The Miami results on porcine islet-Sertoli cell xenotransplantation.
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Animals↗
Biomedical subjects
Armando J Mendez
Publications and source records attributed to Armando J Mendez.
Social experience influences hypothalamic oxytocin in the WHHL rabbit.
Social experience influences behavior and the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit, such that WHHL rabbits exposed to a consistent, stable social experience exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Oxytocin (OT) has been implicated in the expression of social behavior, stress responses, and may provide a mechanism by which social experience influences atherogenesis in WHHL rabbits. The current study examined acute and chronic changes in central and peripheral OT before and after WHHL rabbits were exposed to one of three social conditions. Cannula implanted adjacent to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling of extracellular OT concentration via microdialysis. Rabbits were exposed to one of three social conditions: an Unstable group, with initially unfamiliar rabbits paired daily for 4h during the initial week and similarly paired with a different, unfamiliar rabbit each week; a Stable group; with the same 2 littermates paired daily for 4h the entire study; and an Individually Caged group. Dialysates from the PVN and blood from the marginal ear vein were collected twice, 20 days apart, from rabbits before and after 2h of exposure to their respective social condition. Dialysates were assayed for OT and plasma was assayed for OT, catecholamines and glucocorticoids. There were no changes in PVN OT in any group following the initial social experience. In contrast, after 20 consecutive days of exposure to their respective social condition, PVN OT increased significantly in the Unstable group, but was relatively unchanged in the Stable group following the social experience on day 22. Peripheral OT was not altered in any group following the 2h social experience on day 1 or 22. The concentration of peripheral OT was the highest in the Stable group at all times. The Stable group also exhibited significantly less aortic atherosclerosis, consistent with earlier findings from our laboratory. Data from the present study suggest that the type of social experience WHHL rabbits are exposed influences PVN OT, social behavior and the progression of atherosclerosis in the WHHL rabbit model of disease.
Analysis of Variance↗
Evaluation of comorbidity scores to predict all-cause mortality in patients with established coronary artery disease.
BACKGROUND: To assess the value of scores based on the presence of comorbid conditions for mortality risk-stratification in patients with coronary artery disease (CAD) METHODS: We prospectively followed 305 males with CAD undergoing coronary angiography for 58 months. We correlated the modified Charlson Index (MCI) and the recently proposed CAD-specific index (CSI) with the risk of all-cause mortality. RESULTS: The odds ratio (OR) for death increased by 31% per point increase in the MCI (95% CI=17-46%; p<0.0001). The OR for death increased by 16% per point increase in the CSI (95% CI=8.5-25%; p<0.0001). In logistic regression models that adjusted for age, left ventricular ejection fraction, and the number of vessels involved with CAD, both the MCI and the CSI were the strongest predictors of mortality according to the chi2 value for each term, with the MCI having the highest value. The adjusted OR per point increase in the MCI was 1.32 (95% CI=1.17-1.48; p<0.0001); the corresponding adjusted OR per point increase in the CSI was 1.17 (95% CI=1.09-1.26; p<0.0001). The model including the MCI had a slightly higher chi2 value (45.1 vs. 39.1) and area under the receiver operator characteristic curve (0.742 vs. 0.727) than the model including the CSI. CONCLUSION: The MCI and the newly proposed CSI are powerful tools to predict all-cause mortality in patients with established CAD. Although the CSI was not superior to the MCI, its simplicity might make it useful in populations with a low prevalence of comorbidities not included in this score.
Cause of Death↗
Ability of serum to decrease cellular acylCoA:cholesterol acyl transferase activity predicts cardiovascular outcomes.
BACKGROUND: We evaluated whether cholesterol efflux activity of serum is associated with the presence of angiographic coronary artery disease (CAD) and the risk of major adverse cardiovascular events (MACE) and death. METHODS AND RESULTS: We studied 168 men undergoing coronary angiography. Cholesterol efflux activity was measured in vitro by incubation of patient serum with human skin fibroblasts and defined as the ability of serum to decrease the pool of cholesterol available for esterification by the acylCoA:cholesterol acyl transferase (ACAT) reaction. We evaluated whether this activity was associated with the presence of CAD and the risk of MACE and death during a 4.5-year follow-up. Serum-induced changes in ACAT activity did not correlate with HDL levels or the presence of CAD. Patients in the highest tertile of change in ACAT activity had a significantly higher risk for MACE (HR, 2.15; 95% CI, 1.36 to 3.39; P=0.001) and death (HR, 2.23; 95% CI, 1.17 to 4.26; P=0.01). These correlations were independent of other risk markers including LDL, HDL, and C-reactive protein levels. CONCLUSIONS: Serum-induced depletion of cellular cholesterol available for esterification by ACAT was a strong, independent predictor of MACE and death. We speculate that the ability of serum to decrease ACAT activity depends on ATP binding cassette transporter A1 (ABCA1)-mediated efflux. Furthermore, serum samples that induce larger changes in ACAT activity contain increased levels of HDL particles that preferentially interact with ABCA1 and that these particles accumulate in the serum of patients because of low activity of ABCA1 in vivo preventing or limiting the extent of apoA-I lipidation.
Aged↗
Relation between ascending aortic pressures and outcomes in patients with angiographically demonstrated coronary artery disease.
We prospectively followed 324 men, who underwent coronary angiography, for 1,161 +/- 418 days. We analyzed the association between ascending aortic pressures measured during cardiac catheterization and the risk of all-cause mortality and a combined end point of major adverse cardiovascular events (MACEs), including unstable angina pectoris, myocardial infarction, coronary revascularization, stroke, or death. Pulse pressure significantly predicted MACEs (hazard ratio [HR] per 10 mm Hg increase 1.09, 95% confidence interval [CI] 1.002 to 1.17, p = 0.04). Diastolic blood pressure (BP) inversely correlated with the risk of MACEs (HR per 10 mm Hg increase 0.85, 95% CI 0.74 to 0.98, p = 0.02). These correlations remained significant after adjusting for other predictors and potential confounders. The association between lower diastolic BP with the risk of MACEs was more pronounced in patients with triple-vessel coronary artery disease (p for interaction = 0.03). Peripheral diastolic BP (but not pulse pressure) correlated inversely with the risk of MACEs (HR 0.87 per 10 mm Hg increase, 95% CI 0.75 to 0.998, p = 0.047). Aortic pulse pressure significantly predicted death (HR per 10 mm Hg increase 1.18, 95% CI 1.05 to 1.33, p = 0.004), and aortic diastolic BP correlated inversely with the risk of death (HR 0.76, 95% CI 0.62 to 0.94, p = 0.01).
Aorta↗
Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease.
Pulse pressure (PP), a marker of arterial stiffness, predicts cardiovascular risk. We aimed to determine whether augmentation pressure (AP) derived from the aortic pressure waveform predicts major adverse cardiovascular events (MACE) and death independently of PP in patients with established coronary artery disease (CAD). We prospectively followed-up 297 males undergoing coronary angiography for 1186+/-424 days. Ascending aortic pressure tracings obtained during catheterization were used to calculate AP (difference between the second and the first systolic peak). Augmentation index (AIx) was defined as AP as a percentage of PP. We evaluated whether AP and AIx can predict the risk of MACE (unstable angina, acute myocardial infarction, coronary revascularization, stroke, or death) and death using Cox regression. All models evaluating AP included PP to assess whether AP adds to the information already provided by PP. Both AP and AIx significantly predicted MACE. The hazard ratio (HR) per 10 mm Hg increase in AP was 1.20 (95% confidence interval [CI], 1.08 to 1.34; P<0.001); the HR for each 10% increase in AIx was 1.28 (95% CI, 1.11 to 1.48; P=0.004). After adjusting for other univariate predictors of MACE, age, and other potential confounders, AP remained a significant predictor of MACE (HR per 10 mm Hg increase=1.19; 95% CI, 1.06 to 1.34; P=0.002), as did AIx (adjusted HR, 1.28; 95% CI, 1.09 to 1.50; P=0.003). AP was a significant predictor of death (HR per 10 mm Hg increase=1.18; 95% CI, 1.02 to 1.39; P=0.03). Higher AIx was associated with a trend toward increased mortality (HR=1.22; 95% CI, 0.98 to 1.52; P=0.056). Aortic AP predicts adverse outcomes in patients with CAD independently of PP and other risk markers.
Aged↗
Usefulness of C-reactive protein as an independent predictor of death in patients with ischemic cardiomyopathy.
The usefulness of serum C-reactive protein, an inflammatory marker, to predict mortality risk in patients who have ischemic cardiomyopathy was investigated. C-reactive protein was measured in 123 men who underwent cardiac catheterization and were noted to have left ventricular ejection fraction <or=45% and significant angiographic coronary artery disease. They were prospectively followed for 3 years. Higher levels of C-reactive protein were associated with increased mortality rate. This correlation was independent of other prognostic factors, such as age, ejection fraction, symptoms of severe congestive heart failure, use of angiotensin-converting enzyme inhibitors, and use of beta blockers.
Biomarkers↗
Evidence for an exaggerated postprandial lipemia in chronic paraplegia.
BACKGROUND/OBJECTIVE: Excessive delay in triglyceride (TG) metabolism after ingestion of dietary fat represents a significant cardiovascular disease (CVD) risk. The objective of this study was to compare the postprandial lipemic responses of individuals with paraplegia with those of healthy nondisabled individuals. METHODS: The ability of 3 recreationally active individuals with paraplegia having normal fasting TG (mean = 103 mg/dL) to metabolize TG after ingestion of a high-fat test meal was compared with a previously published cohort of 21 recreationally active individuals without paraplegia (TG mean = 86 mg/dL) who underwent identical testing. The subjects with paraplegia had venous blood taken under fasting conditions, and then ingested a milkshake containing premium ice cream blended with heavy whipping cream (approximately 92% of calories from fat). Additional blood samples were obtained at 2, 4, and 6 hours after ingestion. The area under the curve (AUC) for TG clearance for both subject groups was measured with an area planimeter. RESULTS: TG uptake for both groups was almost identical for the first 2 hours after ingestion. At 4 and 6 hours after ingestion, the TG levels were 50 and 35 mg/dL higher, respectively, in subjects with paraplegia than in nondisabled subjects. When corrected for small baseline differences in TG concentrations (16 mg/dL), the AUC was 46.5% greater for the group with paraplegia than in the nondisabled group. A near mirror association across time was observed between postprandial serum high-density lipoprotein cholesterol (HDL-C) and TG levels in subjects with paraplegia. CONCLUSION: This case series finds an exaggerated postprandial lipemia (PPL) in persons with paraplegia with normal fasting TGs. This finding is the first evidence, in a small population, of an unreported potential CVD risk in persons with paraplegia.
Adult↗
Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study.
OBJECTIVE: Porcine islets of Langerhans for xenotransplantation into humans have been proposed as a solution to the shortage of human donors. Rejection is one of the main constraints. This study presents the results of a clinical trial using a novel method for transplanting and immunoprotecting porcine islets in type 1 diabetic patients. DESIGN: A 4-year follow up of a clinical trial involving 12 patients, with no immunosuppressive drugs at any point. Eleven age matched untransplanted diabetics served as controls. METHODS: We have developed a procedure for protecting neonatal porcine islets by combining them with Sertoli cells and placing them in a novel subcutaneous autologous collagen-covered device. RESULTS: In the patients in the treatment group, no complications arose and no porcine endogenous retrovirus infection was detected. Half of the patients showed a significant reduction in insulin requirements compared with both their pre transplant levels and controls, and this reduction was maintained for up to 4 years. Two patients became insulin-independent for several months. Porcine insulin was detected in three patients' sera following glucose stimulation up to 4 years post transplant. Three years post transplant, one of four devices was removed from four patients, and the presence of insulin-positive cells in the transplant was demonstrated by immunohistology in all 4 patients. CONCLUSIONS: Long-term cell survival with concurrent positive effects on metabolic control are possible by this technique.
Adolescent↗
Postprandial hypertriglyceridemia increases circulating levels of endothelial cell microparticles.
BACKGROUND: This study evaluated a possible relationship between levels of endothelial microparticles (EMPs), known to be a sensitive indicator of endothelial disturbance, and changes in postprandial lipid levels in healthy volunteers after a low- or high-fat meal. METHODS AND RESULTS: Eighteen healthy subjects without known cardiovascular risk factors were evaluated. Lipid and EMP levels were measured before and 1 and 3 hours after a single low- or high-fat isocaloric meal. The low-fat meal had no significant postprandial effect on EMPs or lipids compared with fasting levels. In contrast, a single high-fat meal significantly increased EMP levels after 1 and 3 hours, from 389+/-54 (thousands per milliliter) when fasting to 541+/-139 (P=0.0002) and 677+/-159 (P<0.0001), respectively, and correlated with a postprandial elevation in serum triglycerides. CONCLUSIONS: A single high-fat meal led to a significant elevation of plasma EMP levels in healthy, normolipidemic subjects and correlated with a postprandial elevation of serum triglycerides. EMPs may be an indirect marker of endothelial dysfunction or injury induced by postprandial triglyceride-rich lipoproteins.
Adult↗
Adenoviral gene transfer of erythropoietin confers cytoprotection to isolated pancreatic islets.
BACKGROUND: The transfer of cytoprotective genes to isolated pancreatic islets may contribute to their enhanced survival in the transplant setting. Our laboratory established the expression of functional erythropoietin (EPO) receptors throughout pancreatic islets. Because EPO is a cytokine that promotes survival, we examined whether adenovirus-mediated gene transfer of EPO would result in cytoprotection of human pancreatic islets in culture and in the transplant setting. METHODS: Isolated human islets were transduced using an adenoviral vector coding for human EPO or green fluorescent protein. Comparison of cell death in culture was measured using annexin V-phycoerythrin and propidium iodide. Transplantation of transduced islets into diabetic nude mice was used to assess the effect of EPO on islet function and in vivo survival. RESULTS: Adenoviral delivery of EPO to pancreatic islets resulted in high-level EPO synthesis and secretion, which did not affect islet function in vitro or in vivo. Islets transduced with EPO were protected from apoptosis in culture and were at a functional advantage in vivo when compared with islets transduced with green fluorescent protein or untransduced islets. The high level of EPO had a negative effect on the blood chemistry of the animals that underwent transplantation. CONCLUSIONS: Overexpression of EPO protects islets from destruction and does not compromise islet function. Genetic engineering with EPO may be a viable approach for improving islet survival and engraftment in the transplant setting, but regulation of the gene's expression will be an important prerequisite to this strategy.
Adenoviridae↗
Neuronal expression of myeloperoxidase is increased in Alzheimer's disease.
Myeloperoxidase, a heme protein expressed by professional phagocytic cells, generates an array of oxidants which are proposed to contribute to tissue damage during inflammation. We now report that enzymatically active myeloperoxidase and its characteristic amino acid oxidation products are present in human brain. Further, expression of myeloperoxidase is increased in brain tissue showing Alzheimer's neuropathology. Consistent with expression in phagocytic cells, myeloperoxidase immunoreactivity was present in some activated microglia in Alzheimer brains. However, the majority of immunoreactive material in brain localized with amyloid plaques and, surprisingly, neurons including granule and pyramidal neurons of the hippocampus. Confirming neuronal localization of the enzyme, several neuronal cell lines as well as primary neuronal cultures expressed myeloperoxidase protein. Myeloperoxidase mRNA was also detected in neuronal cell lines. These results reveal the unexpected presence of myeloperoxidase in neurons. The increase in neuronal myeloperoxidase expression we observed in Alzheimer disease brains raises the possibility that the enzyme contributes to the oxidative stress implicated in the pathogenesis of the neurodegenerative disorder.
Aged↗
Human, nonhuman primate, and rat pancreatic islets express erythropoietin receptors.
BACKGROUND: Erythropoietin (EPO) promotes survival in a variety of cells by mediating antiapoptotic signals through the EPO receptor (R). The authors examined pancreatic islets for the presence of EPO-R to determine whether these cells are protected by EPO from cytokine-induced apoptosis. METHODS: Reverse-transcriptase polymerase chain reaction, immunohistology, and Western blots were used to establish the presence and localization of EPO-R on rat, nonhuman primate, and human islets. Islets were exposed to cytokines in the presence and absence of recombinant EPO and apoptosis was measured using a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay followed by fluorescence-activated cell sorter analysis. Glucose stimulation indices were measured to assess the effect of EPO on islet function. RESULTS: The presence of EPO-R was demonstrated on islets regardless of species. Recombinant EPO protected islets in culture from cytokine-induced apoptosis in a dose-dependent manner. Furthermore, the presence of EPO in the media does not adversely affect islet function. CONCLUSIONS: This is the first demonstration that pancreatic islets express EPO-R and that EPO may prevent islet-cell apoptosis in culture. In vivo trials to evaluate the potential of long-term expression of EPO to augment islet survival in transplantation are underway.
Animals↗
Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I.
The ABCA1 transporter contains two large domains into which many of the genetic mutations in individuals with Tangier disease fall. To investigate the structural requirements for the cellular cholesterol efflux mediated by ABCA1, we have determined the topology of these two domains and generated transporters harboring five naturally occurring missense mutations in them. These mutants, unlike wild type ABCA1, produced little or no apoA-I-stimulated cholesterol efflux when transfected into 293 cells, establishing their causality in Tangier disease. Because all five mutant proteins were well expressed and detectable on the plasma membrane, their interaction with the ABCA1 ligand, apolipoprotein (apo) A-I, was measured using bifunctional cross-linking agents. Four of five mutants had a marked decline in cross-linking to apoA-I, whereas one (W590S) retained full cross-linking activity. Cross-linking of apoA-I was temperature-dependent, rapid in onset, and detectable with both lipid- and water-soluble cross-linking agents. These results suggest that apoA-I-stimulated cholesterol efflux cannot occur without a direct interaction between the apoprotein and critical residues in two extracellular loops of ABCA1. The behavior of the W590S mutant indicates that although binding of apoA-I by ABCA1 may be necessary, it is not sufficient for stimulation of cholesterol efflux.
ATP Binding Cassette Transporter 1↗
Agonist-induced capping of adhesion proteins and microparticle shedding in cultures of human renal microvascular endothelial cells.
Capping and release of membranous, small (< 1.5 microm) endothelial microparticles were quantified by immunofluorescence microscopy and flow cytometry after treatment of cultures of human renal microvascular endothelial cells with agonists tumor necrosis factor-alpha (TNF-alpha) or mitomycin C. For constitutive marker CD31, both agonist-treated attached, monolayer, and detached, free endothelial cells formed caps and released microparticles. TNF-alpha and mitomycin C induced dissimilar appearing CD31-containing caps after 3 h, followed by endothelial microparticle release after 6 h. The degree of capping correlated with increasing counts of released microparticles. For lymphokine-inducible CD54, TNF-alpha also induced CD54-containing caps and microparticle release, but mitomycin C failed to induce the expression of either entity. Neither capping nor microparticle release caused by TNF-alpha was part of an apoptotic pathway that involved caspase 3. Mitomycin C treatment of endothelial cells caused capping and microparticle release with a time course similar to TNF-alpha induction for 15 to 24 h, but assays for caspase 3 were positive, confirming the apoptotic action of mitomycin C. Membrane capping and microparticle release from endothelial cells are a convenient experimental model for studying protein movement, release of microparticles, and their possible biological significance.
Antibodies, Monoclonal↗
Effect of behavioral interventions on insulin sensitivity and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.
OBJECTIVE: A previous study suggested that insulin metabolic variables play a role in the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. The present study sought to determine: 1) if young, individually caged WHHLs are insulin-resistant relative to New Zealand white (NZW) rabbits and 2) whether dietary or exercise interventions can improve insulin sensitivity and slow the development of atherosclerosis in these animals. METHODS: Forty-two WHHLs were assigned to a dietary, exercise, or control condition, and 12 NZWs were used as a comparison control group. The intervention ran from 3 to 7 months of age, and all animals received an intravenous glucose tolerance test at the beginning and end of the intervention. RESULTS: WHHLs were insulin-resistant relative to NZWs at 3 months of age. Whereas the dietary intervention was effective in controlling insulin resistance, WHHLs in the exercise group without dietary restriction and the control group exhibited significant increases in insulin resistance. No intervention significantly influenced the progression of atherosclerosis. CONCLUSIONS: Young WHHLs are insulin-resistant during an early period when atherosclerosis is developing rapidly. Dietary restriction, but not exercise without weight control, is effective in controlling insulin metabolic variables in the WHHL model. Although dietary intervention can reduce cardiovascular risk factors such as insulin resistance, it is not effective in slowing the development of atherosclerosis in these genetically dyslipidemic animals. Similarly, exercise training, without dietary control, does not influence the progression of disease in WHHLs.
Age Factors↗