Halliday Idikio

Aging-Related Early Changes in Markers of Ventricular and Matrix Remodeling After Reperfused ST-Segment Elevation Myocardial Infarction in the Canine Model Effect of Early Therapy With an Angiotensin II Type 1 Receptor Blocker

Background— Elderly patients with reperfused ST-segment-elevation myocardial infarction are at increased risk for left ventricular remodeling. Extracellular matrix damage has been implicated in early remodeling. We hypothesized that aging results in enhanced early reperfusion injury and left ventricular remodeling after reperfused ST-segment-elevation myocardial infarction and that early therapy initiated at the time of reperfusion with an angiotensin II type 1 receptor blocker such as candesartan attenuates age-related increases in reperfusion injury and remodeling. Methods and Results— We randomized 3 groups of dogs (age, 1 to 2, 2.1 to 5, and 5.1 to 10 years) with reperfused ST-segment-elevation myocardial infarction (90 minutes of ischemia, 2 hours of reperfusion) to therapy with placebo or candesartan (1 mg/kg CV-11974) over 30 minutes from the onset of reperfusion. Reperfusion in placebo groups was associated with aging-related changes in the ischemic zones in markers of damage (increased ischemic injury, infarct size [as percent risk], cardiomyocyte apoptosis, blood flow impairment, no reflow), structural remodeling (increased left ventricular dilation and dysfunction), extracellular matrix remodeling (increased expression of secretory leucocyte protease inhibitor, secreted protein acidic and rich in cysteine, osteopontin, a disintegrin and metalloproteinase-10 and -17, and matrix metalloproteinase-9 and -2), and inflammation (increased inducible nitric oxide synthase, proinflammatory cytokines interleukin-6 and tumor necrosis factor-&agr;, and transforming growth factor-&bgr;1; decreased antiinflammatory cytokine interleukin-10). Compared with placebo, candesartan attenuated these age-dependent changes. Conclusion— Aging results in age-dependent early increases in markers of damage and adverse structural and matrix remodeling after ST-segment-elevation myocardial infarction reperfused after 90 minutes of ischemia, and early therapy initiated at the time of reperfusion with the angiotensin II type 1 receptor blocker candesartan attenuates these changes. This strategy needs clinical confirmation.

Apoptosis and oncosis in acute coronary syndromes: assessment and implications.

The rational design of therapeutic interventions for protection of ischemic myocardium from ultimate death requires an understanding of the mechanistic basis of cardiomyocyte (CM) cell death, its timing and the tools for its quantification. Until recently, CM cell death following ischemia and/or reperfusion was considered to involve necrosis or ‘accidental cell death’ from very early on. Collective evidence over the past decade indicates that early CM cell death after myocardial ischemia and post-ischemic reperfusion involves apoptosis with cell shrinkage and drop-out, and/or oncosis with cell swelling followed by necrosis. This paradigm shift suggests that different approaches for cardioprotection are required. Oncologists, pathologists, anatomists and basic scientists who have studied apoptosis over the last three decades separated physiological apoptosis from inappropriate apoptosis in pathological states. Until recently, cardiologists resisted the concepts of CM apoptosis and regeneration. Cumulative evidence indicating that apoptosis in the heart may occur in different cell types, spread from one cell type to another, and occur in bursts, may have profound implications for therapies aimed at protection of ischemic myocardium by targeting CM apoptosis in acute coronary syndromes. This review focuses on a critique of the methods used for the assessment of CM apoptosis and the implications of CM apoptosis in acute coronary syndromes. (Mol Cell Biochem 270: 177–200, 2005)

Vascular remodeling during healing after myocardial infarction in the dog model: Effects of reperfusion, amlodipine and enalapril

OBJECTIVES We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ). BACKGROUND The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined. METHODS We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks. RESULTS Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ. CONCLUSIONS The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.

Role of healing-specific-matricellular proteins and matrix metalloproteinases in age-related enhanced early remodeling after reperfused STEMI in dogs

We assessed whether aging augments left ventricular (LV) damage, remodeling, and dysfunction and alters expression of healing-specific-matricellular proteins (HSMPs), matrix metalloproteinases (MMPs) and other pertinent proteins after acute reperfused-ST-segment-elevation myocardial infarction (RSTEMI) in the dog model. The findings suggest a novel role for HSMPs, MMPs, and the other proteins in the age-related increase in LV damage, remodeling, and dysfunction. Potentially detrimental effects of the altered proteins appear to outweigh beneficial effects and contribute to adverse outcome. Deleterious changes include the increase in matrix-degrading MMPs, inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α, HSMPs such as secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN), the blunted increase in endothelial-NOS (eNOS), and the decrease in IL-10 and neuronal NOS (nNOS). Potentially beneficial changes include increases in the HSMP secretory-leucocyte-protease-inhibitor (SLPI) and cytokine transforming growth factor (TGF)-β1. Targeting these proteins may mitigate enhanced LV remodeling and dysfunction with aging.

Lewis blood group antigens (a and b) in human breast tissues. Loss of Lewis-b in breast cancer cells and correlation with tumor grade.

The Lewis blood group antigens (Lewis‐a [Lea] and Lewis‐b [Leb]) and their precursors are present on various normal human epithelial cell surfaces. The authors examined 35 benign and malignant human breast lesions using mouse monoclonal antibodies to synthetic Lea and Leb carbohydrate antigens. Normal breast lobular and ductal epithelium and benign breast lesions showed Leb staining but only occasional Lea staining. In invasive ductal carcinomas of breast, of all grades, a loss of Leb antigen staining was found in 80% of the breast cancer cases. This reduced Leb antigen expression increased with the grade of malignancy. Therefore, the loss of Leb blood group antigens on breast cancer cell surfaces may suggest altered fucosylation patterns in malignant cells and reflect the degree of malignancy and/or invasiveness.

Comparison of vasopeptidase inhibitor omapatrilat and angiotensin receptor blocker candesartan on extracellular matrix, myeloperoxidase, cytokines, and ventricular remodeling during healing after reperfused myocardial infarction.

We determined effects of the vasopeptidase inhibitor (VPI) omapatrilat and angiotensin II type 1 receptor (AT1R) blocker (ARB) candesartan in rats during healing between day-2 and day-21 after reperfused myocardial infarction (RMI) on left ventricular (LV) remodeling and function, and regional matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-3, inducible-nitric-oxide-synthase (iNOS), oxidant-generating myeloperoxidase (MPO), and cytokines tumor-necrosis-factor (TNF)-α, interleukin (IL)-6 and IL-10, and transforming-growth-factor (TGF)-β1, and collagens. Compared to RMI-placebo, both agents reversed adverse LV remodeling and systolic and diastolic dysfunction, improved collagen remodeling, and normalized MMP-9 (activity, protein, and mRNA), TIMP-3 (protein and mRNA), and iNOS, MPO, TNF-α, IL-6, and TGF-β1 proteins, and improved MMP-9/TIMP-3 balance and IL-10 levels in previously ischemic zones. The results suggest that modulation of matrix proteases, oxidants, cytokines, and NOSs with omapatrilat and candesartan contribute to reversal of adverse collagen and LV remodeling and attenuation of LV dysfunction during healing after RMI.

A, B, H, and Lewis-a and Lewis-b blood group antigens in human breast cancer : correlation with steroid hormone receptor and disease status

Estrogen (ER) and progesterone (PR) hormone receptor status and levels were correlated with blood group antigen (A, B, H, Lewis-a and Lewis-b) expression in 48 cases of human breast cancer. Reduced expression of all the blood group antigens was observed with statistically significant reductions for H, Lewis-a and Lewis-b (P<0.05). The proportions of ER- and PR-positive breast cancers staining for Lewis-b were greater than in hormone-receptor-negative cancers but the differences were not significant. The loss of Lewis-b antigen in breast cancer increased with tumor grade but did not correlate with axillary lymph node metastases. Loss of Lewis-b antigen is probably not a predictor of local recurrence and survival in the short period of observation. We conclude that the loss of H, Lewis-a and especially, Lewis-b in breast cancer reflects the invasiveness of breast cancer and that Lewis-a and b expression is probably only marginally and not significantly affected by steroid hormone receptor status and levels.

Galectin-3 and Beclin1/Atg6 Genes In Human Cancers: Using cDNA Tissue Panel, qRT-PCR, and Logistic Regression Model to Identify Cancer Cell Biomarkers

Background Cancer biomarkers are sought to support cancer diagnosis, predict cancer patient response to treatment and survival. Identifying reliable biomarkers for predicting cancer treatment response needs understanding of all aspects of cancer cell death and survival. Galectin-3 and Beclin1 are involved in two coordinated pathways of programmed cell death, apoptosis and autophagy and are linked to necroptosis/necrosis. The aim of the study was to quantify galectin-3 and Beclin1 mRNA in human cancer tissue cDNA panels and determine their utility as biomarkers of cancer cell survival. Methods and Results A panel of 96 cDNAs from eight (8) different normal and cancer tissue types were used for quantitative real-time polymerase chain reaction (qRT-PCR) using ABI7900HT. Miner2.0, a web-based 4- and 3- parameter logistic regression software was used to derive individual well polymerase chain reaction efficiencies (E) and cycle threshold (Ct) values. Miner software derived formula was used to calculate mRNA levels and then fold changes. The ratios of cancer to normal tissue levels of galectin-3 and Beclin1 were calculated (using the mean for each tissue type). Relative mRNA expressions for galectin-3 were higher than for Beclin1 in all tissue (normal and cancer) types. In cancer tissues, breast, kidney, thyroid and prostate had the highest galectin-3 mRNA levels compared to normal tissues. High levels of Beclin1 mRNA levels were in liver and prostate cancers when compared to normal tissues. Breast, kidney and thyroid cancers had high galectin-3 levels and low Beclin1 levels. Conclusion Galectin-3 expression patterns in normal and cancer tissues support its reported roles in human cancer. Beclin1 expression pattern supports its roles in cancer cell survival and in treatment response. qRT-PCR analysis method used may enable high throughput studies to generate molecular biomarker sets for diagnosis and predicting cancer treatment response.

A floor of mouth teratoid cyst with tract in a newborn—Case report and English literature review unraveling erroneous quotes and citations

Dysontogenetic cysts are thought to fall into one of three classes: epidermoids, dermoids or teratoids. Floor of mouth teratoid cysts are the least common presentation reported. Over the last 70 years, fewer than 20 histologically proven cases have been described in the English literature. We report an infant presenting with this lesion in association with a midline tract. The cyst was identified at birth and interfered with feeding. It was surgically excised with no recurrence at 10 month point of follow-up. A literature search revealed that confusing terminology and indirect quotation disseminated false beliefs regarding the epidemiology. Contrary to most reports, floor of mouth teratoid cysts are most commonly encountered in childhood with only a handful of cases in older age groups.

Castleman’s disease with vascular encasement and renal sinus involvement

Castleman’s disease is a relatively rare entity. Approximately 4% of cases are located in the retroperitoneum or pelvis [1]. The plasma cell variety accounts for 10% of all cases of Castleman’s disease [1]. A case of the plasma cell variant involving the renal sinus and retroperitoneum is presented.