Ischemia in the ambulatory setting--the total ischemic burden: relation to exercise testing and investigative and therapeutic implications

To establish the relation between treadmill exercise testing and ambulatory St segment monitoring in the detection of ischemia in patients with coronary artery disease, and to assess whether standard medical therapy affects any such relation, 277 patients with stable angina and angiographically documented coronary artery disease were studied with treadmill exercise testing and 48 h ambulatory ST segment monitoring. One hundred forty-six patients (52%) were studied while receiving no routine antianginal therapy, and 131 (48%) while receiving standard medical therapy. In 187 patients (67%) the exercise test was positive for ischemia. During 11,964 h of ambulatory monitoring, 881 episodes of ischemia (645 [73%] silent) were recorded, of which 809 (92%) occurred in patients with a positive exercise test. The mean heart rate at the onset of ischemic episodes during ambulatory monitoring was significantly less than that at the onset of 1 mm ST segment depression during exercise testing (94.5 versus 105.9 beats/min, p less than 0.0001). However, the frequency of ambulatory ischemic episodes was strongly related to a positive exercise test (p less than 0.001), and this relation was similar for both silent and painful ischemia (p less than 0.0001 for both) and in patients who were and were not receiving therapy (p less than 0.0001 for both). The total duration of ischemia was similarly related to a positive exercise test (p less than 0.0001). Only one patient with a negative exercise test had frequent (greater than 5/day) episodes of ischemia on ambulatory monitoring and had documented coronary artery spasm. Thus, exercise testing identifies the majority of patients likely to have significant ischemia during their daily activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dual Antiplatelet Therapy Duration Determines Outcome After 2- But Not 1-Stent Strategy in Left Main Bifurcation Percutaneous Coronary Intervention

Objectives

The aim of this study was to investigate clinical outcomes after left main coronary artery (LM) bifurcation percutaneous coronary intervention (PCI) and the impact of the duration of dual antiplatelet therapy (DAPT) according to treatment strategy.

Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C

BACKGROUND & AIMS: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection. METHODS: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant. RESULTS: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048). CONCLUSIONS: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.     

Prognostic significance of bcl-2, bax,and p53 expression in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLCL) exhibits heterogeneous clinical features and varies markedly in response to treatment and prognosis. Because apoptosis-related proteins may play an important role in predicting the prognosis of DLCL, the current study investigated the prognostic significance of a high level of bcl-2, bax, and p53 expression in relation to clinical characteristics in patients with DLCL. Paraffin-embedded specimens from 94 patients with de novo DLCL were analyzed immunohistochemically for bcl-2, bax, and p53 gene expression. Cases with a positive immunohistological stain in more than 50% of the tumor cells were considered to have DLCL-positive expression. Patients were treated optimally, i.e., with radiotherapy including brief cycles of CHOP or CHOP-like regimens for patients with stage 1-2A diseases and with at least 6 cycles of CHOP or CHOP-like regimens for stage 2B-4 diseases. The responses to therapy and survival were then analyzed in 94 uniformly staged patients. bcl-2 expression was identified in 24 patients (26.4%), bax expression in 35 patients (37.6 %), and p53 expression in 21 patients (22.6%). bax expression proved to be a statistically significant prognostic factor in predicting the overall survival (OS) (P = 0.0015) and disease-free survival (DFS) (P = 0.0052), regardless of other clinical factors or immunohistological results. There was no significant difference in the OS (P = 0.0682) or DFS (P = 0.088) between the bcl-2-positive (n = 24) and bcl-2-negative (n = 67) groups. However, bcl-2 expression was found to be unfavorably associated with the OS (P = 0.0054) in a confined group with low (n = 51) or low intermediate (n = 22) IPI scores. The expression of p53 exhibited no statistical correlation with the OS or DFS. A multivariate analysis revealed that IPI score, bulky mass, and bax expression were all significantly associated with the DFS or OS. bax and bcl-2 should be considered as independent biologic prognostic parameters in DLCL, thereby aiding in the identification of patient risk groups. As such, bcl-2-positive patients with a low or low intermediate IPI score, or without a high level of bax expression could be candidates for more intensive therapy or alternative therapeutic approaches.     

Adult Hirschsprung's disease

Eleven patients with adult Hirschsprung's disease were treated at Seoul National University Hospital (SNUH, 8 cases) and Chosun University Hospital (CUH, 3 cases) between 1985 and 1992. Of the 11 patients, seven were male. The age of the patients ranged from 11 to 30 years, and all presented with chronic constipation and recurrent faecal impactions that required periodic enemas and laxatives. The Duhamel's operation, as a single or staged procedure, was performed in all patients. Levels of aganglionosis in 9 patients were confined to the rectosigmoid colon (82%). There were three major post-operative complications. Two patients developed fistula-in-ano at the anastomotic site, and one patient developed ileus. However, these complications resolved with conservative management. The longterm results were excellent except for one patient who developed impotence. The mean frequency of bowel movements was usually once or twice a day without the aid of other treatments. Our results indicate that Duhamel's operation is a highly acceptable procedure in the management of adult Hirschsprung's disease.

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Résumé 11 patients adultes porteurs d'une maladie de Hirschsprung ont été traités à l'Hôpital Universitaire National de Séoul (8 cas) et à l'Hôpital Universitaire de Chosun (3 cas) entre 1985 et 1992. Des 11 patients 7 étaient des sujets mâles. L'âge des patients variait de 11 à 30 ans et tous se présentaient avec une constipation chronique et des sujets mâles. L'âge des patients variait de 11 à 30 ans et tous se présentaient avec une constipation chronique et des impactions fécales récidivantes nécessitant des lavaments périodiques et la prise de laxatifs. L'opération de Duhamel en un temps ou en plusiers temps opératoires a été réalisée chez tous les patients. Le niveau du segment aganglionnaire était limité au rectosigmoïde chez 9 patients (82%). 3 complications postopératoires majeures sont à déplorer. 2 patients ont développé une fistule anale au niveau de la zone anastomotique et un patient a développé un iléus postopératoire. Ces complications toutefois se sont résolues par un traitement conservateur. Les résultats à long terme étaient excellents à l'exception d'un patient qui a développé une impuissance. La fréquence moyenne des exonérations était habituellement de une à deux exonérations quotidiennes sans recours à un traitement complémentaire autre. Nos résultats indiquent que l'opération de Duhamel est une intervention très satisfaisante dans le traitement dela maladie de Hirschsprung de l'adulte.

     

Organization of the human transferrin gene: direct evidence that it originated by gene duplication.

We present the characterization of two overlapping human transferrin genomic clones isolated from a liver DNA library. The two clones represent a total length of 24 kilobase pairs and code for 70% of the protein. The organization of this gene region was elucidated by restriction mapping and DNA sequencing. It contains 12 exons, ranging from 33 to 181 base pairs, separated by introns of 0.7-4.9 kilobase pairs. This gene can be divided into two unequal parts corresponding to the known domains of the protein. Each part is essentially composed of an equal number of exons; introns interrupt the coding sequences, creating homologous exons of similar size in each moiety. Moreover, the pattern of intron interruption of the codon sequence is identical for all the analyzed homologous exon pairs. Comparison with the organization of the ovotransferrin gene shows an identical exon size distribution. These data confirm, at the gene level, the hypothesis that transferrins originated by a gene-duplication event. A model accounting for the origin of the human transferrin gene is presented.     

General 2.5 power law of metallic glasses

Metallic glass (MG) is an important new category of materials, but very few rigorous laws are currently known for defining its “disordered” structure. Recently we found that under compression, the volume (V) of an MG changes precisely to the 2.5 power of its principal diffraction peak position (1/q₁). In the present study, we find that this 2.5 power law holds even through the first-order polyamorphic transition of a Ce₆₈Al₁₀Cu₂₀Co₂ MG. This transition is, in effect, the equivalent of a continuous “composition” change of 4f-localized “big Ce” to 4f-itinerant “small Ce,” indicating the 2.5 power law is general for tuning with composition. The exactness and universality imply that the 2.5 power law may be a general rule defining the structure of MGs.Metallic glasses (MGs) possess many unique and superior properties, such as extremely high strength, hardness, and corrosion resistance, etc., making them promising metallic materials with widespread applications (1, 2). Thousands of MGs with a wide range of compositions and properties have been synthesized over the past decades. However, so far the development of MGs is mainly based on tedious composition mapping in multicomponent space to pinpoint the combination of elements with optimized glass-forming ability (GFA). This method for development of MGs is a time- and resource-intensive strategy of trial and error which highlights the need for the guidance of a general theory (2, 3). Intensive research effort has been devoted to finding general rules in various MGs to understand the fundamentals and to guide the development of new MGs (4, 5). Quantitative correlations between their properties have been observed. For instance, compressive yield strength and elastic moduli of MGs are found to be intimately connected with their glass transition temperature T_g (6–10), and the ductility, fragility (11, 12), and Poisson’s ratio of MGs are closely related (13–16). The extensive correlations in properties suggest that the disordered MGs may share general rules in their structure. To clarify this scenario, detailed and accurate structural information spanning short range to long range is required. However, the current experimental probes and theories are limited to local structure in MGs (17). Therefore, understanding how the atoms efficiently fill up the 3D space and how this controls the bulk properties of MGs remains a long-standing theoretical challenge (18–23). To date, few general and exact rules regarding structure–property relationships have been established in MGs (23).Encouraging progress on understanding structure–property relationships in MGs has recently been made through the discoveries of the noncubic (2.3 or 2.5) power laws that correlate the principal diffraction peak (PDP) position q₁ with the bulk density ρ or average atomic volume, V_a, i.e., ρ∝(q₁)^D or V_a∝(1/q₁)^D, where D equals ∼2.3 with varying the composition of MGs at ambient pressure (19) or ∼2.5 for tuning the density of MGs with pressure (22, 24). Whereas composition and pressure show similar exponents in the power laws in MGs, composition and pressure are two independent variables for controlling the density (volume) of materials; they usually have dramatically different effects on MGs. For example, pressure is thought to cause only elastic densification in MGs without obvious structural change because of their already densely packed structure; the structure and properties of MGs are very sensitive to even minor compositional variations (25, 26). In addition, to achieve composition change, different samples usually have to be synthesized. And, many other variables are thought to be inevitably involved, making the compositional change complex (23). Therefore, some basic questions have been perplexing to the glass community: Why do “complex” compositional and “simple” pressure power laws show similar exponents? Is there any connection between them? These questions remain unanswered and have been the major obstacle in understanding the nature of these noncubic power laws.To address these questions, a systematic study in the 2D pressure-composition space seems to be required. However, the consistency of the data in this kind of study will be questionable. Alternatively, in the present study, we choose the polyamorphous Ce₆₈Al₁₀Cu₂₀Co₂ MG as a model system. It is well known that Ce-based MG systems show a polyamorphic transition between ∼2 GPa and ∼5 GPa caused by the pressure-induced 4f electron localized-to-itinerant transition (27, 28). During this polyamorphic transition, both the atomic size and the electronegativity of Ce are significantly changed (29). Composition tuning in MGs mainly means the variation of atomic size and electronegativity of components, which controls the formation of MGs (30). Therefore, although nothing changes in the nucleus, for MGs this pressure-induced polyamorphic transition is equivalent to a continuous “composition” change with the 4f-localized “big Ce” gradually substituted by 4f-itinerant “small Ce.” As a result, we are able to vary both pressure and composition of a MG in a well-controlled way for the first time, to our knowledge.     

Ultrastructural and phenotypic analysis of in vitro erythropoiesis from human cord blood CD34<Superscript>+</Superscript> cells

Erythropoietin (EPO) induces erythropoiesis in vitro as well as in vivo, and the process of erythroid differentiation has been explored phenotypically and morphologically. However, morphological analysis of in vitro erythropoiesis of human hematopoietic progenitor cells at the ultrastructural level has not been reported before. In the present study, we have traced the ultrastructural changes of erythroid differentiation during ex vivo expansion of human cord blood (CB) CD34(+) cells in the presence of EPO by electron microscopy (EM), along with concurrent phenotypic analysis. CD34(+) cells purified from ten CBs by immunomagnetic selection were cultured in serum-free essential media in the presence of a combination of the several cytokines including EPO, thrombopoietin, flt3-ligand (FL), stem cell factor (SCF), granulocyte colony-stimulating factor, interleukin (IL)-3 and/or IL-11. Phenotypic analysis was performed by flow cytometric analysis for erythroid markers, including glycophorin C (GPC), Kell-related, glycophorin A (GPA), band 3, Lu(b), and RhD. Ultrastructural analysis was performed by electron-microscopic examination of the cultured cells stained with uranyl acetate and lead citrate. Phenotypic analysis revealed that in the absence of EPO, genuine erythroid fraction expressing the typical pattern of erythroid markers did not appear. The order of the above markers expressed in the cultured cells in the presence of EPO was GPC, Kell-related, GPA, band 3, Lu(b), and RhD, irrespective of the type of cytokine added. Of the cytokines used in combination with EPO, FL + IL-3 was the most efficient in inducing erythroid differentiation, which was followed by SCF + IL-3. EM examination demonstrated complete process of erythroid development from pronormoblasts to reticulocytes with nuclei having been extruded and mature erythrocytes. These results suggest that morphologically intact erythrocytes could be produced by ex vivo expansion of CB CD34(+) cells using EPO.     

Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer

Fibroblast growth factor (FGF), a key regulatory factor of cell growth and differentiation, is involved in embryonic development, angiogenesis, and tumorigenesis. To date, four different FGF receptors (FGFRs) have been cloned and characterized. We examined the expression of four FGFRs in human gastric cancer tissues and cell lines using Northern analysis, ribonuclease protection assay, and immunohistochemistry. The mRNAs of FGFR-1 (10/14), FGFR-2 (9/14), and FGFR-4 (9/14) were up-regulated in cancer compared with normal tissues. FGFR-3 mRNAs were barely detectable in both normal and cancer tissues. These FGFR mRNAs were co-expressed in various combinations of two or three in the same tissue. Immunohistochemistry confirmed specific staining of multiple FGFRs, except FGFR-3, in the cancer specimens. To investigate the functional significance of FGFR co-expression we examined the invasive property of SNU-16 cells, which exhibited gene amplification of FGFR-2, -3, and -4 as well as over-expression of keratinocyte growth factor receptor (KGFR), a splice variant of FGFR-2, and FGFR-4 mRNA. KGF plus acidic FGF (aFGF), KGF, and aFGF treatment enhanced the invasive potential of SNU-16 cells over the control by 100%, 107%, and 47%, respectively, indicating that neither additive nor synergistic effect was induced by stimulation with aFGF plus KGF. These results suggest that co-expression of FGFRs in various combinations may cause subtle changes in the progression of gastric cancer. Received: 16 February 1999 / Accepted: 6 March 2000     

Correlation between hMLH1/hMSH2 and p53 protein expression in sporadic colorectal cancer

BACKGROUND/AIMS: The aim of this study was to analyze expression of hMLH1 and hMSH2 mismatch repair proteins in terms of p53 protein expression and clinicopathological parameters in sporadic colorectal cancer. METHODOLOGY: Four hundred and two cases of curative colorectal surgery for primary colorectal cancer were included in this study (patients with a familial history of colorectal cancer and familial adenomatous polyposis were not included). Clinicopathological parameters were reviewed retrospectively. HMLH1, hMSH2 and p53 protein expression in tumor tissue sections was determined using immunohistochemical staining with specific monoclonal antibodies. RESULTS: Of the 402 cases, immunohistochemical analysis showed 35 (8.7%) had loss of expression of hMLH1, 19 (4.7%) had loss of expression of hMSH2, and three cases (0.7%) had loss of expression of both proteins. Multivariate analysis showed that early age of onset (p=0.023), right side dominance (p<0.001) and poorly differentiated or mucinous cell type (p<0.001) were associated with loss of expression of hMLH1 or hMSH2. Loss of expression of hMLH1 or hMSH2 correlated with low p53 expression (p<0.001). In terms of clinicopathological parameters, p53 expression was associated only with hMLH1 or hMSH2 expression. CONCLUSIONS: Colorectal cancers not expressing hMLH1 or hMSH2 may have distinct features from those expressing these mismatch repair proteins. p53 expression appears to be implicated in a compensatory pathway with mismatch repair proteins.