.007 and 0.004, respectively). A significant trend of the association was also found on the high levels of high-density-lipoprotein cholesterol (HDL-C) among carriers with the -514T and -250A alleles as opposed to that of non-carriers (P=0.030 and 0.023, respectively). Multivariate analysis has demonstrated that the effects of HL-514C/T and HL-250G/A polymorphisms on HDL-C levels were not affected by subjects' sex, body mass index, plasma triglyceride levels and the cholesterol ester transfer protein gene TaqIB polymorphism. Subgroup analysis on each sex has revealed that the two studied polymorphisms were significantly associated with HDL-C levels among males but not significant in women. The same association between obese and non-obese men was not consistent. The P-value of the respective polymorphisms on HDL-C levels were 0.012 and 0.002 among obese men, but not significant among non-obese men. CONCLUSION: Analysis of our data revealed an independent association between the HL gene promoter polymorphisms and HDL-C levels in Taiwanese-Chinese. The data also suggests that the HL-514C/T and HL-250G/A polymorphisms interact with sex and obesity on HDL-C levels. The findings give clues for identifying high risk population in preventive medicine and clinical diagnosis. The subsequent impacts on treatment profiles and prognosis were derived from this study.

Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis.

BACKGROUND: The effect of percutaneous transluminal angioplasty (PTA) in the treatment of hemodialysis vascular access stenosis is attenuated by a high restenosis rate, which results mainly from neointimal hyperplasia. Cellular proliferation is one of the most important biological mechanisms involved in neointimal hyperplasia and may be a potential target of intervention to prevent restenosis. METHODS: We investigated the activity of cellular proliferation of restenotic lesions by means of immunohistochemistry, using an antibody to the proliferating cell nuclear antigen. Specimens from 10 primary stenotic and 20 restenotic lesions of 30 Brescia-Cimino fistulae were obtained during revision. RESULTS: The proliferation index of the restenotic group was strikingly significantly greater than that of the primary stenotic group (intima, P < 0.001; media, P = 0.001). Proliferation indices of patients with diabetes in the restenotic group were significantly higher than those of patients without diabetes (intima, P = 0.028; media, P = 0.002). In the restenotic group, proliferation indices correlated negatively with the interval from PTA to restenosis (intima, r = -0.741; P < 0.001; media, r = -0.589; P = 0.006) and positively with the number of PTAs per lesion (intima, r = 0.754; P < 0.001; media, r = 0.506; P = 0.004). CONCLUSION: We show markedly high cellular proliferation activity in early restenotic lesions of arteriovenous fistulae. These findings indicate that adjunctive antiproliferative therapy is mandatory in preventing restenosis after PTA, especially in patients with diabetes.

Acute myocardial infarction in a young man complicated with left ventricular thrombi.

Premature coronary artery disease is very rare and complication with thrombus formation in the left ventricle is rarer still. A 23-year-old man was admitted to hospital for recent acute myocardial infarction after being struck by a basketball eight days previously. Echocardiography identified two peduncle thrombi at the apex of the left ventricle, which were confirmed with computed tomography. The proximal left anterior descending coronary artery was totally occluded. Following two weeks of treatment with heparin and warfarin, the patient agreed to undergo a coronary artery bypass graft and thrombectomy. The ecchymosed tissue around the coronary artery implied that a trauma injury might have been the cause of the coronary artery disease in this case. This work reviews the pathophysiology and natural history of coronary artery disease in a case of very young myocardial infarction.