bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Dermatofibrosarcoma Protuberans, Fibrosarcomatous Variant, Metastatic
Authors: Aziz Tariq , Mir Rabia N.
Published: June 2007

Dermatofibrosarcoma protuberans (DFSP), a rare low-grade mesenchymal subcutaneous neoplasm, is characterized by a propensity for local recurrence in up to 50% of patients but has a low metastatic potential. The reported incidence of metastases in a large series was 0-9%. The metastasis is usually a late event and often follows local recurrences. The presence of fibrosarcomatous areas (FS) within DFSP (DFSP-FS) increases the risk for local recurrence and metastases. We report a patient who developed metastatic disease in the lungs 6 months after complete excision of DFSP-FS of the thigh without local recurrence.
Intracapsular Chondroma of the Knee: An Unusual Neoplasm
Authors: Rodriguez-Peralto J. L. , Lopez-Barea F. , Gonzalez-Lopez J.
Published: June 2007

Intracapsular chondroma is a rare lesion that has been reported under different names on 23 occasions. We describe a 52-year-old woman with intracapsular chondroma that involved the left knee. Radiologically, the mass was multilobulated, calcified, and sharply circumscribed and was lying between the patella and the anterolateral surface of the tibia. The peculiar histologic pattern of the tumor was composed of hyaline cartilage nodules with enchondral ossification or calcification, in apparent transition with septa of connective and adipose tissue. The most common differential diagnoses for this tumor are primary synovial chondromatosis and chondrosarcoma. We emphasize a possible metaplastic origin of the chondromatous component due to some mechanical posttraumatic disturbance of the infrapatellar fat pad. To our knowledge, the present case is the second intracapsular chondroma to be described in the European literature.
Failed Methotrexate-Treated Ectopic Pregnancies: Clinicopathologic Correlations
Authors: Doss Barbara J. , Ramirez Nilsa C. , Lawrence W. Dwayne
Published: June 2007

Methotrexate (MTX) administration as an alternative to surgical therapy for unrupured ectopic pregnancies (EPs) has a 5-11% failure rate. The histologic findings in surgical specimens from patients for whom MTX therapy failed have not been exensively described. Review of pathology records from January 1991 through June 1996 revealed 12 MTX-treated tubal EPs that subsequently required surgical interention. Clinical data and histologic findings were compared with those from tubal EPs from maternalagend gestational-age-matched controls. Semiquantitative obervations of chorionic villous morphology were assessed by a senior pathologist unware of the treatment regimens. The average maternal age was 27 years and the mean gestational age was 9 weeks. Patients received one to two intramuscular injecions of MTX (50 mg/M2) and were followed up with serial serum betahuman chorinic gonadotropin (f-hCG) determinations. P-hCG levels fell from presentation to surgical intervention in 36.4% of MTX-treated patients, increased in 9.1%, and rose then fell in 54.5%. Peak r-hCG titers were significantly higher in MTX-exposed paients as compared with controls. There was no correlation between,3-hCG profile and villous morphology. Sixty-seven percent of MTX-treated EPs showed significant trophoblastic atypia as compared with 25% of control cases. Atypical villous trohoblasts had enlarged nuclei with irregular contours, smudged chromatin, and prominent nucleoli. There were no significant differences between failed MTX-exosed EPs and controls in terms of the presence or degree of villous necrosis, trohoblastic vacuolization, or embryonic development. Chorionic villous morphology in failed MTX-treated EPs showed no significant differences from that of nontreated EPs except for a trend toward increased trophoblastic atypia, features that may be confused with early gestational trophoblastic disease. Failed MTX-treated EPs may represent a subset of gestations that are resistant to MTX. As the uses of MTX are exanded to encompass the termination of early intrauterine pregnancies, the recogniion of possible treatmentrelated alterations in the histologic appearance of chorinic villi, trophoblasts, and implantation sites will be pertinent to avoid misdiagnosis.
Intravascular Lymphoma Clinically Mimicking Pulmonary Thromboembolic Disease
Authors: Spies Jessica A. , Guinee Donald G. , Bonacci Christine A. , Howell Lydia P. , Lie J. T.
Published: June 2007

A 62-year-old man presented with a 2-week history of fatigue and easy bruising. During hospitalization he developed progressive dyspnea, which, on the basis of abormal findings from a ventilation-perfusion scan, was attributed to multiple small pulmonary emboli. Postmortem examination demonstrated intravascular lymphoma prominently involving the pulmonary interstitium and vasculature. This case is unsual in its clinical presentation as pulmonary thromboembolic disease.
Multicystic Mesothelioma
Authors: Chen Karl T. K.
Published: June 2007

The immunohistochemical and histochemical findings of five multicystic mesothe-liomas, including a unique case of inguinal soft tissue location, are reported. The results of this study indicate that the histochemical and immunohistochemical profiles of multicystic mesothelioma parallel those of malignant mesothelioma.
Pseudolymphoma (Reactive Lymphoid Hyperplasia) of the Liver Containing Epithelioid Cell Granulomas and Schaumann's Bodies in Giant Cells
Authors: Nonomura Akitaka , Minato Hiroshi , Shimizu Kohichi , Kadoya Masumi , Matsui Osamu , Sawasaki Aiko , Nakamura Shinobu
Published: June 2007

Nodular lymphoid hyperplasia, also known as pseudolymphoma (PL), of the liver is a benign reactive process of lymphoid tissue and is extremely rare. To our knowledge, only four cases of hepatic PL have been reported to date. We present a 59-year-old woman patient with hepatic PL that was preoperatively diagnosed as hepatocellular carcinoma (HCC), based on the findings of a variety of imaging modalities. However, resection of the tumor specimen at hepatic lobectomy revealed that the tumor was not a true tumor but a PL composed of proliferated nonneoplastic, polyclonal lymphocytes and plasma cells with abundant lymphoid follicles, together with mononuclear and multinuclear histiocytes with granuloma formation. Sporadic multinucleated giant cells had concentrically or eccentrically laminate ‘conchoidal’ bodies, known as Schaumann's bodies. Immunohistochemical staining of lymphocytes and plasma cells for T and B cells, or IgGK and IgGk revealed the polyclonal nature of these cells. Furthermore, clonal immunoglobulin heavy-chain gene rearrangement was not detected in the lymphoid cells in the lesion with polymerase chain reaction (PCR) analysis. The background hepatic tissue showed no cirrhosis, but some lymphocytes had infiltrated into the portal tracts around the tumor. Since hepatic PL is extremely rare and no association of PL with granuloma with Schaumann's bodies has been described in previously reported cases with hepatic PL, the clinical and histologic features in this case are described with a literature review.
Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections
Authors: Tóth Káiroly , Vaughan Mary M. , Schwartz Gary , Winston Janet S. , Skenderis Basil S. , Slocum Harry K. , Rustum Youcef M.
Published: June 2007

An immunohistochemical method was developed and applied to detect multidrug resistance related protein (MRP) in sections of formalin-fixed, paraffin-embedded human tissues. Monoclonal antibodies MRPm6, MRPrl, and QCRL-1 were used on sections of paraffin-embedded cell pellets of known MRP expression (HL60, HT1080, HeLa). None of the antibodies succeeded without pretreatment, but microwave epitope retrieval with 6M urea resulted in excellent specific staining with MRPm6. Moderate or weak staining was seen with MRPrl and QCRL-1. Various carcinomas were tested for MRP with MRPm6, and for MDRl P-glycoprotein (Pgp) expression with MAb JSB-1, by our previously described method (Am J Pathol 144:227-236, 1994) to investigate the possible coexpression of multidrug resistance markers in the same solid tumor. The incidence of positive immunoreactions/case with MRPm6 and JSB-1 respectively, in various human cancers was as follows: lung, 15 and two of 26; esophagus, eight and two of 15; head and neck, nine and one of 27; colorectal, 13 and 11 of 20; breast, 25 and 23 of 55; bladder, 0 and 0 of seven; ovarian, 0 and 0 of 10 cases. The overall incidence of MRP expression in these tumors was higher 70/160 (44%) than that of Pgp 41/160 (26%). Among Pgp-negative tumors 38% proved to be MRP positive. Coexpression of MRP and Pgp was found in 25/160 cases (16%), which is statistically significant (p=.0 17). A relatively higher incidence of strong MRP-positive staining was found in lung and esophageal cancers (4/26 and 5/15); otherwise staining was weak to moderate. No detectable MRP was found in stromal cells and in normal organs. Thus, MRPm6 by this method allows detection of MRP overexpression versus normal cells in paraffin sections of archived surgical specimens for investigation of the clinical significance of MRP.
Lymphomatoid Papulosis Associated with Cutaneous T-Cell Signet Ring Lymphoma
Authors: Cordoba Alicia , Querol Ignacio , Monzon Francisco Jose , Ayensa Jesus , Martinez-Peñuela Jose Maria , Idoate Miguel
Published: June 2007

The authors describe a new case of cutaneous T-cell lymphoma of signet ring cell type with CD-30 (Ki-t) expression. The patient was a 52-year-old woman with a 20-year history of recurrent papulonodular lesions characteristic of lymphomatoid papulosis (LP). Subsequent to developing the signet ring cell lymphoma (SRL) the patient's cutaneous lesions did not resolve as previously, and a skin biopsy showed a diffuse proliferation of atypical lymphoid cells with cytoplasmic vacuoles. SRL was first reported in 1985 by Weiss, and a literature search found only six further reports since then. Vaillant suggests that the peculiar morphology is retated to the special indolent course of this condition and that the cutaneous form should be considered a distinct entity. This is the first report of a patient with LP who subsequently developed a cutaneouis T-cell signet ring lymphoma with CD-30 antigen expression. The case could be an example of a so-called borderline lymphoma.
Myofibroblastic Tumors of the Breast: A Histologic Spectrum with a Case of Recurrent Male Breast Myofibrosarcoma
Authors: Gonzalez-Palacios Fernando , Enriquez Jose L. , Miguel Pilar , Vazzquez Rosario , Carcia-Cosio Monica
Published: June 2007

The breast is a site of choice of the benign myofibroblastic lesions, but only three myofibrosarcomas have been reported, and only one was in the male breast. We report three tumors of the male breast with the features of myofibroblastic differentiation. These tumors comprise a spectrum including two benign neoplasms with a different histologic aspect and one recurrent sarcoma of myofibroblasts with a 10-year follow-up. This is the fourth case to be reported of mammary myofibroblastic sarcoma and the second case in the male breast.
Clinicopathologic Features of Misplaced Glands in Colonic Polyps: Morphologic Spectrum and Association with Dysplasia
Authors: Goonewardene Shanth , Palazzo Juan P. , Reale Douglas
Published: June 2007

Misplaced glands in colonic polyps are important to identify and to differentiate from invasive adenocarcinomas. Certain microscopic features are considered helpful to make this distinction. We have examined 650 polyps and found 23 (3%) with misplaced glands. A significant number (17 of 23 cases) lacked the typical previously described microscopic features of misplaced glands. TWo distinct growth patterns of the misplaced glands were identified in our series: an infiltrative and a pushing pattern, both lacking stromal desmoplasia. Only six of the 23 polyps showed the previously described associated changes such as hemorrhage and mucin pools. In addition, five of the polyps had high-grade dysplasia in the misplaced glands, four of which showed the infiltrative pattern of growth. TWo cases were associated with a synchronous adenocarcinoma of the colon. The recognition of these two patterns of misplaced glands with or without stromal changes, and the association with high-grade dysplasia should be considered in the differential diagnosis between misplaced glands and adenocarcinoma.
Large Cell Calcifying Sertoli Cell Tumor of the Testis
Authors: Kie Jeong Hae , Park Young Nyun , Han Sang Won , Cho Nam Hoon , Ro Jae Yoon
Published: June 2007

Large cell calcifying Sertoli cell tumor (LCCST) is a rare testicular tumor, usually occurring in young men before the age of 20. Ultrastructural study has been performed rarely demonstrating Sertoli cell features. We report a case of LCCST in a 7-year-old boy. A well-circumscribed yellowish-tan, 1.5-cm-sized mass was located within the left testicular parenchyma. The cut surface was somewhat resilient with multiple calcifications. On microscopic examination, the tumor was composed of large eosinophilic polygonal cells with abundant eosinophilic cytoplasm arranging in solid tubular and trabecular patterns, superficially mimicking Leydig cell tumor. However, there were multiple calcifications and the tumor cell nests were surrounded by PAS-positive basement membrane. Ultrastructural examination revealed the features of the Sertoli cell with Spangaro's crystals. The right testis showed a normal appearance by ultrasonogram and there were no other clinical features associated with Carney syndrome.
The Prognostic Significance of Mast Cell Count in Soft Tissue Sarcomas
Authors: Zhang Paul J. , Kobos Jozef W. , Brooks John J.
Published: June 2007

Mast cells (MC) are known to play an important role in IgE-dependent allergic reaction, host defense against parasite infestation, local hemostasis, inflammation, and angiogenesis. The significance of MC in tumor surveillance has been studied with conflicting results. The presence of MC in tumor has been described as evidence of a host immunologic antitumor response, and a high count of tumor-associated MC has been considered as a favorable prognostic factor in sarcomas. In other studies, MC have been shown to have an adverse role in neoplastic proliferation. In this study, tumor-associated MC were histologically quantitated in 75 soft tissue sarcomas. We found that soft tissue sarcomas with a higher MC count (n=or>six) were associated with significant better survival and relatively low incidence of metastasis in contrast to those with a lower count (n<six). There was no correlation between MC count and the histologic type, grade, or size of the sarcomas. Although the role of mast cells in tumor surveillance is still under investigation, quantitive assessment of tumorassociated MC on routine histologic sections could be used as an additional prognostic factor in soft tissue sarcomas.
Angiomyofibroblastoma
Authors: Vasquez Mariela D. , Ro Jae Y. , Park Yong W. , Tornos Carmen S. , Ordofiez Nelson G. , Ayala Alberto G.
Published: June 2007

We report the clinicopathologic features of eight new cases of angiomyofibroblastoma and review the literature on this recently described entity. Most of our female patients had a vulvar mass that clinically was thought to be a Bartholin's gland cyst. The tumors were well circumscribed and measured 2.9 to 11 cm (mean, 5.2 cm). No recurrences or metastases were observed during follow-up, which ranged from 2 months to 4 years. The tumors were characterized by a myxomatous background with prominent vessels surrounded by plump stromal cells. Immunohistochemically, the stromal cells were reactive for vimentin, but staining for desmin was not always present. Angiomyofibroblastoma should be distinguished from aggressive angiomyxoma because the two entities behave differently. Morphologic and immunohistochemical features should also be considered.
Prognostic Significance of Histologic and Cytometric Factors in Supratentorial Astrocytomas
Authors: Roselló-Sastre E. , Cerdá-Nicolás M. , Callaghan R. , Barcia J. L. , Llombart-Bosch A.
Published: June 2007

There is no agreement in the literature on selecting the principal parameters that contribute to explain the different outcomes in supratentorial astrocytomas. Hence, we designed a global study using morphologic parameters and DNA quantification measured by flow cytometry (FCM) and image analysis (IA) on 116 tumors contrasting the results with patients' survival in a univariate and multivariate study. In the Kaplan-Meier study besides the necrosis (p<0.0001) there were other parameters with significant prognostic value such as nuclear atypia (p=0.0001), presence of anaplastic large cells (p=0.0003) and the morphology of the tumor vessels (p=0.009). Proliferative parameters like mitotic index, cell density, the cell fraction in S phase or G2/M phase, and the proliferative phase measured by image analysis (IA) or ploidy patterns did not influence the prognosis. In the Cox's proportional hazards model the presence of necrosis remained as the only prognostic predictor (p=0.001) and increased 5.9 times the risk of mortality in gliomas.
Well-Differentiated Intramedullary Osteosarcoma
Authors: Meneses Abelardo , Mohar Alejandro , de la Garza Jaime , Ro Jae Y. , Ayala Alberto G.
Published: June 2007

Well-differentiated intraosseous osteosarcoma (WDIOS) is a rare tumor and histologically similar to parosteal osteosarcoma. This study reports the clinicopathological features of five patients with WDIOS tumor seen at the Instituto Nacional de Cancerologia in Mexico City. The patients' ages ranged from 29 to 42 years with a median age of 32 years. Four of the five patients presented with pain and a mass that had been present for more than 3 years prior to the diagnosis. Radiologically, four of the lesions were present in the long bones and showed a predominantly trabeculated appearance with some small ill-defined lytic areas. The bony sclerosis was more prominent within the medullary cavity than in the soft tissue extension. The majority of the tumors were large, averaging 21 cm in size. Histologically, the tumors were characterized by spindle cells with areas of cytologic atypia and presence of mature bone formation. In two patients a high-grade sarcoma component was found in addition to WDIOS component: in both patients the high-grade sarcoma component was identified in the amputation specimens, and in one of these it was also recognized in the pulmonary metastasis. This study demonstrated that WDIOS is a slowgrowing malignant neoplasm that may show a histologic progression to dedifferentiation (dedifferentiated osteosarcoma) and an aggressive behavior with distant metastasis.
Exercise Tolerance and Quality of Life in Elderly Patients with Chronic Atrial Fibrillation
Authors: Howes Christopher J. , Reid M. Carrington , Brandt Cynthia , Ruo Bernice , Yerkey Michael W. , Prasad Bhargavi , Lin Carol , Peduzzi Peter , Ezekowitz Michael D.
Published: June 2007

Background: Atrial fibrillation is the most common arrhythmia affecting the elderly. Although the risk of cardioembolic stroke is well defined, the effects of chronic atrial fibrillation on exercise tolerance and quality of life have been less well quantified.

Methods: We compared a group of 52 elderly patients with chronic atrial fibrillation to a group of 48 control patients in sinus rhythm. Each patient underwent an interview that incorporated the Short Form-36 Health Survey (SF-36) to quantify individual perceptions on quality of life. In addition each person underwent physiologic testing that included a Modified Bruce Protocol exercise tolerance test, 24-hour ambulatory monitor test, and an echocardiogram.

Results: Both groups were elderly, 77 vs 76 years of age (P=0.35).The two groups had similar ejection fractions, 55.4% vs 58.4% (P=0.10). The atrial fibrillation patients demonstrated a higher level of comorbidity based on the Charlson Comorbidity Index, 2.46 vs 1.57 (P=0.03). On formal exercise testing there was no statistical difference in exercise duration between the two groups 9.0 vs 10.1 minutes (P=0.24). Similarly the Physical Summary Score (PCS) and the Mental Summary Score (MCS) of the SF-36 quality of life survey did not demonstrate a statistical difference between the two groups. PCS: 43.0 vs 45.9 (P=0.24); MCS: 52.5 vs 55.7 (P=0.07).

Conclusions: Despite a higher level of comorbidity, elderly, ambulatory patients with chronic atrial fibrillation demonstrate similar exercise tolerance and report similar quality of life to a group of age-matched control patients in sinus rhythm. There is a cohort of patients in chronic atrial fibrillation in whom a strategy of rate control and anticoagulation may be appropriate.
Heparin Reacts With and Inactivates Nitric Oxide
Authors: Upchurch Gilbert R. , Goodman Dorinda G. , Willoughby Scott R. , Zhang Ying-Yi , Welch George N. , Freedman Jane E. , Ye Song , Costello Catherine E. , Loscalzo Joseph
Published: June 2007

Although heparin is a well-known anticoagulant, in some cases it promotes a prothrombotic state and does so through both antibody-dependent and antibody-independent platelet activation. In this study, heparin was found to reverse the antiplatelet effect of an NO donor, S-nitroso-glutathione (SNO-Glu), with an EC50of 1.8 U/mL. Ultraviolet/visible spectral analysis and the Griess assay showed that increasing heparin concentrations on a dose-dependent basis eliminated acidified NOx species. Since heparin is a heterogeneous mixture of glycosaminoglycans, the effects of six different heparin disaccharides were compared with various substitutions on the hexose rings to determine which functional group(s) of the polysaccharide interact with acidified NOx. Among the six disaccharides tested, only types I-S and 1I-S had the effect, suggesting that the sulfamino-group at the C2 position of the glucosamine moiety was critical for the elimination of acidified NOx species. Mass spectrometry experiments gave results consistent with these observations, indicating that only the I-S and 11-S heparin disaccharides were modified upon treatment with NaNO2/HCl. Negative-ion electrospray ionization MS and tandem MS analyses of the native compounds and their deuteriumlabeled analogs confirmed that the reaction products from nitrosation of these N-sulfated disaccharides had eliminated the C2-sulfamino-moiety and replaced it with methoxide derived from the solvent. Participation of the 6-sulfato-substituent appears to facilitate the elimination reaction. These data show that heparin can impair the antiplatelet properties of nitric oxide by interacting with the nitrosating species, and suggest that heparin-like glycosamino-glycans may interact with endothelium-derived nitric oxide in vivo to regulate the bioactivity of this important antiplatelet and vasorelaxant substance.
Vasodilator Responses to ATP and UTP are cAMP Dependent in the Mesenteric Vascular Bed of the Cat
Authors: Shah Mrugeshkumar K. , Bivalacqua Trinity J. , Champion Hunter C. , Kadowitz Philip J.
Published: June 2007

Background: This study was designed to examine the responses to and the mechanism by which purinergic agonists decrease vascular resistance in the mesenteric vascular bed of the cat.

Methods and Results: Injections of ATP, UTP, and 2-MethylThioATP (2-MetSATP) into the mesenteric perfusion circuit elicited dose-dependent decreases in perfusion pressure while injections of P,y-MethylATP (f3,y-MetATP) produced a biphasic response with an initial vasopressor response followed by a vasodilator response. The order of potency of the vasodilator response was 2-MetSATP > ATP > UTP > P,y-MetATP. The vasodilator responses to ATP, UTP, 2-MetSATP, and P,y-MetATP were increased in duration by the cAMP phosphodiesterase inhibitor, rolipram. However, vasodilator responses were not altered by the adminstration of a nitric oxide synthase inhibitor, a cGMP phosphodiesterase inhibitor, or a cyclooxygenase inhibitor. Treatment with PPADS, a P2X,, P2Y, and P2Y4receptor antagonist, did not alter vasodilator responses to the purinergic agonists; however, the vasopressor component of the response to P,y-MetATP was decreased.

Conclusions: These data suggest that ATP, UTP, 2-MetSATP, and P,Y-MetATP dilate the mesentary vascular bed in the cat by a cAMP dependent mechanism, and that nitric oxide or prostaglandin release, cGMP accumulation, or activation of P2X,, P2Y, or P2Y4receptors play little or no role in mediating vasodilator responses to the purinergic agonists in this regional vascular bed. In addition, these results suggest that the pressor component of the response to P,y-MetATP is mediated by the activation of P2X, receptors.
Role of Desethylamiodarone in the Anticoagulant Effect of Concurrent Amiodarone and Warfarin Therapy
Authors: Naganuma Miyoko , Shiga Tsuyoshi , Nishikata Kaori , Tsuchiya Takanori , Kasanuki Hiroshi , Fujii Emiko
Published: June 2007

Background: The concurrent use of amiodarone and warfarin inhibits metabolism of S-war-farin by cytochrome P450 (CYP) 2C9, thereby increasing the anticoagulant effect of war-farin. Amiodarone primarily inhibits CYP1A2 and CYP3A4, and desethylamiodarone primarily inhibits CYP2C9. We investigate whether a relationship exists between the plasma concentration of desethylamiodarone and anticoagulation when amiodarone is administered to patients receiving warfarin therapy.

Methods and Results: The correlation between the plasma concentration of either amiodarone or desethylamiodarone, and prolongation of prothrombin time-international normalized ratio/dose of warfarin (A INR/Dose) on day 7 of amiodarone administration was studied in 25 patients (22-74 years old) with structural heart disease and refractory arrhythmias receiving stable warfarin therapy.

Results: No correlation was found between the plasma concentration of amiodarone and A INR/Dose, but a correlation was found between the plasma concentration of desethylamiodarone and A INRIDose.

Conclusions: It was suggested that inhibition of CYP2C9 by desethylamiodarone, the active metabolite of amiodarone, plays an important role in the interaction of warfarin and amiodarone.
Oxidized Low-Density Lipoprotein Receptor LOX-1 and Apoptosis in Human Atherosclerotic Lesions
Authors: Li D. Y. , Chen H. J. , Staples E. D. , Ozaki K. , Annex B. , Singh B. K. , Vermani R. , Mehtat J. L.
Published: June 2007

Background: Lectin-like oxidized LDL receptor-I (LOX-1), a novel receptor for oxidized low-density lipoprotein, mediates oxidized low-density lipoprotein-induced apoptosis of endothelial cells, monocyte adhesion to endothelium, and phagocytosis of aged cells. The present study examined the role of LOX-1 and apoptosis in human atherosclerotic lesions.

Methods and Results: Grafted vein (n = 8), human carotid artery endarterectomy (n = 11), and normal human internal mammary artery (n = 8) specimens were used to study the expression of LOX-1 and apoptosis. LOX-1 expression was determined by reverse transcriptasepolymerase chain reaction, Western analysis, and immunostaining. Presence of apoptosis was determined by fluorescent in situ nick end-labeling staining and by the presence of poly (ADP-ribose) polymerase protein (an apoptotic marker). Expression of LOX-1 was significantly increased in atherosclerotic grafted vein and carotid artery specimens compared with that in normal arteries. LOX-1 was expressed in endothelial cells, macrophages, and smooth muscle cells. LOX-I was extensively expressed in the new blood vessels in the core of advanced atherosclerotic lesions. Double immunostaining showed LOX-1 expression to be colocalized with apoptotic cells. Fluorescent in situ nick end-labeling staining showed that the apoptotic cells were present mostly in the rupture-prone regions of the atherosclerotic plaque.

Conclusion: These observations indicate that LOX-I is extensively expressed in the proliferated intima of grafted veins and in advanced atherosclerotic carotid arteries. Further, LOX-1 is colocalized with apoptotic cells. These observations may relate to the phenomenon of plaque rupture, and provide targets for developing new therapies.
Nesiritide: A New Drug for the Treatment of Decompensated Heart Failure
Authors: Elkayam Uri , Akhter Mohammed Waseem , Tummala Priya , Khan Salman , Singh Harpreet
Published: June 2007

Nesiritide, a recombinant human B-type natriuretic peptide, is the first in a new drug class for the treatment of decompensated heart failure. The drug binds to receptors in the vasculature, kidney, adrenal gland, and brain, and overcomes resistance to endogenous BNP present in patients with CHF. Nesiritide administration leads to a rapid and balanced vasodilatory effect, which results in a significant decrease in right and left ventricular filling pressures and systemic vascular resistance and at the same time in an increase in stroke volume and cardiac output without a change in heart rate. These early hemodynamic changes result in a rapid improvement in symptoms of heart failure. In addition, nesiritide lowers aldosterone, catecholamines, and endothelin-1 levels and its effect on the kidney leads to an increased natriuresis and diuresis without effect on serum potassium or renal function. Prior to its approval for clinical use, nesiritide was studied in 10 different clinical trials involving 941 patients with moderate and severe CHF, including elderly patients, patients with both systolic and diastolic dysfunction, and patients with arrhythmias, renal insufficiency, and acute ischemic syndrome. In comparative studies with available vasoactive therapies frequently used for treatment of patients with decompensated heart failure, nesiritide was proven comparable in efficacy to inotropic drugs such as dobutamine, but superior in safety. In a recent study, nesiritide was found to be more effective and better tolerated than the vasodilator, nitroglycerin. The most common side effects expected with the use of nesiritide are headaches and decrease in blood pressure. At the recommended dose of nesiritide, headache was reported during the first 24 hours of treatment in 8% of patients and symptomatic hypotension in 4% of patients, compared to 20% and 5% in nitroglycerin-treated patients.
Thiazolidinediones Could Improve Endothelial Dysfunction and Risk of Premature Coronary Heart Disease in HIV-Infected Patients
Authors: Carrillo-Jimenez Rodolfo , Lamas Gervasio A. , Hennekens Charles H.
Published: June 2007

The use of Human Immunodeficiency Virus (HIV) protease inhibitors as part of the Highly Active Antiretroviral Therapy (HAART) is associated with atherogenic dyslipoproteinemia, insulin resistance, hypertension and endothelial dysfunction, all of which contribute to premature coronary heart disease. These abnormalities appear to be associated with an increase in cardiovascular events in HIV-infected patients. Beneficial metabolic effects of anti-diabetic agents used in HIV-infected patients have been reported. The thiazolidinediones (TZDs), a new group of antidiabetic drugs, may modulate the proliferative and inflammatory cascades involved in atherosclerosis. Thus, an increasing totality of evidence suggests that TZDs may represent a unique and powerful research tool to find a common denominator underlying the pathophysiology and treatment of the metabolic cardiovascular risk factors associated with HIV infection.
Arterial Injury in Mice with Severe Insulin-Like Growth Factor-1 (IGF-1) Deficiency
Authors: Li Hongyan , Dimayuga Paul , Yamashita Makoto , Yano Juliana , Fournier Mario , Lewis Michael , Cercek Bojan
Published: June 2007

Background: Insulin-like growth factor-1 plays a significant role in wound healing. Injury to the arterial wall is followed by a marked increase in insulin-like growth factor-1 expression and inhibition of insulin-like growth factor-1 action is associated with diminished intimal thickening after injury.

Methods and Results: The role of insulin-like growth factor-1 in arterial response to cuffinjury was investigated in genetically modified mice with severe insulin-like growth factor-1 deficiency (m/m mice). Tissue and serum insulin-like growth factor-1 was severely decreased, by 40% to 60% before the injury and by 50% to 60% following the arterial injury in insulin-like growth factor-1 m/m mice compared to control mice. Nevertheless, following the cuff induced injury to the carotid arteries, insulin-like growth factor-1m/m mice had a similar number of proliferating medial cells 3 days after injury and similar neointimal thickening (0.019 ± 0.015 C57BL/6J vs. 0.016 ± 0.014 mm2, P = 0.26) 21 days after injury compared to wild type C57BL/6J mice. The phases of the response to injury that are mediated by insulin-like growth factor-1 were studied with recombinant human insulin-like growth factor-1 in rats with balloon-injured femoral arteries. Treatment of rats with recombinant human insulin-like growth factor-1 increased neointimal thickening (0.0265 ± 0.0099 vs 0.0156 ± 0.0049 mm2, P = 0.03), intimal smooth muscle cell numbers (195.6 ± 40.2 vs 145.3±27.3; P = 0.03), and the ratio of proliferating intimal to medial smooth muscle cells (10.7 ± 6.9 vs 3.0 ± 2.1; P = 0.03) 7 days after injury compared to untreated rats. At 14 days neointimal area was similar in the 2 groups of rats.

Conclusions: The data in insulin-like growth factor-1 deficient mice suggest a relatively low threshold tissue concentration for insulin-like growth factor-1 to exhibit its role in vascular response to injury. The findings in rats treated with recombinant human insulin-like growth factor-1 suggest that insulin-like growth factor-1 is primarily involved in the early phases of neointimal formation.
Blockade of 5-HT2A Receptors by Sarpogrelate Protects the Heart Against Myocardial Infarction in Rats
Authors: Brasil David , Temsah Rana M. , Kumar Kanwal , Kumamoto Hideo , Takeda Nobuakira , Dhalla Naranjan S.
Published: June 2007

Background: It has been shown that serotonin (5-hydroxytryptamine, 5-HT) is involved in exacerbating vascular abnormalities; however, its role in mediating changes in cardiac function due to myocardial injury has yet to be established. This study examined the effect of sarpogrelate, a 5-HT2Areceptor blocker, in preventing cardiac dysfunction due to myocardial infarction (MI).

Methods and Results: Rats were treated 3 days before surgery with or without 5 mg.kg-1.day-1sarpogrelate, and the left coronary artery was ligated for 3 weeks to induce MI. Sarpogrelate reduced the mortality from 40% to 30%, infarct size from 35% to 25%, and left ventricular end diastolic pressure from 15 mm Hg to 10 mm Hg in MI rats. Electrocardiographic (ECG) tracings showed a marked deviation in the ST-segment and prolongation of the QTc interval in MI rats during the 3 weeks; these changes were attenuated by sarpogrelate pretreatment. In another set of experiments, MI rats were treated with 5 mg.kg-1.day-1sarpogrelate 1 hour after the surgery, and the hemodynamic and electrocardiograph changes were assessed at 3 weeks. This posttreatment was also found to reduce infarct size, improve cardiac function, and attenuate ECG changes.

Conclusions: Sarpogrelate attenuates cardiac dysfunction, infarct size, and changes in the ECG due to MI. These results also support the view that serotonin and 5-HT2Amay contribute to the deleterious effects of ischemic injury in the heart.
Atrial Electrophysiology and Mechanisms of Atrial Fibrillation
Authors: Nattel Stanley
Published: June 2007

Atrial fibrillation is the most common cardiac arrhythmia in clinical practice, and its management remains challenging. A solid understanding of the scientific basis for atrial fibrillation therapy requires insight into the mechanisms underlying the arrhythmia, about which an enormous amount has been learned over the past 10 years. The basic information presently available about atrial fibrillation mechanisms is reviewed. The particular properties of normal atrial electrophysiology are discussed, including salient ionic determinants of the atrial action potential and key anatomic features. Reviewed are three crucial arrhythmia mechanisms long held to be involved in atrial fibrillation: 1) rapid ectopic activity, 2) single-circuit reentry with fibrillatory conduction, and 3) multiple-circuit reentry. The determinants of each and the evidence for their involvement in clinical and/or experimental atrial fibrillation are noted. The physiological consequences, various contributing mechanisms, and clinical implications of the role of atrial-tachycardia remodeling are analyzed. Atrial-tachycardia remodeling links the potential mechanisms of atrial fibrillation, since atrial fibrillation beginning by any mechanism is likely to cause tachycardia-remodeling and thus promote the maintenance of atrial fibrillation by multiple-circuit reentry. Atrial structural remodeling is discussed as a paradigm of atrial fibrillation in which the classic features required for reentry (reduced refractory period and reentrant wavelength) may be lacking. Finally, the importance of recent insights into potential genetic determinants of atrial fibrillation is reviewed. The classic understanding of atrial fibrillation pathophysiology saw the different possible mechanisms as being alternative and opposing hypotheses. We now consider the multiple potential mechanisms as contributing to the pathophysiology of the arrhythmia to a different extent in different clinical settings and interacting with each other in a dynamic way at various stages of the natural history in many patients. It is hoped that this improved mechanistic understanding will lead to the development of improved therapeutic options.
Vasopressor Agents for Cardiopulmonary Resuscitation
Authors: Cao Lan , Weil Max Harry , Sun Shijie , Tang Wanchun
Published: June 2007

The primary goal of cardiopulmonary resuscitation is to reestablish blood flow to vital organs until spontaneous circulation is restored. Adrenergic vasopressor agents produce systemic vasoconstriction. This increases aortic diastolic pressure, and consequently, coronary and cerebral perfusion pressures. The pharmacologic responses to the adrenergic agents are mediated by a group of receptors that are classified as alpha (α), including α1, and α2, and beta (β), including β1and β2. Epinephrine, which has each of these adrenergic actions, has been the preferred adrenergic agent for the management of cardiac arrest for almost 40 years. Its primary efficacy is due to its ca-adrenergic vasopressor effects. This contrasts with its β-adrenergic actions, which are inotropic, chronotropic, and vasodilator. Accordingly,,B-adrenergic actions prompt increases in myocardial oxygen consumption, ectopic ventricular arrhythmias, and transient hypoxemia due to pulmonary arteriovenous shunting. This may account for the failure to demonstrate that epinephrine improves ultimate outcomes in human victims of cardiac arrest. Major interest has more recently been focused on selective α-adrenergic agonists. Both α1,-agonists and α2-agonists are peripheral vasopressors. However, rapid desensitization of α-adrenergic receptors occurs during cardiopulmonary resuscitation. Moreover, ax-adrenergic receptors are present in the myocardium, and α1-agonists, like β-adrenergic agonists, increase myocardial oxygen consumption. If they cross the blood-brain barrier, α2-adrenoceptor agonists also have centrally acting vasodilator effects. In the absence of central nervous system access, α2-adrenergic agonists have selective peripheral vasoconstrictor effects. Under experimental conditions of cardiopulmonary resuscitation, selective α2-agonists, which do not gain entrance into the brain, produce only systemic vasoconstriction. Experimentally, these selective Ut2-agonists are as effective as epinephrine for initial cardiac resuscitation and have the additional advantage of minimizing myocardial oxygen consumption during the global myocardial ischemia of cardiac arrest. Accordingly, myocardial ischemic injury during cardiopulmonary resuscitation is minimized, and postresuscitation myocardial function is preserved with improved survival.
Efficacy of Alternate-Day Dosing Versus Daily Dosing of Atorvastatin
Authors: Jafari Mahtab , Ebrahimi Ramin , Ahmadi-Kashani Mastaneh , Balian Harry , Bashir Mohammad
Published: June 2007

Background: Atorvastatin is a synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In placebo-controlled trials, it has been shown to achieve significant dose-dependent reductions in low-density lipoprotein cholesterol, total cholesterol, and triglycerides. This trial compared the efficacy of daily atorvastatin administration with that of alternate-day dosing.Methods: This was a randomized, prospective, nonblinded, controlled clinical trial. Fiftyfour patients with low-density lipoprotein cholesterol of 100 to 200 mg/dL were enrolled. Baseline fasting lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), liver function tests (aspartate transaminase and alanine aminotransferase), and creatine kinase were drawn. Patients were randomized to three atorvastatin dose groups. Group I received 10 mg of atorvastatin every day, Group II received 10 mg every other day, and Group III received 20 mg every other day. After 6 weeks of treatment with atorvastatin, fasting lipid profiles, liver function tests, and creatine kinase concentrations were redrawn. Compliance to treatment was assessed at each visit.Results: Of the 54 patients enrolled, 46 completed the study. All three regimens significantly reduced total cholesterol and low-density lipoprotein cholesterol compared to baseline. No statistically significant differences existed between the three groups in regards to total, or a percentage, decrease in total cholesterol and low-density lipoprotein cholesterol at 6 weeks compared to baseline. All regimens were well tolerated and none of the patients had a significant elevation of liver enzymes or creatine kinase during the course of the study.Conclusion: Alternate-day dosing of atorvastatin is an efficacious and safe alternative to daily dosing.
A Prospective, Nonrandomized, Open-Labeled Pilot Study Investigating the Use of Magnesium in Patients Undergoing Nonacute Percutaneous Coronary Intervention with Stent Implantation
Authors: Rukshin Vladimir , Santos Raul , Gheorghiu Mitch , Shah Prediman K. , Kar Saibal , Padmanabhan Sriram , Azarbal Babak , Tsang Vivian T. , Makkar Raj , Samuels Bruce , Lepor Norman , Geft Ivor , Tabak Steve , Khorsandhi Mehran , Buchbinder Neil , Eigler Neil , Cercek Bojan , Hodgson Keta , Kaul Sanjay
Published: June 2007

Background: Magnesium has recently been shown to inhibit acute stent thrombosis in animal models. This study tested the feasibility of magnesium administration in patients undergoing nonacute percutaneous coronary intervention with stent implantation.

Methods: Twenty-one patients undergoing nonemergent percutaneous coronary intervention were enrolled and received intravenous magnesium sulfate (2-g bolus over 20 minutes prepercutaneous coronary intervention, followed by 14 g over 12 hours infusion). Endpoints: safety outcomes-hypotension, bradycardia, bleeding complications and heart block within first 24 hours; angiographic outcomes-acute thrombotic occlusion and need for platelet glycoprotein Ilb/Illa inhibitor bailout; and clinical outcomes-death, myocardial infarction, recurrent ischemia, and need for urgent revascularization at 48 hours and 30 days.

Results: No significant effects on heart rate or blood pressure, major bleeding complication, or new electrocardiographic changes were observed. Angiographic thrombus was visualized in two cases, and coronary artery dissection in one case poststent deployment. None of these cases required the use of glycoprotein inhibitors for bailout. Death, myocardial infarction, recurrent ischemia, and need for urgent revascularization were not observed. The serum magnesium level increased from 2.1 ± 0.3 mg/dL at baseline to 3.5 ± 0.8 mg/dL at the end of the infusion (P < .0001). Platelet activation was significantly inhibited at the end of the magnesium sulfate infusion.

Conclusion: Intravenous magnesium sulfate has been demonstrated as a feasible and safe agent in patients undergoing nonacute percutaneous coronary intervention with stent implantation. A randomized clinical trial comparing magnesium with glycoprotein inhibitors during percutaneous coronary intervention is warranted.
Elevated Levels of Plasma Homocysteine in Hypertensive Patients with Diabetes Mellitus
Authors: Qureshi Mabood , Khsandwala Hasnain , Ul Haq Inam , Prasad Kailash
Published: June 2007

Background: Homocysteine generates oxygen radicals (superoxide anion and hydrogen peroxide) that are known to produce vasoconstriction. Hypertension is a common problem in individuals with diabetes mellitus. It is possible that hypertension in diabetic patients may be due to increased levels of plasma homocysteine. We investigated the plasma levels of homocysteine, factors involved in homocysteine metabolism (serum folic acid and vitamin B12) and lipid peroxidation product in the serum of diabetic patients with hypertension.

Methods and Results: The studies were conducted in three groups: 1) healthy controls, and diabetic patients who were 2) normotensive and 3) hypertensive. Plasma homocysteine, serum malondialdehyde (a lipid peroxidation product), vitamin B12, and folic acid were measured in these patients. Plasma homocysteine and serum malondialdehyde levels were elevated in diabetic patients compared to the control group. Plasma levels of homocysteine and serum levels of malondialdehyde were higher in the hypertensive diabetic patients than in those who were normotensive. Levels of serum folate were lower in hypertensive diabetic patients compared to the normotensive group. Levels of serum vitamin B12 were similar in both the normotensive and hypertensive diabetic patients.

Conclusions: Levels of plasma homocysteine and serum malondialdehyde are elevated in hypertensive diabetic patients. Hyperhomocysteinemia may be involved in the induction and sustaining of hypertension in diabetic patients.
Comparison of the Effect of Class IA Antiarrhythmic Drugs on Transmembrane Potassium Currents in Rabbit Ventricular Myocytes
Authors: lost Norbert , Virág László , Varró András , Papp Julius Gy.
Published: June 2007

Background: The blockade of cardiac transmembrane potassium channels, which is commonly seen with vanous antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (It.) and on the inward rectifier (Ikl), ATP sensitive (I), and delayed rectifier (IK) potassium currents in rabbit ventricular myocytes.

Methods and Results: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37°C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10,uM), disopyramide (10 itM), and procainamide (50,uM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I”, (activated by 50,uM pinacidil) and IK currents. None of them influenced significantly Lk. The amplitude of I, was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I,o was not changed by procainamide and was significantly accelerated by quinidine and disopyramide.

Conclusion: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.