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Biomedical subjects

L Sen

Publications and source records attributed to L Sen.

At least 19 recordsLinked to original sources
PubMed2001

Increased incidence of atrial flutter associated with the rejection of heart transplantation.

Atrial fibrillation (AF) and atrial flutter (Afl) are common dysrhythmias that occur after orthotopic heart transplantation (OHT); however, their etiology and clinical significance have not been defined. To determine the precise incidence of sustained AF and Afl and their association with cardiac rejection, 892 consecutive patients who underwent OHT were studied. A total of 104 patients had 113 episodes of Afl; 102 patients had 117 episodes of AF. The incidence of Afl (12.7%) was the same as AF (13.1%). Sixty-nine AF episodes occurred in first 2 weeks after transplantation, and 22 of which were associated with rejection. In contrast, only 20 Afl episodes occurred the first 2 weeks after OHT, 10 of which were associated with rejection. Fifty-two episodes of Afl occurred during from the third week to 6 months after transplantation, 34 of which were associated with moderate to severe cellular or humoral rejection and/or transplant coronary artery disease (TCAD). All 41 Afl episodes that occurred 6 months after transplantation were associated with cellular and humoral rejection, and/or TCAD. The prevalence of Afl was significantly higher in biatrial than bicaval anastomosis. Atrial conduction defect, manifested by the increase of terminal force of the P wave in lead V(1) of the surface electrocardiogram, predicted the occurrence of Afl and AF associated with rejection in OHT with a sensitivity of 89% and specificity of 92%. These results demonstrate that the incidence of Afl increased after OHT, which might be a consequence of cellular and humoral rejection, and coronary vasculopathy of the transplanted hearts.

Adolescent↗
PubMed2001

Concordance between the CC chemokine receptor 5 genetic determinants that alter risks of transmission and disease progression in children exposed perinatally to human immunodeficiency virus.

If CC chemokine receptor 5 (CCR5)-dependent mechanisms at the time of initial virus exposure are important determinants of virus entry and disease outcome, then the polymorphisms in CCR5 that influence risk of transmission and disease progression should be similar; this hypothesis was tested in a cohort of 649 Argentinean children exposed perinatally to human immunodeficiency virus type 1 (HIV-1). Two lines of evidence support this hypothesis. First, CCR5 haplotype pairs associated with enhanced risk of transmission were the chief predictors of a faster disease course. Second, some of the haplotype pairs associated with altered rates of transmission and disease progression in children were similar to those that we previously found influenced outcome in European American adults. This concordance suggests that CCR5 haplotypes may serve as genetic rheostats that influence events occurring shortly after initial virus exposure, dictating not only virus entry but, by extension, also the extent of early viral replication.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic.

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1alpha) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV- individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1alpha, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1alpha, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.

Africa↗
PubMed2001

Association between high serum prolactin levels and concomitant infections in HIV-infected patients.

Although prolactin (PRL) is now recognized as a cytokine and persistent immune activation is a common immunopathogenic feature of the human immunodeficiency virus infection (HIV), the circumstances associated with the onset of hyperprolactinemia during the course of this infection remain controversial. Given that PRL is able to exert not only endocrinologic effects but also immunologic influences, a study was conducted to investigate whether raised serum levels of PRL were more likely to prevail when HIV-infected patients developed concomitant infections. Serum PRL concentrations, as well as immunoglobulin isotypes, plasmatic viral burden, CD3+, CD4+, CD8+, CD19+, and natural killer (NK) cell counts were measured in 46 nonselected HIV-infected patients stratified on the basis of the presence or absence of clinically active concomitant infections. Serum PRL levels were significantly higher in patients presenting secondary infections as compared with the asymptomatic ones, with hyperprolactinemia being detected in 10/18 (55%) and 2/28 (7%) of these patient groups, respectively. Hyperprolactinemia was not related with viral burden, antiretroviral treatment, gender differences, or CD4+ cell counts. CD3+, CD4+, CD8+, and CD19+ cells were significantly lower in the group presenting active infections, whereas comparisons in NK cell counts, immunoglobulin levels and HIV viral burden revealed no differences between groups. These results provide evidence that hyperprolactinemia is more prevalent during the onset of secondary infections, which might have diagnostic and therapeutic consequences.

AIDS-Related Opportunistic Infections↗
PubMed2001

Effects of human tissue plasminogen gene transfer on allograft coronary atherosclerosis.

BACKGROUND: Transplant coronary atherosclerosis is a major limiting factor to successful long-term cardiac transplantation. The depletion of tissue plasminogen activator (tPA) in the arteriolar smooth muscle cells has been associated with a higher incidence of accelerated graft atherosclerosis. In vivo overexpression of tPA may inhibit accelerated graft atherosclerosis and improve the long-term results of heart transplantation. We evaluated the feasibility, distribution, and effects of intracoronary transfer of the human tPA (htPA) gene in a rabbit heterotopic cardiac transplant model, using a novel cationic liposome compound designed for improved delivery to vascular endothelium. METHODS: Human tPA cDNA under the control of the SV40 promoter (100 microg) was complexed with the novel cationic liposome (+/-)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(dodecyloxy)-1-propanaminium bromide (GAP: DLRIE) (50 microg), and delivered ex vivo to the donor heart by slow intracoronary infusion. Control hearts received an "empty" liposome preparation. Grafts were then implanted into recipient rabbits in the heterotopic cervical position. For the analysis of gene expression, beating donor hearts were collected at 4 days. To examine the effects of htPA expression on graft atherosclerosis, animals received a 0.5% cholesterol diet for 30 days posttransplant, as well as 10 mg/kg cyclosporine A daily. Beating hearts were collected at 30 days posttransplant and analyzed for the development of transplant atherosclerosis by image analysis. RESULTS: Northern blot analysis for the htPA messenger RNA (mRNA) transcripts showed significantly higher counts in hearts receiving the htPA gene as compared to controls. The distribution of these transcripts favored the left ventricle (LV) and septal regions over the right ventricle (RV). Scintillation analysis of specimens stained by immunoflourescence showed expression of htPA throughout the perivascular myocardium that was significantly higher in grafts transduced with the htPA gene than in control or native hearts. Expression in the vascular wall was also significantly enhanced. Scintillation counts per x 200 field were 262 +/- 145 in htPA-transduced hearts and 20 +/- 27 in controls (p = 0.001), and mean luminescence was 83.7 +/- 12.5 in htPA-transduced hearts and 62.9 +/- 12.8 in controls (p = 0.01). Intimal hyperplasia was assessed by mean percent luminal stenosis in small- and medium-sized arteries and was 31.12 +/- 23.5% in htPA-transduced hearts and 86.59 +/- 17.5% in control hearts (p < 0.0001). These results demonstrate that expression of the htPA gene can be induced by ex vivo intracoronary gene transfer at the time of allograft preservation. Liposome-mediated delivery of the htPA gene at the time of transplantation results in significant early transgene expression, and significantly inhibits the development of graft coronary atherosclerosis.

Animals↗
PubMed2001

Electron and light microscopy of neutrophil responses in mice vaccinated and challenged with third-stage infective hookworm (Ancylostoma caninum) larvae.

The role of neutrophils in mediating host inflammation was examined in mice vaccinated with living third-stage infective hookworm larvae (L3). Mice were vaccinated by oral immunization with 500 L3 (Ancylostoma caninum) once every 2 weeks for a total of three immunizations. The vaccinated mice were then challenged intraperitoneally with 2000 L3) 1 week after the final immunization. To stimulate peritoneal production of neutrophils, 2 ml of 2% glycogen were injected intraperitoneally at 16 h prior to the challenge infection. Neutrophils were found to comprise 85% of the peritoneal cell population. L3 from the challenge infection were collected and then examined at timed intervals by inverted light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Greater than a fivefold increase in the total numbers of peritoneal cells was noted in the vaccinated mice as compared to unvaccinated mice. In the peritoneal cavity of vaccinated mice, the neutrophils adhered to the L3 within 2 h, and over 55% of the L3 were surround by clusters of neutrophils to form a sausage-like sheath 4 h later. At 24-72 h after challenge, almost all of the L3 recovered from the vaccinated mice were covered with thick clusters of cells. Both SEM and TEM demonstrated extensive ultrastructural damage to the L3. In contrast, the L3 recovered from the unvaccinated mice appeared to be unaffected by neutrophils. These studies suggest that neutrophils, like macrophages, can have an important role as effector cells in L3-vaccinated mice.

Ancylostoma↗
PubMed2001

Distribution of CCR5-Delta 32 and CCR2-64I alleles in an Argentine Amerindian population.

In order to evaluate the frequency distributions of CCR5-Delta 32 and CCR2-64I polymorphisms in an Amerindian population, we tested a total of 42 Chiriguanos individuals that are aboriginal inhabitants of the north west of Argentina. Only one carried the CCR5-Delta 32 allele (0.0238), while 17 out of 35 carried the CCR2-64I mutation, including one homozygous for the mutated allele (0.2571). Although the cohort studied is considered highly endogamic, the HLA genotyping revealed that 8 out of 42 subjects had a gene flow from Caucasian populations. The only heterozygous CCR5+/Delta 32 found and three heterozygous CCR2+/64I belonged to the admix group. In conclusion, the protective deletion CCR5-Delta 32 is practically absent in Chiriguanos whereas the CCR2-64I allele is highly frequent.

Alleles↗
PubMed2001

Estrogenic status influences nitric oxide-regulated TNF-alpha release from human peripheral blood monocytes.

Cytokines and nitric oxide (NO) have been implicated in bone loss caused by estrogen deficiency. Here we evaluated the effect of nitric oxide synthase (NOS) inhibitors on the bone particle resorbing activity and TNF-alpha release of cultured peripheral blood monocytes (PBM) obtained from 10 premenopausal (PreM) and 10 postmenopausal (PostM) women. Gonadal status (menopause < 3 yr) was assessed by FSH and estradiol. Bone alkaline phosphatase and N-Telopeptide were significantly increased in PostM. Significant differences between PreM and PostM women were observed in bone mineral density of lumbar spine. The bone particle resorbing activity of PBM cultured in the presence of L-arginine-methyl ester (NAME) or aminoguanidine, NOS inhibitors, was determined by (45)Ca release from rat bone labeled particles. TNF-alpha release was assayed in supernatants by ELISA. (45)Ca release was higher in PostM (p < 0.01) and was enhanced by NAME (p < 0.02). Furthermore, TNF-alpha release from PBM was significantly higher in PostM (p < 0.01). Aminoguanidine significantly increased TNF-alpha release in PreM. Based on these findings and on the evidence that estrogen stimulates NOS, we suggest that estrogen withdrawal may reduce the inhibitory effect of NO on TNF-alpha release. Thus, this increased production of TNF-alpha could contribute to the increased postmenopausal bone turnover.

Adult↗
PubMed2001

Efficiency, efficacy, and adverse effects of adenovirus vs. liposome-mediated gene therapy in cardiac allografts.

Virus- and nonvirus-mediated immunosuppressive cytokine gene therapy prolongs cardiac allograft survival in various nonfunctional heart transplant animal models, but its cardiac adverse effects have not been addressed. Recently, we developed a functional heterotopic heart transplant model in rabbits. For the first time, we were able to systematically compare the efficiency, efficacy, and adverse effects of optimized adenovirus- and liposome-mediated ex vivo interleukin (IL)-10 gene transfer in functional donor hearts. The efficiency of liposome-mediated gene transfer was greatly improved in physiologically functioning donor hearts and was only three- to fourfold lower than adenovirus-mediated gene transfer. The efficacy of liposome-mediated IL-10 gene transfer was much higher than that mediated by adenovirus. Significant negative inotropic and arrhythmogenic adverse effects on transplanted hearts were observed due to viral cytotoxicity and immunogenesis, which greatly abated the therapeutic efficacy of this first generation adenovirus-mediated gene therapy.

Adenoviridae↗
PubMed2000

Atrial conduction disturbance as an indicator of rejection after cardiac transplantation.

BACKGROUND: Abnormalities of the terminal force of the P wave in Lead V1 (ptf-V1) and dispersion of corrected atrial repolarization (Ta-TcD) are believed to represent interatrial conduction defect. METHODS AND RESULTS: To determine whether atrial conduction disturbance correlates with cardiac allograft rejection, we analyzed 249 twelve-lead-electrocardiograms, echocardiograms, hemodynamic parameters, and endomyocardial biopsys from 137 patients with heart transplantation. Both ptf-V1 and Ta-TcD were significantly increased in patients with severe, moderate, and mild rejection. In 22 patients, significant increases of the ptf-V1 and Ta-TcD were observed before positive histological findings, and significantly correlated with severity of rejection during 5- week to 1-year follow-up. Increase of 0.030 mm x sec in ptf-V1 or 0.040 s1/2 in Ta-TcD indicated cardiac rejection > or =1B with sensitivity of 88 and 83%, specificity of 85 and 77%, respectively. CONCLUSION: These results suggest that the ptf-V1 and Ta-TcD might be an adjunct to detect rejection and reduce the number of surveillance EMB.

Atrial Function↗
PubMed2000

Hookworm burden reductions in BALB/c mice vaccinated with recombinant Ancylostoma secreted proteins (ASPs) from Ancylostoma duodenale, Ancylostoma caninum and Necator americanus.

Vaccination of mice with alum-precipitated recombinant Ancylostoma secreted protein-1 from the canine hookworm Ancylostoma caninum (Ac-ASP-1) results in protection against A. caninum larval challenge. Vaccine protection is manifested by host reductions in hookworm burden compared to control mice. The goal of this study was to determine whether ASP antigens cloned and expressed from different hookworm species will cross protect against A. caninum larval challenge. Cross-species protection against A. caninum challenge infections was observed with immunizations using recombinant ASP-1 from the human hookworms Ancylostoma duodenale and Necator americanus. However, the degree of protection was proportional to the extent of amino acid sequence homology between the ASP immunogen used for vaccination and the Ac-ASP-1 produced by the challenge larval strain. Vaccine protection was noted to decrease significantly as amino acid sequence homologies diverged 10% or more. It was also determined that Ac-ASP-2, a molecule cloned from A. caninum having 55% amino acid sequence homology to the C-terminus of Ac-ASP-1, did not elicit vaccine protection. These observations were partly reflected in the titer of antibodies that recognize Ac-ASP-1. The studies reported here will help to design immunogenic peptide vaccines based on the sequence divergence of hookworm ASPs.

Ancylostoma↗
PubMed2000

Protective effect of CCR2-64I and not of CCR5-delta32 and SDF1-3'A in pediatric HIV-1 infection.

The effects of chemokine and chemokine receptor genetic polymorphisms such as stromal derived factor 1 (SDF1-3'A), CCR2-64I, and CCR5-delta32 associated with HIV-1 transmission and/or rate of disease progression in infected study subjects remain highly controversial and have been analyzed primarily only in adults. We have investigated whether these polymorphisms may provide similar beneficial effects in children exposed to HIV-1 perinatally. The prevalence of CCR2-64I allele was significantly increased (p = .03) and the CCR2-64I genotype distribution was not in Hardy-Weinberg equilibrium, among HIV-1-exposed uninfected infants. Moreover, in the HIV-1-infected group, a delay to AIDS progression was observed among carriers of CCR2-64I allele. This is the first report that suggests a protective role of CCR2-64I allele in mother-to-infant HIV-1 transmission and documents a delay in disease progression, after the child has been infected with HIV-1. However, SDFI-3'A and CCR5-delta32 alleles did not modify the rate of HIV-1 transmission or disease progression in HIV-1-infected children.

Adolescent↗
PubMed2000

Differences in mechanisms of SR dysfunction in ischemic vs. idiopathic dilated cardiomyopathy.

We examined 1) contractile properties and the intracellular Ca(2+) concentration ([Ca(2+)](i)) transient in cardiac myocytes and 2) sarcoplasmic reticulum (SR) Ca(2+) uptake and release function in myocardium from patients with end-stage heart failure caused by ischemic (ICM) vs. idiopathic dilated cardiomyopathy (DCM). The amplitude of cell motion was decreased 43 +/- 6% in ICM and 68 +/- 7% in DCM compared with that in normal organ donors (DN). Time to peak of shortening was increased 43 +/- 15% in DCM, but not in ICM. Prolongation of the relaxation time was more predominant in ICM. In DCM the systolic [Ca(2+)](i) was decreased 27 +/- 9% and diastolic [Ca(2+)](i) was increased 36 +/- 11%. In ICM the diastolic [Ca(2+)](i) was increased 59 +/- 12% but the systolic [Ca(2+)](i) was unchanged. A significant decrease of the ATP-dependent SR Ca(2+) uptake rate associated with the reduction of the SR Ca(2+)-ATPase protein level was found in ICM. In contrast, the significant decrease in SR Ca(2+) release rate was distinct in DCM. The large amount of Ca(2+) retained in the SR associated with a significant decrease in the maximum reaction velocity and increase in the Michaelis-Menten constant in the caffeine concentration-response curve suggests a fundamental abnormality in the SR Ca(2+) release channel gating property in DCM. We conclude that potentially important differences exist in the intracellular Ca(2+) homeostasis and excitation-contraction coupling in ICM vs. DCM. The SR Ca(2+) release dysfunction may play an important pathogenetic role in the abnormal Ca(2+) homeostasis in DCM, and the SR Ca(2+) uptake dysfunction may be responsible for the contractile dysfunction in ICM.

Adult↗