bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited Review/Controversial Issue: Can Duodenal Mucosa Appear Normal in Gluten-Sensitive Enteropathy (Celiac Disease)?
Authors: Urbanski Stefan J.
Published: June 2007

Increasing popularity of serologic and permeability studies in patients investigated for possible celiac disease has resulted in a growing awareness among clinicians that currently accepted histologic criteria for diagnosis of celiac disease lack sensitivity. The patients who improve on a gluten-free diet with abnormal findings from serologic and permeability studies may have normal or “almost” normal villous/crypt morphology. The population of intraepithelial lymphocytes once extensively discussed in the literature may after all prove useful in identifying the individuals who may benefit from dietary gluten withdrawal. A recently outlined spectrum of the mucosal pattern (M. N. Marsh), which may be seen in the gluten-sensitive enteropathy is valuable in assessing histomorphology of small bowel biopsies from the patients investigated for celiac disease.
Endometrioid Cystadenofibroma Developing in Juxtahepatic Endometriosis
Authors: Nuovo Margaret , Bayani Elaine , Gerold Thomas , Leong Mary , Mir Rabia
Published: June 2007

A 32-year-old woman presented with acute right upper quadrant pain. A computerized tomogram disclosed a 15.5 cm multicystic mass in the subhepatic space adherent to the liver. A hepatic hydatid cyst and metastasis from an ovarian carcinoma were considered as possible diagnoses. Surgical removal led to a diagnosis of an endometrioid cystadenofibroma in conjunction with endometriosis. To our knowledge, this is the first report of an endometrioid cystadenofibroma arising in juxtahepatic endometriosis.
E-Cadherin Expression Is Correlated with the Isolated Cell/Diffuse Histotype and with Features of Biological Aggressiveness of Gastric Carcinoma
Authors: Machado José C. , Carneiro Fáitima , Beck Stefanie , Rossi Simone , Lopes Joanne , Taveira-Gomes António , Cardoso-Oliveira Manuel
Published: June 2007

We studied the pattern of immunohistochemical expression of E-cadherin in a series of 50 gastric carcinomas, aiming to analyze its relationship with histotype and features of biological aggressiveness of the tumors and survival of the patients. Abnormal E-cadherin expression was significantly (p=.0007) higher in diffuse/isolated-cell type carcinomas than in intestinal/glandular carcinomas. In mixed carcinomas abnormal E-cadherin expression in the diffuse/isolated-cell-type component (94.4%) was significantly (p=.007) higher than in intestinal/glandular component (55.6%). Significant relationships were observed between abnormal E-cadherin expression and nodal metastases (p=.004) and pTNM stages (p=.05). Survival of patients with tumors displaying abnormal E-cadherin expression was worse than that of patients with tumors presenting normal expression, though not attaining the threshold of statistical significance (p=.l9). We conclude that abnormal E-cadherin expression is correlated with diffuse/isolated-cell histotype and features of biological aggressiveness of gastric carcinoma.
Numerical Chromosomal Aberration in NodePositive Early Gastric Carcinomas: Analysis by Fluorescence in Situ Hybridization and Immunohistochemical Staining
Authors: Oya Masafumi , Yao Takashi , Tsuneyoshi Masazumi
Published: June 2007

Tissue from surgically resected early gastric carcinomas with nodal involvement (NI) and without nodal involvement (NNI) were examined by fluorescence in situ hybridization (FISH) by use of a set of alpha-satellite probes. Numerical gain was observed in seven cases (70%) by a probe of chromosome 17 and in three cases (30%) by a probe of chromosome 18 among the NI cases, whereas such a gain was not detected in any NNI cases examined. Cases with numerical aberration in chromosome 17 exhibited immunohistochemical positivity of oncogene or tumor suppressor gene products related to chromosome 17 more frequently than the cases lacking those aberrations. Numerical chromosomal aberration as well as DNA aneuploidy determined by FISH may be related to genetic instability and biological behavior in early gastric carcinomas.
Desmoplastic Fibroblastoma (Collagenous Fibroma)
Authors: Li Shiyong , Junkins-Hopkins Jacqueline M. , Fraker Douglas L. , van de Rijn Matthijs
Published: June 2007

We report a case of desmoplastic fibroblastoma/collagenous fibroma in a 42-year-old African-American male. The 10 cm tumor mass was located subcutaneously on the right lower back. Grossly, the tumor was firm and well-circumscribed and, on cut surface, had a white and homogeneous appearance. Microscopically, the tumor was composed of medium-sized spindled and stellatefibroblasts sparsely distributed in a densely fibrous background. No significant nuclear pleomorphism, mitotic figures, or necrosis were identified. The tumor cells were diffusely positive for vimentin and factor XIIIa but were negative for all other markers tested. Ultrastructurally, the tumor cells had features of fibroblasts with abundant rough endoplasmic reticulum. No recurrence has been seen at 5 months after excision.
Correlation of GI Cyclins and Cyclin-Dependent Kinase Inhibitors Relative to Human Papillomavirus Infection in the Uterine Cervical Lesions
Authors: Cho Nam Hoon , Ahn Hee Jeong , Kim Young Tae , Kim Jae Wook
Published: June 2007

We attempted to investigate the relationship between GI cyclins and cyclin-dependent kinase inhibitors (CDKIs) while also taking into account earlier studies about the relationship between GI cyclins and human papillomavirus (HPV) status. Previously, we observed that cyclin D was downregulated in cases associated with HPV, while cyclin E played a leading role in neoplastic transformation. In this study, we analyzed the expression of CDKIs such as p21WAFI/CIPI, pI6INK4A, and p27KIP1 by means of immunohistochemistry in 22 cases of normal cervix, six cases of adenocarcinoma, 30 cases of cervical intraepithelial neoplasia (CIN), and 41 cases of squamous cell carcinoma (SCC). Stratum intermedium and parabasalis demonstrated strong intranuclear staining for all CDKIs. Reserve-cell hyperplasia and koilocytes revealed strong expression of CDKIs, whereas the neoplastic transformation in squamous lesions showed significantly decreased expression (ANOVA, p<.05). While normal endocervical cells revealed focal and weak expression to CDKIs, adenocarcinoma as well as glandular dysplasia revealed strong expression for all CDKIs but pI6INK4A. Both p16INK4A and cyclin D were negative in adenocarcinoma, and p16INK4A may be independent of cyclin D. There was strong correlation between cyclin E and p27KIP1, and cyclin E and p2 1wAFI/cIPl as well as among CDKIs. P16INK4A expression in case of SCC in cases associated with HPV type 16/18 was higher than in those lacking any type of HPV (t-test, p=.023). Downregulation of cyclin D in SCC associated with HPV seems to be inversely correlated with a relative overexpression of p16INK4A. On the other hand, p2lWAFI/CIPI and p27KIP1 demonstrated lower expressions in HPV-positive cases than in cases devoid of HPV, but they were not statistically significant. In conclusion, all CDKIs were downregulated in neoplastic transformation, with p1 6INK4A being relatively increased in SCC cases associated with HPV where cyclin D was kept inert. In addition, cyclin E could be activated in neoplastic transformation by eluding p2lWAFI/cIP1 and p27KIPI.
Breast Cancer: Prognosis in the Presence of One Tumor-Bearing Node in the Axilla
Authors: Hartveit F.
Published: June 2007

Of 1,069 women with breast carcinoma, 183 had one tumor-bearing node in the axilla; a micrometastasis in 72%. Ten years postoperatively their overall survival was worse than that of their node-negative controls (p<0.01). Nodal tumor load alone identified 31 cases at high risk, i.e., under 0.000 1 or over 1.0 cm2. On 10-year followup 18 of them had died, of whom 13 had also been picked out as at special risk on histology. The survival difference between these 31 cases and those with an intermediate tumor load was marked (p<0.0005). Thus on routine nodal investigation 18 of the 49 women who died of breast cancer could have been identified at the time of operation. In this era of early diagnosis it is essential that such cases should not be missed.
Multiple Lipomas of the Ileum (Lipomatosis) Presenting with Intussusception
Authors: Gaertner Erich M. , McNeil Jennifer , Frishberg David , Maniscalco-Therberge Mary
Published: June 2007

Small intestinal lipomatosis is a distinctly uncommon lesion that primarily affects the distal ileum and frequently presents with signs of obstruction or intussusception. The affected segment is often carpeted by numerous, generally submucosal, lipomas. Radiologic imaging is helpful in making the diagnosis preoperatively, and surgical cure can be obtained by resection of the involved area. This case report highlights this unusual entity, discusses the preoperative and operative management, and reviews the available literature.
Dyshormonogenetic Goiter Pathology
Authors: Fadda Guido , Baloch Zubair W. , LiVolsi Virginia A.
Published: June 2007

Dyshormonogenetic goiter (DG) presents a pathological picture characterized by many solid nodular lesions with different patterns, a peculiar appearance of the surrounding nonnodular thyroid tissue, and the presence of features suspicious for carcinoma. Such features are caused by a high serum level of TSH (thyroid-stimulating hormone) in response to defects in the production of the thyroid hormone. The pathophysiology of DG is described, with regard to the hyperplastic and oncogenetic mechanisms attributed to TSH. The various histopathological features are reviewed, in particular those that help in differentiating the hypercellular nodules of DG from differentiated thyroid carcinoma. The literature on the histopathology of DG is reviewed and clues to avoid inappropriate overdiagnosis of malignancy are given.
A New Mutation of the p53 Gene in Human Neuroblastoma, Not Correlated with N-myc Amplification
Authors: Mejia Carmen , Pellin Antonio , Navarro Samuel , Castel Victoria , Llombart-Bosch Antonio
Published: June 2007

N-myc gene amplification and/or loss of heterozygosity of chromosome 1 (LOH lp) are important criteria for prognosis and progression in human neuroblastoma (NB). Despite the high incidence of alterations of the p53 gene in human cancers, very few p53 mutations have been reported in NB. The objective of our study was to search for p53 mutations in NB and their correlation with N-myc amplification and clinical or pathologic parameters. We analyzed 14 selected cases of NB from the Spanish Protocol N-II-92. We found a missense mutation in codon 248 CGG to GGG (Arg/Gly) in one case of stage 4 NB with no N-myc amplification. Our results confirm the low incidence of p53 gene mutation in neuroblastoma and the absence of correlation with histopathologic parameters.
Anaplastic Large Cell Lymphoma of the Breast
Authors: Pillay P. , Chetty R.
Published: June 2007

A primary anaplastic large cell lymphoma of the breast is presented. A 19-year-old man presented with a swelling of the breast of a short duration. This was not associated with lymphadenopathy or ulceration of the skin. Biopsy of this lesion showed the presence of large, anaplastic cells with multinucleation and markedly indented, ‘embryo-like’ nuclei. The tumor cells were present within breast tissue and surrounded breast ducts. A panel of immunohistochemical markers showed these large cells to be CD30, CD3, and EMA positive. This case emphasizes the occurrence in the breast of anaplastic large cell lymphoma as a primary tumor. It should be considered in the differential diagnosis of anaplastic tumors occurring in the breast, and pertinent immunohistochemistry is recommended.
Nonfunctional Glial Proteins in Tripartite Synapses: A Pathophysiological Model of Schizophrenia
Authors: Mitterauer Bernhard
Published: June 2007

A model for the pathophysiology of schizophrenia is proposed that focuses on an unbalance of transmission in tripartite synapses. Synaptically associated astrocytes should be viewed as integral modulatory elements of tripartite synapses consisting of the presynapse, the postsynapse, and the glial element. Astrocytes may secrete glial binding protein into the synaptic cleft, thus binding free neurotransmitters and thereby reducing the levels of neurotransmitters available for stimulating the postsynapse. Astrocytes also have membrane-bound receptors for neurotransmitters, and when these bind neurotransmitters, the astrocytes upregulate the amount of binding protein secreted into the synapse, resulting in a negative feedback to the presynaptic terminal. The hypothesis presented here is that glia lose their negative feedback function due to loss of function mutations in the genes encoding the binding proteins and glial receptors. The mutations generate proteins that cannot be occupied by their cognate substances of the neuronal system, primarily neurotransmitters. Therefore, the glial-neuronal interaction in tripartite synapses affected becomes totally unbalanced, and the glia lose their inhibitory or boundary-setting function. As a result, neural flux is unconstrained by normal glial boundaries, also the flux of thought on the phenomenological level. Schizophrenia may be caused by the inability to delimit conceptual boundaries.
Cardiovasc Pharmacol Therapeut 6(1):57-63, 2001 Low-Dose ACE with Alphaor Beta-Adrenergic Receptor Inhibitors Have Beneficial SHR Cardiovascular Effects
Authors: Varagic Jasmina , Susic Dinko , Frohlich Edward D.
Published: June 2007

Background: There are no data regarding the prolonged effect of alpha-I adrenergic receptor antagonists on ventricular collagen content and coronary hemodynamics in spontaneously hypertensive rats (SHR). This study, therefore, was designed to determine the effects of chronic treatment with the alpha-I adrenergic receptor inhibitor doxazosin on SHR systemic and regional (especially coronary) hemodynamics, cardiovascular mass, and ventricular collagen. The effects of the combination of doxazosin with low-dose angiotensin-converting enzyme inhibitor were studied versus the alpha-I antagonist alone. These effects were compared with those of a beta-I adrenergic receptor inhibitor.

Methods and Results: Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular weight, hydroxyproline concentration, and aortic weight were measured at age 35 weeks. Doxazosin reduced arterial pressure and total peripheral resistance without changing left ventricular mass and collagen content, whereas monotherapies with the beta-l antagonist metoprolol or a subdepressor dose of the ACE inhibitor enalapril were effective in reducing left ventricular mass and hydroxyproline without altering pressure. Doxazosin combined with the same low-dose ACE inhibitor reduced left ventricular mass and hydroxyproline without potentiating the hypotensive effect of doxazosin. By contrast, the combination of beta-I antagonist with the low-dose ACE inhibitor reduced pressure, unlike either agent alone. Aortic weight index was significantly reduced only by doxazosin whether when used alone or with the ACE inhibitor. Low-dose ACE inhibitor with doxazosin or the beta-I receptor antagonist as well as doxazosin alone decreased renal vascular resistance.

Conclusion: These data show that the low subdepressor dose ACE inhibitor with an alphaor beta-adrenergic receptor antagonist provides beneficial cardiovascular effects in SHR.
Different Isoforms of Tocopherols Enhance Nitric Oxide Synthase Phosphorylation and Inhibit Human Platelet Aggregation and Lipid Peroxidation: Implications in Therapy with Vitamin E
Authors: Li Dayuan , Saldeen Tom , Romeo Francesco , Mehta Jawahar L.
Published: June 2007

Background: oc-Tocopherol has received much attention in the primary and secondary prevention of coronary artery disease. Absence of other isoforms, such as y- and &-tocopherol, in commercial preparations of vitamin E may account for the inconsistent results of clinical trials. Since platelet aggregation is intimately involved in thrombogenesis, the relative effects of ox-, y-, and 6-tocopherol and their combination were examined on human platelet aggregation, lipid peroxidation, and constitutive nitric oxide synthase (cNOS) activity.

Methods and Results: Human platelets were incubated with the three different isoforms of tocopherol and their combination for 30 minutes, and then ADP-induced platelet aggregation measured. All three isoforms of tocopherol markedly and similarly decreased platelet aggregation in a concentration (120-480,uM)-dependent manner. All three tocopherols also decreased the level of the lipid peroxidation product, malondialdehyde (MDA), and increased NO release (P < 0.05 vs control). These isoforms of tocopherol did not affect cNOS protein expression, but enhanced cNOS phosphorylation in platelets. The combination of three tocopherols in a concentration found in nature was more potent than oc-, y-, or 6-tocopherol alone in this regard.

Conclusion: These observations suggest that all three major isoforms of tocopherol have a similar effect on human platelet aggregation. The three isoforns appear to attenuate platelet aggregation at least in part via a decrease in free radical generation and an increase in platelet cNOS activity. The combination of tocopherols has a synergistic platelet inhibitory effect. Future clinical trials should concentrate on the combination of these three isoforms of tocopherols.
Activation of ATP-Sensitive Potassium Channels in Hypoxic Cardiac Failure Is not Mediated by Adenosine-1 Receptors in the Isolated Rat Heart
Authors: Reffelmann Thorsten , Skobel Erik C. , Kammermeier Helmut , Hanrath Peter , Schwarz Ernst R.
Published: June 2007

Background: Hypoxic cardiac failure is accompanied by action potential shortening, which in part might be a consequence of opening of cardiac ATP-sensitive potassium channels (KMp channels). Coupling of the adenosine-1 receptor (A-1 receptor) to these channels has been described; however, the interaction of A-I-receptors and KMP channels in different models of ischemia is still under debate. The hypothesis as to whether A-1 receptors are involved in hypoxic K,, channel-activation in the saline-perfused rat heart was tested.

Methods and Results: Pharmacologic modulation of the KTP channel by Glibenclamide (inhibitor) and Rimalkalim (activator) and of the A-1 receptor by R(-)-N6-(1-methyl-2-phenylethyl)-adenosine (R(-)-PIA, agonist) and 1,3-diethyl-3,7-dihydro-8-phenyl-purine-2,6-dione (DPX, antagonist) at different oxygen tensions (95% 02 and 20% 02) was performed in isolated Langendorff-rat hearts. Peak systolic pressure (PSP, intraventricular balloon), duration of monophasic action potential (epicardial suction electrode, time to 67% of repolarization: MAP67%), coronary flow, and heart rate (HR) were registered. Hypoxic perfusion resulted in a significant reduction of PSP (from 106 ±1 to 56 ± mmHg, P < 0.005) and shortening of MAP67% (from 37 ± to 25 ± ms, P < 0.005). With application of 1 pM Glibenclamide, MAP67% returned to normoxic values and PSP increased to 78 ± mmHg (P < 0.005 vs hypoxia). In normoxia, 2 pM Rimalkalin resulted in reduction of MAP67%/ and PSP, which was reversed by Glibenclamide. Application of 0.1 pM R(-)-PIA in normoxia resulted in a decrease of HR (from 235 ±6/min to 75 +41/min, P < 0.005), which was accompanied by an increase of PSP from 96 ± to 126 ± mmHg (P < 0.05) without changes in MAP67%. These effects were reversible by 1 MM DPX and remained unaffected by application of 1 PM Glibenclamide. Application of 1 pM DPX in hypoxia had no effect on the measured parameters.

Conclusion: In isolated rat hearts, the K,p channel-system is activated in hypoxic cardiac failure and contributes to action potential shortening and reduced contractile performance. These effects seem to be independent of the A- I receptor in this model.
HRCT Findings of Amiodarone Pulmonary Toxicity: Clinical and Radiologic Regression
Authors: Poll Ludger Wilhelm , May Philip , Koch Jens-Albrecht , Hetzel Gerd , Heering Peter , Mödder Ulrich
Published: June 2007

Amiodarone is an antiarrhythmic drug that can cause interstitial pneumonitis leading to pulmonary fibrosis. A 62-year-old man suffering from atrial fibrillation and recurrent dyspnea was treated with amiodarone. After 15 months of treatment, HRCT revealed bilateral interstitial and alveolar opacifications with high-attenuating pleural-parenchymal consolidations, suggesting amiodarone induced pneumonitis. Three months after cessation of amiodarone treatment, HRCT shows complete regression of pneumonitis. Amiodarone pneumonitis can be misinterpreted and mistreated in patients with further underlying diseases. The present case report demonstrates the diagnostic value of HRCT in the diagnosis of interstitial pneumonitis.
Treatment of Diabetic Microangiopathy and Edema with HR (Paroven, Venoruton; 0-(β-hydroxyethyl)-rutosides): A Prospective, Placebo-Controlled, Randomized Study
Authors: Incandela L. , Cesarone M. R. , DeSanctis M. T. , Belcaro G. , Dugall M. , Acerbi G.
Published: June 2007

This study was planned to demonstrate in a prospective, placebo-controlled, randomized study, whether HR (Paroven, Venoruton; 0-(P-hydroxyethyl)-rutosides), is effective in improving the microcirculation in subjects with diabetic microangiopathy and neuropathy. Patients with severe diabetic microangiopathy, neuropathy and edema, patients with microangiopathy, without neuropathy, and 20 healthy subjects were included. Microangiopathy was defined by laser Doppler flowmetry and capillary filtration (rate of ankle swelling (RAS)). Inclusion criteria were: increase in resting flux (RF) and RAS, a decrease in venoarteriolar response (VAR), and alterations in flux increase with temperature. The 2 groups of patients and the control group were randomized in a treatment sub-group which received HR (1 g, twice daily for 6 months); those in the placebo group received similar treatment.

Results: Groups were comparable; there were no drop-outs. There were no differences in the treatment and placebo groups at inclusion. Treatment was well tolerated; no adverse effects were reported. No variations were observed in healthy subjects at 6 months. In both groups of patients, significant decreases (P < 0.05) in RF and RAS were observed in the active treatment groups. The decrease in RAS was associated with a decrease in edema (P < 0.05) in both treatment groups. The decrease in RF and the increase in VAR were associated with a proportional decrease in RAS (P < 0.05). In patients without neuropathy, the variations in RF, VAR, and RAS were larger (P < 0.05) at 6 months. The variations in healthy subjects were limited and not significant.

Conclusion: The decrease in capillary filtration and edema with HR is associated with symptomatic improvement. The action on edema is beneficial for the evolution of neuropathy. The effects of HR on flux, RAS, and edema are important in early stages of microangiopathy to avoid progression to clinical stages.
Cocaine-Induced Channelopathies: Emerging Evidence on the Multiple Mechanisms of Sudden Death
Authors: Bauman Jerry L. , DiDomenico Robert J.
Published: June 2007

Sudden death due to cocaine in the absence of myocardial infarction has been attributed to the precipitation of life-threatening arrhythmias not unlike that due to antiarrhythmic drugs. Cocaine is a slow on-off sodium blocker and a fast on-off potassium blocker. Effects on repolarization are biphasic: At low concentrations, cocaine delays ventricular recovery, whereas at higher levels, cocaine hastens it. Two distinct clinical profiles emerge from case reports of electrocardiographically documented life-threatening arrhythmias attributed to cocaine. The first is monomorphic slow ventricular tachycardia or idioventricular rhythm that occurs in overdose situations and appears to reflect excessive sodium channel block; it may respond to sodium bicarbonate. The second is torsade de pointes that occurs in recreational users who have underlying risks for this tachycardia (such as fully or partially expressed congenital long QT syndrome) and reflects potassium channel blockade. These clinical observations can be explained by recent findings regarding the electrophysiologic effects of cocaine. Other patterns of severe arrhythmias due to cocaine may yet emerge.
The Role of Approximate Entropy in Predicting Ventricular Defibrillation Threshold
Authors: Hamzei Ali , Ohara Toshihiko , Kim Young-Hoon , Lee Moon-Hyoung , Voroshilovski Olga , Lin Shien-Fong , Weiss James N. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2007

Background: The role of myocardial tissue mass on ventricular defibrillation threshold (DFT) is unclear. We hypothesized that changes in tissue mass modulate DFT by changing ventricular fibrillation (VF) wavefront regularity (entropy).

Methods and Results: The right ventricles (RV) of seven farm pigs were isolated, superfused and perfused through the right coronary artery with oxygenated Tyrode's solution at 37 The epicardial surface was stained with the voltage sensitive dye, di-4-ANEPPS, and activation wavefront numbers (AWN) during VF were determined from the optical maps using a CCD camera (96 x 96 pixels over a 3.5 x 3.5 cm area). The RV mass was progressively reduced by sequential cutting of 1 to 2 g of tissue (approximately 12 cuts in total) distal to the perfusion site. After each cut, VF was reinduced, optical maps obtained, and the 50% probability of successful DFT50 determined using an up-down algorithm. After each cut, the approximate entropy (ApEn) was also computed using 5 seconds of VF data obtained with a bipolar electrode and a pseudo-electrocardiogram. Tissue mass reduction of up to one third of the RV mass (ie, from 48.4 ± 4.25 g to 34 ± 4.7 g) caused little or no change in the DFT, ApEn or AWN. However, further progressive reduction of the RV mass near the critical mass of VF resulted in a significant (P < 0.05) progressive decrease in all three measured parameters. DFT energy was reduced by 27% (1.47 ± 0.34 J vs. 1.02 ± 0.14 J). There was a significant (P < 0.01) correlation between the DFT and ApEn, which significantly further increased (P < 0.001) near the critical mass. In a separate series of 6 isolated RVs, the ApEn correlated well with the Kolmogorov-Sinai (K-S) entropy, the standard method of calculating entropy.

Conclusion: Tissue mass reduction significantly reduces DFT when the mass reduction increases VF wavefront regularity.
Cocaine Produces Cardiac Hypertrophy by Protein Kinase C Dependent Mechanisms
Authors: Henning Robert J. , Li Yongxiang
Published: June 2007

Background: Chronic cocaine users can have as much as a 69% increase in left ventricular muscle mass without associated increases in arterial blood pressure, heart rate, renin, aldosterone, or cortisol. We determined whether cocaine directly increases cardiomyocyte protein content and whether protein kinase C is important in this process.

Methods and Results: Adult rat cardiomyocytes were isolated and grown in cultures. In Series I experiments, cocaine, 10-8to 10-6M, or vehicle, in the absence or presence of phentolamine or metoprolol, was added to each culture and the cells were subsequently harvested. In Series II, cocaine, 10-6M, cocaine, 10-6M, plus bisindolylmaleimide, 10-6M, a protein kinase C inhibitor, or vehicle were added to each culture and the cells subsequently harvested. We determined the total protein content, the content of α-myosin and fetal β-myosin heavy-chain protein, and the presence of protein kinase C isoforms in the cardiomyocyte soluble and particulate fractions. Protein kinase C translocation from the soluble to particulate fraction is indicative of activation. In Series III, we determined the cocaine effects on ERK, SAPK/JNK, and p38. In Series I, cocaine, 10-8to 10-6M, dose-dependently increased myocyte protein content by as much as 28%±2% (P < .001) and fetal,β-myosin heavy-chain protein content by 80% ± 2% (P < .001). Neither phentolamine nor metoprolol inhibited this process. In Series II, we determined that ventricular myocytes contain alpha (α), beta (β), delta (δ), epsilon (ε), and zeta (ξ) protein kinase C isoforms. Cocaine, 10-6M, caused a 45 ± 5% increase (P<.001) in protein kinase Cα in the particulate fraction. The addition of a protein kinase C inhibitor to the myocyte cultures prevented the cocaine-induced translocation of protein kinase Cα and limited the increase in β-myosin heavy-chain protein content by >75% (P<.001). However, cocaine did not increase the phosphorylation of ERK, SAPK/JNK or p38 in Series III.

Conclusions: Cocaine increases adult cardiomyocyte protein content by protein kinase Cα-dependent mechanisms, and this process can contribute to the cardiac hypertrophy and cardiomyopathy that results from chronic cocaine use.
Electrical Storm: Case Series and Review of Management
Authors: Srivatsa Uma N. , Ebrahimi Ramin , El-Bialy Adel , Wachsner Robin Y.
Published: June 2007

Electrical storm is defined as a recurrent episode of hemodynamically destabilizing ventricular tachyarrhythmia that usually requires electrical cardioversion or defibrillation. We describe three cases presenting with electrical storm under differing circumstances: (1) a 57-year-old man with ST-elevation myocardial infarction within 1 week of a posterior circulation stroke who developed refractory sustained ventricular tachycardia 10 days after an acute myocardial infarction; (2) a 65-year-old man who developed polymorphic ventncular tachycardia and ventricular fibrillation following dobutamine echocardiography; and (3) a 20-year-old woman who developed intractable ventricular fibrillation following an overdose of a weight-reduction pill. The management of electrical storm is discussed, and evolving literature supporting the routine use of intravenous amiodarone and β-blockers in place of intravenous lidocaine is critically examined.
Right Atrial and Ventricular Thrombus Infiltrated with Osteoblastic Osteosarcoma
Authors: Shah Atman P. , Parmar Simrit , O'Regan Ruth
Published: June 2007

The presenting signs of osteogenic osteosarcoma are commonly pain, local swelling, local warmth, pathologic fracture, and metastatic disease. Deep venous metastasis of osteoblastic osteosarcoma is most often a postmortem diagnosis. This paper describes the case of a previously healthy 18-year-old woman who presented with dyspnea and lower extremity edema. This is a rare, and to our knowledge, a previously unreported case of right atrial and ventricular tumor thrombus infiltrated with osteoblastic osteosarcoma.
Bivalirudin (Angiomax) Use during Intracoronary Brachytherapy May Predispose to Acute Closure
Authors: Sharma Sanjiv , Bhambi Brijesh , Nyitray William , Desai Kirit , Davis Dean L. , Sharma Geetanjali , Shukla Pankaj , File Carla , Ishimori Tetsuo
Published: June 2007

We describe two cases of intracoronary vascular brachytherapy where bivalirudin (Angiomax), employed as an anticoagulant, led to abrupt vessel closure or threatened abrupt closure. Use of bivalirudin (Angiomax) during intracoronary brachytherapy may predispose to the formation of intracoronary thrombus, related to the reversible binding kinetics of the bivalirudin to thrombin, and resulting in recovery of thrombin functional activity during periods of prolonged stasis that occur during intracoronary brachytherapy. Intracoronary abciximab administration may be a useful strategy in resolving the acute closure, since abciximab administered early during the formation of thrombus has been shown to facilitate clot lysis.
Cardiovascular Pharmacogenomics: Current Status, Future Prospects
Authors: Anderson Jeffrey L. , Carlquist John F. , Home Benjamin D. , Muhlestein Joseph B.
Published: June 2007

Pharmacogenomics is a field dedicated to exploring the contribution of genetics to interindividual variability in drug response. A goal of cardiovascular pharmacogenomics is to guide cardiovascular drug development and selection so as to optimize therapeutic benefit and minimize the potential for toxicity. Genetic-based differences in drug metabolism have long been recognized but just now are on the verge of wider clinical application. Differences in efficacy of cardiovascular drugs (independent of drug concentration) based on common genetic variations (polymorphisms) only recently have begun to be explored, but the potential for clinical application appears promising. Examples are presented of important pharmacodynamic effects of genetic variants on several drugs, including those in antiarrhythmic, reninangiotensin, f-blocker, lipid-lowering, and antithrombotic classes. Principles of pharmacogenomics applied to drug metabolism are discussed that are relevant to drug development and clinical use, and examples are given for CYP450 phase I enzymes, phase II enzymes, and drug transporters. Challenges in establishing true pharmacogenetic associations are discussed, and current and future clinical potential is summarized. Rapid research progress and initial clinical applications with pharmacogenomics are foreseen in the near future.
The Role of Nitric Oxide and Vasopressin in Refractory Right Heart Failure
Authors: Wasson Sanjeev , Govindarajan Gurushankar , Reddy H. K. , Flaker Gregory
Published: June 2007

The standard treatment for right heart failure includes aggressive fluid resuscitation, inotropic agents, and avoiding drugs, such as diuretics or nitrates, or maneuvers that decrease preload. Even an increase in vagal tone caused by the insertion of a bladder catheter can acutely decrease preload and lead to cardiogenic shock. Other modalities include early reperfusion therapy and pacemaker implantation for complete heart block or loss of atrioventricular synchrony. Acute right heart failure carries a very high mortality because of the limited options available for its management. Among newer treatments, inhaled nitric oxide and intravenous vasopressin have shown promise for acute right ventricular failure.
Effect of Fenofibrate on Serum Inflammatory Markers in Patients With High Triglyceride Values
Authors: Tsimihodimos Vasilis , Kostoula Angeliki , Kakafika Anna , Bairaktari Eleni , Tselepis Alexandros D. , Mikhailidis Dimitri P. , Elisaf Moses
Published: June 2007

Background: Atherosclerosis is the leading cause of death in developed countries. Although the mechanisms that underlie this process are not well defined, it has been proposed that atherosclerosis is mainly an inflammatory disease. In this context, a number of inflammatory markers have been studied for their ability to predict future cardiovascular events in asymptomatic individuals or patients with established atherosclerotic disease.

Methods and Results: The aim of our study was to evaluate the effect of micronized fenofibrate on serum inflammatory markers, such as C-reactive protein, fibrinogen, and plasma platelet-activating factor acetylhydrolase (PAF-AH) in patients with high triglyceride values. An analysis of baseline values revealed that hypertriglyceridemic patients (n = 58) exhibit an atherogenic phenotype, characterized not only by elevated lipid values but also by high concentrations of serum inflammatory markers. Along with the improvement in serum lipid profile (reduction in triglycerides and total cholesterol, low-density lipoprotein, and nonhigh-density lipoprotein-cholesterol, with a concomitant increase in high-density lipoprotein-cholesterol levels), fenofibrate administration significantly reduced the values of serum inflammatory markers by 34%, 9.5%, and 24.8% for C-reactive protein, fibrinogen, and plasma PAF-AH, respectively. However, with the exception of PAF-AH, these reductions in inflammatory markers were not correlated with the changes in lipid values.

Conclusions: In addition to its well-known hypolipidemic effects, fenofibrate may also possess significant anti-inflammatory properties that can contribute its antiatherogenic effect.
β-Adrenergic Blockers as Antiarrhythmic and Antifibrillatory Compounds: An Overview
Authors: Singh Bramah N.
Published: June 2007

β-Adrenergic blockers have a wide spectrum of action for controlling cardiac arrhythmias that is larger than initially thought. Data from the past several decades indicate that, as an antiarrhythmic class, β-blockers remain among the very few pharmacologic agents that reduce the incidence of sudden cardiac death, prolong survival, and ameliorate symptoms caused by arrhythmias in patients with cardiac disease. As a class of compounds, β-blockers have a fundamental pharmacologic property that attenuates the effects of competitive adrenergic receptors. However, the net clinical effects of the different β-receptor blockers may vary quantitatively because of variations in associated intrinsic sympathomimetic agonism and in their intrinsic potency for binding to β-receptors. These individual compounds also differ in their selectivity for β1- and β2-receptors. Metoprolol is a β1-selective blocker, whereas carvedilol is a nonselective β1- and β2-blocker, an antioxidant, and has a propensity to inhibit α1-receptors and endothelin. Evolving data from controlled and uncontrolled clinical trials suggest that there are clinically significant differences among this class of drugs. Recent evidence also suggests that the antiarrhythmic actions of certain β-receptor blockers such as carvedilol and metoprolol extend beyond the ventricular tissue to encompass atrial cells and help maintain sinus rhythm in patients with atrial fibrillation, especially in combination with potent antifibrillatory agents such as amiodarone. This introduction provides a current perspective on these newer developments in the understanding of the antiarrhythmic and antifibrillatory actions of β-blockers.
Antiarrhythmic Action ofβ-Blockers: Potential Mechanisms
Authors: Dorian Paul
Published: June 2007

Sympathetic nervous system overactivity has been linked to ventricular tachyarrhythmias and sudden death. It has been hypothesized that the extent and nature of the arrhythmogenic effect of sympathetic stimulation depends on the underlying myocardial substrate, the mechanism of the arrhythmia, and the integrated effects of sympathetic stimulation in the particular individual circumstance. Multiple direct and indirect mechanisms of adrenergic action on the heart may benefit from the known antiarrhythmic actions of β-blocker therapy and other interventions that decrease sympathetic tone. The antiarrhythmic mechanism of β-blockade (and possibly α-blockade) will depend on the specific mechanism of the individual arrhythmia and will differ for those arrhythmias caused by tachycardia and ischemia, those caused by reentry and promoted by decreased conduction velocity and shortened refractoriness, and those caused by early or delayed afterdepolarizations, usually in the context of prolonged action potential duration. Antagonism of cardiac adrenergic activity by β-blockade in particular is the best-established drug therapy to prevent ventricular arrhythmias.
Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion–Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy
Authors: Nordlie Margaret A. , Wold Loren E. , Simkhovich Boris Z. , Sesti Casilde , Kloner Robert A.
Published: June 2007

Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.
Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure
Authors: Dhalla Naranjan S. , Dent Melissa R. , Tappia Paramjit S. , Sethi Rajat , Barta Judit , Goyal Ramesh K.
Published: June 2007

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.
Compliance by Referring Physicians With Recommendations on Heart Failure Therapy from a Tertiary Center
Authors: Rocca Hans Peter Brunner-La , Capraro J. , Kiowski W.
Published: June 2007

Background: We tested the assumption that general practitioners do not use medication as recommended and do not follow recommendations made by heart failure specialists.

Methods: The study included 193 stable patients referred to and subsequently seen at our heart failure clinic between 1995 and 2001 with an ejection fraction of 40% or less. They had 1906 visits (1661 with structured follow-up). Recommendations by heart failure specialists regarding medication influencing prognosis and adherence of referring physicians to them were recorded.

Results: Ninety-six percent of patients were taking angiotensin-converting enzyme (ACE) inhibitor/angiotensin-II receptor blocker (ARB) when referred. The prescription rate of β-blockers and spironolactone increased after publication of large trials (more than 80% in 2001). Doses were inappropriate for both ACE-inhibitors/ARBs (55% ± 30% of target dose) and β-blockers (29% ± 24%). Recommendations were followed closely for dose reduction/discontinuation of all drugs (82%) and start/uptitration of spironolactone (78%). Adherence was less ( P < .01) for start/uptitration of ACE inhibitors/ARBs (62%) and β-blockers (48%). Recommendations regarding single-step start/uptitration were more successful (ACE-inhibitors/ARBs, 70%; β-blockers, 63%; single-step of both, 67%) than multiplestep uptitration (ACE inhibitors/ARBs, 48%; β-blocker, 38%; P < .001). This was particularly true if recommendations concerned multiple-step uptitration of both drugs (25%, P < .001). There was no difference between general practitioners and cardiologists.

Conclusions: Although penetration of drugs beneficial in heart failure was high upon referral, doses were lower than recommended, and recommendations regarding changes were insufficiently adhered to by the referring physicians. Simple, one-step recommendations were better implemented and may be combined with direct prescriptions during control visits to guarantee adequate medical therapy.
Preoperative Platelet Inhibition With Eptifibatide During Coronary Artery Bypass Grafting With Cardiopulmonary Bypass
Authors: Dyke Cornelius M. , Jennings Lisa K. , Maier George , Andreou Costa , Daly Robert , Tamberella Michael R.
Published: June 2007

Platelet glycoprotein IIb-IIIa antagonists reduce cardiac events in acute coronary syndromes (ACSs), but their use is limited during coronary artery bypass grafting (CABG) because of bleeding concerns. Patients with ACS, however, are at increased risk for cardiac events after CABG. The use of short-acting glycoprotein IIbIIIa inhibitor eptifibatide in patients with ACS undergoing CABG was investigated. Fifteen patients with ACS and undergoing CABG with cardiopulmonary bypass were enrolled. One withdrew before surgery. Patients received heparin and eptifibatide preoperatively. Eptifibatide concentration and receptor occupancy (RO) at termination of infusion were similar in the two groups. Immediately before surgery, eptifibatide levels in the 2-hour group were twice that in the 4-hour group, and platelet RO was higher. Cessation of eptifibatide 4 hours before surgery results in less bleeding and transfusions than 2 hours before surgery. The optimal balance between bleeding and platelet inhibition is approximately 60% platelet RO. Further investigation of upstream therapy should target this threshold.
Development of Professional Practice Based on a Family Systems Nursing Framework: Nurses’ and Families’ Experiences
Authors: LeGrow Karen , Rossen Beth Ellen
Published: June 2007

The purpose of this evaluation project was to elicit nurses’and families’ experiences about differences and changes for nurses and families and the familynurse relationship when a family systems nursing approach was used to guide practice. Following nurses’ involvement in an educational workshop, the evaluation examined changes in nurses’and families’ experiences over an 8-week period of a child’s hospitalization in a pediatric rehabilitation center. A total of 17 nurses and 13 parents participated in the project. Nurses and parents completed questionnaires and participated in semi-structured interviews and focus groups. Nurses completed journals reflecting on their interactions with families. Data were analyzed using descriptive statistics and content analysis. Findings indicate that a family systems nursing approach had a positive impact on how nurses viewed their nursing practice and their work with families, thereby enhancing family-nurse relationships. Such findings have relevance to clinical nursing practice, professional development, and evaluation research design.