bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Doxazosin on Oxidative Stress-Related Proteins in Benign Prostatic Hyperplasia
Authors: Calò Lorenzo A. , Pagnin Elisa , Davis Paul A. , Lodde Michele , Mian Christine , Semplicini Andrea , Pycha Armin
Published: January 2006

Background and Objectives: Oxidative stress can induce cell mutations or proliferation which then can progress to carcinogenesis or remodeling. The same oxidative stress-mediated mechanism could participate in prostate cell proliferation and remodeling present in benign prostatic hyperplasia (BPH). Doxazosin induces prostate epithelial and stromal cell apoptosis through production of transforming growth factor-β (TGF-β), but cellular mechanisms are not completely clarified. In 10 prostate samples from BPH untreated patients who underwent TUR, we have assessed the gene and protein expression of: p22phox (subunit of NAD(P)H oxidase essential for O2– production); heme oxygenase-1 (HO-1) (induced by oxidative stress and antiapoptotic); TGF-β (inhibitor of prostatic epithelial and stromal cell growth); the in vitro effect of doxazosin on expression of these markers. Methods: RT-PCR and Western blot with specific primers and antibodies. p22phox, HO-1 and TGF-β were quantified by the ratio between their PCR and Western blot products and GAPDH. Results: Doxazosin significantly reduced p22phox gene and protein expression (0.61 ± 0.04 vs. 0.36 ± 0.04 d.u., p < 0.0002; 0.85 ± 0.03 vs. 0.47 ± 0.03, p < 0.0001, respectively). Doxazosin concentration dependently reduced HO-1 gene and protein expression (0.57 ± 0.07 vs. 0.49 ± 0.06 d.u. (1 µM) p < 0.04, vs. 0.22 ± 0.08 (10 µM) p < 0.0001; 0.78 ± 0.04 vs. 0.44 ± 0.1 (10 µM) p < 0.003 respectively) and increased TGF-β protein expression (0.58 ± 0.05 vs. 0.74 ± 0.16 (1 µM) n.s. vs. 0.81 ± 0.07 (10 µM) p < 0.01). Conclusions: Induction of oxidative stress-related proteins seems to be involved in the prostate cell proliferation and remodeling present in BPH. Doxazosin may reduce oxidative stress through reduction of p22phox. Surprisingly, HO-1, which is induced and protected by oxidative stress, is also reduced by doxazosin. HO-1 is a potent antiapoptotic factor and downregulator of TGF-β. From the results of this preliminary study it could be proposed that the proapoptotic effect of doxazosin could be mediated, at least in part, through the contemporary inhibition of HO-1.
Effects of Selective Alpha-1-Adrenergic Receptor Blockers on Bladder Weight
Authors: Egilmez Tulga , Pourbagher Mir Ali , Guvel Sezgin , Kilinc Ferhat , Turunc Tahsin , Ozkardes Hakan
Published: January 2006

Introduction: This study was undertaken to investigate the effects of two different α1-adrenergic blockers on bladder hypertrophy using ultrasound-estimated bladder weight (UEBW) and to assess the relation between changes in UEBW and other objective and subjective parameters of disease severity in patients with benign prostatic hyperplasia (BPH). Materials and Methods: 41 men were enrolled in the study and they were subjected to either watchful waiting (group 1) or α1-adrenergic receptor blocker therapy (group 2 with alfuzosin; group 3 with tamsulosin). The patients were investigated by symptom evaluation using the International Prostate Symptom Score (IPSS) and quality of life score (QOL), uroflowmetry and UEBW. The parameters were assessed again 3 months after initiation of treatment and compared with the initial values. Results: While the mean UEBW increased in group 1 (42.2 ± 10.3 to 52.5 ± 12.2 g), it decreased in both the other groups that received α-blocker therapy (61.3 ± 18.7 to 41.1 ± 13.2 and 59.4 ± 17.2 to 43.5 ± 17.6 g, respectively). In groups 2 and 3, the mean UEBW, post-void residual urine, IPSS and QOL values decreased, and the mean maximum flow rate increased. All of the changes in group 2 and all except QOL in group 3 were statistically significant (p < 0.05). The changes correlated well with each other with regard to treatment success. The highest decreases in UEBW were encountered in patients with heavier bladders. Conclusions: UEBW decreases with α1-adrenergic receptor blockers. When used together with the other objective and subjective parameters, UEBW is a promising quantitative parameter as a follow-up tool and can be useful in monitoring the therapeutic effects of α1-adrenergic receptor blockers.
Relation between Cyclooxygenase-2 Expression and Clinicopathologic Parameters with Patient Prognosis in Transitional Cell Carcinoma of the Bladder
Authors: Gurocak Serhat , Sozen Sinan , Erdem Ozlem , Özkan Seçil , Kordan Yakup , Alkibay Turgut , Akyol Gulen , Bozkirli Ibrahim
Published: January 2006

Objective: To evaluate the correlation between cyclooxygenase-2 (Cox-2) expression and clinicopathologic findings with the effect of these variables on prognosis of bladder cancer. Methods: Cox-2 expression was examined immunohistochemically in paraffin blocks of 99 patients. Correlations between Cox-2 expression and variables like cancer stage and grade, number of mitoses, angiolymphatic invasion, number and size of the lesions were determined. Results: Cox-2 expression was detected in 52 (52.5%) patients. Univariate regression analysis between Cox-2 expression and clinicopathologic findings showed a significant correlation only in the pathologic stage of the patients (p = 0.048) (OR =2.64, CI = 0.97–7.81). Multivariate regression analysis in stage T1 revealed an increasing number of mitoses as an independent prognostic factor for recurrence (p = 0.002) (OR = 1.5, CI = 1.16–1.92) and progression (p = 0.030) (OR = 8.23, CI = 1.22–55.27) although a prognostic factor was not found for progression in stage T2. Conclusion: Univariate analysis showed that only the pathologic stage correlated significantly with Cox-2 expression. Cox-2 expression revealed a significant relation with patient prognosis in stage T2 but not in stage T1. These results support the fact that Cox-2 inhibitors may play a role in progression of invasive bladder tumors.
Evaluation of Gram Stain as an Alternative in the Assessment of Human Spermatozoa Quality
Authors: Mantas D. , Msaouel P. , Angelopoulou R.
Published: January 2006

Introduction: During spermiogenesis, protaminosis and sperm chromatin condensation are important prerequisites for the preservation of DNA integrity in spermatozoa. The aim of this study is to assess Gram stain as an alternative technique for the evaluation of human sperm chromatin condensation status. Patients and Methods: Aniline blue and Gram staining were applied to semen samples from 34 donors in order to determine the relationship between sperm chromatin condensation and infertility. In addition, the possible correlation between morphology and vitality (eosin-Y staining) of spermatozoa compared with their nuclear status (aniline blue and Gram staining) was studied. Results: Chromatin condensation and sperm vitality were significantly higher in fertile men compared to the subfertile. A significant correlation was found between chromatin condensation and (a) sperm vitality (p < 0.01), and (b) nuclear protein status (p < 0.01). Conclusions: Gram staining may be used as a routine method in assisted reproduction laboratories and could assist in the evaluation of sperm quality as well as in the selection of the appropriate fertilization technique.
Stereological Evaluation of the Seminiferous Tubules of Rats after Maternal Undernutrition during the Lactation Period
Authors: Ramos Cristiane da Fonte , da Silva Alexandra Moreira , Costa Waldemar Silva , Sampaio Francisco J.B.
Published: January 2006

The goal of this study is to evaluate, through stereological methods, some structural aspects of offspring testes whose dams were submitted to protein and energy-restricted diets during the lactation period. At birth, dams were separated into 3 groups: control group (C), receiving a diet with 23% protein; protein-restricted group (PR), receiving a diet with 8% protein; energy-restricted group (ER), receiving a diet with 23% protein in restricted quantities. At weaning, the offspring was anesthetized and perfused with formalin solution. Then, the testes were excised and processed using routine histological methods. Compared to the C group, both PR and ER groups had a significant reduction in the testis weight (PR = 65%, ER = 60%, p < 0.01), in the total area (PR = 23%, ER = 32%, p < 0.01), in the luminal area (PR = 30%, ER = 36%, p < 0.01), in the epithelial area (PR = 21%, ER = 27%, p < 0.01), and in the epithelial height (PR = 17%, ER = 23%, p < 0.01) of the seminiferous tubule. We conclude that maternal malnutrition during lactation leads to structural changes in the testis that could be responsible for future alterations in this organ physiology.
Serum Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) in Prostate Cancer: A Potential Predictor of Bone Metastases and Prognosticator for Disease Progression and Survival
Authors: Thurairaja R. , Iles R.K. , Jefferson K. , McFarlane J.P. , Persad R.A.
Published: January 2006

Introduction: To determine if amino-terminal propeptide of type 1 procollagen (P1NP) is reliable as a predictor of prostate cancer bone metastases and assess its value as a prognostic indicator of disease progression and survival. Materials and Methods: A cohort of patients with prostate cancer between January 1999 and July 2001 were recruited. Prostate-specific antigen (PSA) and P1NP levels were measured. Two years following completion of recruitment, patient notes were reviewed for symptoms of bone metastases and survival. Results: 24 negative and 12 equivocal or positive bone scans were reported for 36 recruited patients. Mean PSA values for patients with negative, equivocal and positive scans were 18.3, 24.9 and 122.5 ng/ml while mean P1NP for the same groups were 38.2, 73.4 and 119.9 ng/ml. For patients with equivocal and positive scan, mean P1NP with and without bone symptoms were 111.5 and 65.7 ng/ml while for surviving and dead patients the values were 63.9 and 120.8 ng/ml, respectively. Conclusions: Though this study involved a small number of patients, it demonstrates P1NP’s potential as a predictor of bone metastases and a prognosticator for disease progression and survival.
Investigation of Dysfunctional Voiding in Children with Urgency Frequency Syndrome and Urinary Incontinence
Authors: Kuo Hann-Chorng , Liu Hsin-Tzu
Published: January 2006

Purposes: Dysfunctional voiding may result in lower urinary tract symptoms (LUTS) in children and is associated with urinary tract infection and vesicoureteral reflux (VUR). This study analyzed the videourodynamic investigations in children with urgency frequency syndrome and/or urinary incontinence. Methods: Forty children, 1–13 years old, with urgency frequency syndrome and/or incontinence were investigated to determine their LUTS or for the assessment of VUR. Videourodynamic study was performed in all patients and the results were analyzed with clinical characteristics and underlying pathophysiology. Results: Dysfunctional voiding was present in 75.7% of the children with detrusor overactivity, in 73.3% of the children with VUR, in 63% of the children with urinary incontinence, in 77% of the children with episodic urinary tract infection, and in all of the children with diurnal enuresis. Compared to children without dysfunctional voiding, the voiding pressure was significantly higher in children with dysfunctional voiding (with VUR, 61.1 ± 29.8 vs. 24.8 ± 15.8 cm H2O, p = 0.004; without VUR, 53.4 ± 24.1 vs. 24.8 ± 15.8 cm H2O, p = 0.010). Biofeedback pelvic floor muscle training and treatment with antimuscarinic agent effectively decreased detrusor pressure, increased bladder capacity and maximum flow rate, and reduced the grade of VUR in 5 children who had post-treatment urodynamic studies. Conclusions: This study has shown that dysfunctional voiding is highly prevalent in children with symptoms of urgency frequency and incontinence. Biofeedback pelvic floor muscle training is effective in treatment of dysfunctional voiding in children.
Sarcomatous Dedifferentiated Renal Cell Carcinoma Mimicking a Severe Purulent Kidney Infection
Authors: Nagy V. , Schneider H. , Valanský L. , Sokol L.
Published: January 2006

Sarcomatous renal cell carcinomas (SRCCs) originate from a dedifferentiation of renal cell carcinoma (RCC). They are characterized by an aggressive course and very poor prognosis. Less known is their ability to imitate inflammatory diseases of the kidney. The aim of the study was to outline the less usual symptoms of SRCCs in a retrospective analysis of 180 patients operated for RCC in 1997–2001. In 11 (6.1%) patients (8 men and 3 women, age 40–76 years, mean age 60 years) SRCC was present. The pTNM classification, results of histological examination, the stage of RCC dedifferentiation and survival after the operation are presented. In almost every patient SRCC was diagnosed at a late stage with combined histological variants of RCC. Survival of the patients after the operation ranged from 1 to 19 (average 8.8) months. In 2 patients an atypical clinical picture imitated abscess of the kidney and calculous pyonephrosis. The authors warn that in spite of the clinical signs of inflammatory disease of the kidneys, a tumorous origin should be excluded. In doubtful cases a quick peroperative biopsy and histology should be performed. Sometimes only a definitive histological examination can reveal the tumorous origin of the disease.
Reconstruction of Urinary Tract Combined with Surgical Management of Locally Advanced Non-Urological Cancer Involving the Genitourinary Organs
Authors: Harada Ken-ichi , Sakai Iori , Muramaki Mototsugu , Kurahashi Toshifumi , Yamanaka Kazuki , Hara Isao , Inoue Taka-aki , Miyake Hideaki
Published: January 2006

Introduction: The objective of this study was to review our experience with urinary reconstruction in patients undergoing surgical management for locally advanced pelvic cancer, and to evaluate the role of urologists in these procedures. Materials and Methods: This study included a total of 37 patients undergoing some type of urinary reconstruction due to invasion of the urological organs by locally advanced pelvic cancers, including 17 rectal cancers, 9 cervical cancers, 4 sigmoid cancers, 4 retroperitoneal sarcomas, 2 ovarian cancers and 1 appendiceal cancer. Among these 37, 18 were recurrent cancers following initial surgery for primary tumors. The clinical outcomes of these approaches were retrospectively analyzed. Results: Of the 37 patients, 9 underwent cystectomy (group A) with the following urinary diversions: ileal neobladder in 3, ileal conduit in 5 and colon conduit in 1, and 12 underwent partial cystectomy (group B), among whom 11 received additional urinary reconstruction as follows: bladder flap repair in 5, psoas hitch in 2, ileal ureter in 2, bladder augmentation in 1 and ureteroureterostomy in 1, while the remaining 16 (group C), in whom complete bladder preservation was possible, underwent the following types of urinary reconstruction: bladder flap repair in 6, psoas hitch in 3, en bloc removal of the rectum with prostate in 3, ileal ureter in 2, and ureteroureterostomy in 2. There were 10 early urological complications, including leakage of urine in 7 and acute pyelonephritis in 3. As a late urological complication, hydronephrosis was observed in 8 patients, but ureteral stent was not required in any of these 8. There were no significant differences in the incidence of postoperative complications, the status of surgical margin and the survival among groups A–C. Conclusion: Our experience with extended surgical management of non-urological pelvic cancer with reconstruction of the urinary tract suggests that the urological portion of this procedure can be performed with acceptable morbidity, and that the role of the urological surgeon during this procedure is potentially important.
Squamous Cell Carcinoma of the Penis in a Patient with Chronic Isolated Penile Lymphoedema
Authors: Hadway P. , Lynch M. , Corbishley C.M. , Mortimer P.S. , Watkin N.A.
Published: January 2006

Squamous cell carcinoma arising in tissue affected by chronic lymphoedema is rare. We describe, to our knowledge, the first documented case of penile squamous cell carcinoma arising in a patient with a history of idiopathic chronic penile lymphoedema. Patients with chronic lymphoedema should be actively followed for possible malignant changes. We discuss the management and possible aetiology of this unusual case.
Hematuria as the Presenting Symptom of a Metastatic Thyroid Cancer
Authors: Pepe Pietro , Fraggetta Filippo , Galia Antonio , Grasso Giuseppe , Aragona Francesco
Published: January 2006

A 67-year-old man is presented who was admitted to our hospital for the onset of hematuria and acute urinary retention and who was found to have a 10-cm solid mass in the right obturator fossa compressing the bladder wall. Histology revealed the presence of a distant metastases from thyroid cancer. To the best of our knowledge, this is the first case of a thyroid cancer presenting with hematuria and acute urinary retention caused by distant metastases to intrapelvic soft tissue.
Proteus Syndrome with Multiple Genitourinary Abnormalities
Authors: Karabulut Ayhan , Karabulut Ayse Anıl , Sunay Melih , Emir Levent , Erol Demokan
Published: January 2006

Proteus syndrome is a rare hamartomatous disorder comprising a broad spectrum of congenital malformations and overgrowth of multiple tissues. Some rare urogenital malformations have been reported before. This case is unique for the presence of multiple genitourinary anomalies including retroperitoneal cystic mass, intra-abdominal testicle with hematoma and ureterovesical stricture apart from common clinic findings of proteus syndrome.
Primary Renal Inflammatory Myofibroblastic Tumor
Authors: Larbcharoensub Noppadol , Chobpradit Napawan , Kijvikai Kittinut , Chalermsanyakorn Panas
Published: January 2006

A case of primary renal inflammatory myofibroblastic tumor of the left kidney in a 51-year-old man clinically presenting bleeding from the gums with thrombocytopenia and left flank mass is reported. Pathological examination of the left renal tumor characterizes macroscopically by a cortical mass and histologically by spindle cells admixed with variable amounts of extracellular collagen, lymphocytes and plasma cells. Immunohistological stainings are positive vimentin and focal positive smooth muscle actin. Clinical and pathological features with a brief review of the relevant literature are discussed. This is the first reported description in the literature of primary renal inflammatory myofibroblastic tumor associated with thrombocytopenia.
Factors Contributing to Clinical Seizure Lateralization in Patients with Mesial Temporal Lobe Epilepsy
Authors: Kang Suk-Yun , Lee Sang-Ahm , Yim Soo Bin , Lim Young Min , Kang Joong Koo , Lee Jung Kyo
Published: January 2006

Clinical seizure semiology can provide important information on the lateralization of the epileptogenic zone. We investigated factors associated with clinical seizure lateralization in patients with pathologically proven mesial temporal sclerosis. We reviewed 243 seizures of 58 patients. Clinical lateralization was possible in 155 (63.8%) of 243 seizures. Lateralization was correct in 144 (92.9%) of 155 lateralized seizures. Logistic regression analysis showed that age at onset (p = 0.001; odds ra tio = 1.089, 95% confidence interval = 1.035–1.145) and the contralateral propagation pattern of ictal discharges (p = 0.001; odds ratio = 3.544, 95% confidence interval = 1.723–7.289) correlated with clinical seizure lateralization. The patient group with clinically lateralized seizures had a younger age at onset of habitual seizures compared to the clinically nonlateralized group (11.1 ± 6.3 vs. 15.6 ± 8.4 years; p < 0.001). Of seizures without bitemporal asynchrony or switch of lateralization, 70.7% were clinically lateralized compared with only 46.4% of seizures with asynchrony or lateralization switch. The present results suggest that the age of epilepsy onset and the ictal scalp EEG propagation pattern affect clinical seizure lateralization in patients with mesial temporal sclerosis.
Compliance with Risk Factor Modification: Early-Onset versus Late-Onset Stroke Patients
Authors: Choi-Kwon Smi , Kwon Sun U. , Kim Jong S.
Published: January 2006

Objectives: To study the compliance to risk factor modifications and factors related to it, which may be different between early-onset (15–45 years) and late-onset (>45 years) stroke patients. These issues have not yet been addressed properly. Methods: We selected 170 early-onset and 340 late-onset stroke patients from the Asan Stroke Registry. The patients were then followed for 1–5 years (an average of 3.4 years) after the onset of stroke. We used a standardized questionnaire to assess the levelof compliance and examine the factors contributing to noncompliance. Results: Ninety-six early-onset and 160 late-onset patients completed a standardized questionnaire. Early-onset patients were less compliant than late-onset patients in the use of antihypertensive medication (p < 0.01), the cessation of cigarette smoking (p < 0.05) and in regular exercise (p < 0.05). Multivariate analysis showed that factors related to noncompliance in early-onset stroke patients included ‘a lack of insurance’ (noncompliance with the use of antihypertensive medication) and male gender (noncompliance with participation in regular exercise). Factors related to noncompliance in late-onset stroke patients included a high number of cigarettes consumed before the stroke (noncompliance with the cessation of smoking), the lack of regular exercise and a severe modified Rankin scale (noncompliance with regular exercise). Conclusion: Early-onset stroke patients are generally less compliant than late-onset stroke patients and the factors related to noncompliance in these groups are different. Therefore, strategies should be developed for improving patient compliance, based on these differences.
A Portrait of Myasthenia Gravis?
Authors: Budrys Valmantas
Published: January 2006

The paper presents a work of art showing a presumably myasthenic patient painted more than 50 years before the disease was first described.
Induction of Fos Immunoreactivity Labeling in Rat Forebrain Metabolic Loci by Caudal Fourth Ventricular Infusion of the Monocarboxylate Transporter Inhibitor, Alpha-Cyano-4-Hydroxycinnamic Acid
Authors: Briski Karen P. , Patil Gopal D.
Published: January 2006

Caudal fourth ventricular (CV4) infusion of the monocarboxylate transporter inhibitor, α-cyano-4-hydroxycinnamic acid (4CIN), causes hyperglycemia coincident with Fos expression in the hindbrain nucleus tractus solitarius, a rare central source of metabolic deficit signaling. The present studies examined the hypothesis that hindbrain lactoprivic signaling activates central autonomic pathways that regulate systemic glucostasis by examining the effects of this drug treatment paradigm on patterns of Fos expression in forebrain structures that integrate sensory input from metabolic sensors and coordinate motor responses to energy shortages. Two hours after CV4 infusion of graded doses of 4CIN or vehicle alone, adult female rats were sacrificed by transcardial perfusion and sections through the telencephalic and diencephalic metabolic loci were processed for Fos immunoreactivity (-ir). Fos labeling of the hypothalamic paraventricular (PVH), dorsomedial (DMH), and ventromedial (VMH) nuclei was significantly elevated, relative to the vehicle-treated controls, in response to the lowest dose of 4CIN, e.g. 10 µg/animal. Treatment with higher doses of 4CIN (25 or 50 µg) further augmented numbers of Fos-ir-positive neurons in these structures, and also elicited staining of the bed nuclei of the stria terminalis (BST), medial preoptic (MPN), arcuate (ARH), supraoptic (SO), and anterior hypothalamic nuclei (AHN), and lateral hypothalamic area (LHA). Mean numbers of Fos-immunolabeled neurons in the ARH, DMH, LHA, AHN, MPN, and SO were not different between animals infused with 25 versus 50 µg 4CIN, whereas neuronal labeling in the VMH, BST, and PVH was significantly greater in the high- versus the middle-dose groups. The present data show that pharmacological inhibition of lactate uptake within the caudal hindbrain results in dose-dependent neuronal Fos immunoexpression within characterized forebrain components of the central metabolic circuitry, and that these patterns of neuronal transcriptional activation parallel observed drug effects on blood glucose levels. These results suggest that lactoprivic signaling by metabolic ‘sensing’ neurons in the caudal hindbrain initiates central neural mechanisms that control systemic energy availability, and that local lactate-‘sensitive’ neurons are connected neuroanatomically with principal higher-order autonomic metabolic loci that regulate glucostasis.
Renal Resistive Index Early Detects Chronic Tubulointerstitial Nephropathy in Normo- and Hypertensive Patients
Authors: Boddi Maria , Cecioni Ilaria , Poggesi Loredana , Fiorentino Francesca , Olianti Katia , Berardino Sabino , La Cava Giuseppe , Gensini GianFranco
Published: January 2006

Background: We studied whether the measurement of intrarenal vascular resistance by Doppler ultrasonography, capable of investigating renal interstitial compartment, allows the early detection of chronic tubulointerstitial nephropathy (TIN). Methods: 30 normotensive and 28 hypertensive (I-II OMS) patients with a clinical history suggestive of chronic TIN and normal renal function were enrolled. 40 healthy volunteers served as controls. Patients were considered TIN-negative or TIN-positive after investigating tubular function by urine concentrating and acidification tests. Renal sonographic parameters and renal resistive index (RRI) were obtained by duplex scanner. Glomerular filtration rate/effective renal plasmatic flow ratio was investigated by sequential renal scintigraphy in TIN-negative and TIN-positive patients; 99mTc-DMSA scintigraphy was also performed in TIN-positive patients. Results: RRI values of TIN-positive normotensive and hypertensive patients were significantly higher (p < 0.01 for both) than those of TIN-negative patients and of controls. RRI values resulted to be linearly related to uricemia (r = 0.88, p < 0.0001) only in normotensive patients. RRI values also resulted to be linearly related to filtration ratio values (r = 0.60, p < 0.0001). 99mTc-DMSA scintigraphy confirmed interstitial renal damage (grade 1 and 2). Conclusion: RRI measurement allows the early identification of both normotensive and hypertensive patients with chronic TIN and signs of tubular dysfunction, when renal function is still preserved.
Tissue Factor Encryption
Authors: Bach Ronald R.
Published: January 2006

Tissue factor (TF) encryption is the post-translational suppression of TF procoagulant activity (PCA) on the cell surface. There is emerging evidence of encrypted TF in normal blood associated with monocytes and platelets. Expression of this latent TF PCA during the propagation phase of blood coagulation may contribute to hemostasis. One pathway leading to the decryption of TF PCA begins with an increase in cytosolic calcium. A large calcium influx triggers both the exposure of phosphatidylserine and the expression of TF PCA on cell surfaces. The connections between these events are reviewed along with evidence that lipid raft association may also contribute to TF encryption. The last step in the decryption of TF PCA is the proteolytic activation of zymogen factor VII. This event may be a key to understanding the different roles of intravascular and extravascular TF in the process of blood coagulation.
Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice
Authors: Karackattu Sharon L. , Trigatti Bernardo , Krieger Monty
Published: January 2006

Objective—

SR-BI/apolipoprotein (apo) E double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the effects on this pathology of hepatic lipase (HL) deficiency, which has been shown to significantly modulate atherosclerosis.

Method and Results—

The SR-BI/apoE/HL triple knockout (tKO) mice generated for this study lived significantly longer (37%) than corresponding dKO controls (average lifespans: 63.0±0.8 versus 46.0±0.3 days), despite their increased plasma cholesterol levels. At 6 weeks of age, compared with dKO mice, tKOs exhibited significantly less aortic root and coronary artery occlusive atherosclerosis, and improved cardiac structure and function. However, by 9 weeks of age the hearts of tKO mice exhibited lipid-rich coronary occlusions, myocardial infarctions, and cardiac dysfunction essentially identical to that of 6-week-old dKO mice.

Conclusions—

HL-deficiency delays the onset and/or progression of atherosclerosis via a SR-BI–independent mechanism. Extent of occlusive coronary arterial lesions was more closely associated with cardiac dysfunction and lifespan than the amount of aortic root atherosclerosis, suggesting that these occlusions in dKO mice are responsible for ischemia, myocardial infarctions, and premature death.
Increased Aortic Intima-Media Thickness in 11-Year-Old Healthy Children With Persistent
Chlamydia pneumoniae
Seropositivity
Authors: Volanen Iina , Järvisalo Mikko J. , Vainionpää Raija , Arffman Martti , Kallio Katariina , Anglé Susanna , Rönnemaa Tapani , Viikari Jorma , Marniemi Jukka , Raitakari Olli T. , Simell Olli
Published: January 2006

Objective—

The relationship between
Chlamydia pneumoniae
(
Cpn
) infection and arterial measures of preclinical atherosclerosis has remained controversial. Because atherogenesis begins in early life, we examined whether carotid and aortic intima-media thickness (IMT) and brachial artery endothelial function are associated with
Cpn
seropositivity in children.

Methods and Results—

Cpn-
specific IgG and IgA antibodies were assessed by enzyme immunoassay in 199 healthy children followed-up annually from 7 to 11 years of age. Carotid (cIMT) and aortic IMT (aIMT), and brachial artery flow-mediated dilatation (FMD) were measured in 137 of the 199 children at the age of 11 years using high-resolution ultrasound. Children with persistent IgG and/or IgA seropositivity to
Cpn
had significantly increased aIMT compared with seronegative children (IgG≤45 and IgA≤12 enzyme immunounits) or children with transient
Cpn
seropositivity (seronegative, 0.496 [0.054]; transient, 0.494 [0.061]; and persistent, 0.532 [0.086] mm;
P
<0.05 for trend). This trend was not explained by traditional atherosclerotic risk factors or pubertal stage. cIMT and FMD were not associated with
Cpn
seropositivity.

Conclusions—

Eleven-year-old children with persistent
Cpn
seropositivity show increased aIMT but not cIMT, suggesting that
Cpn
may affect the aortic wall, the site where the earliest atherosclerotic lesions are known to occur, in otherwise healthy children.
β-Adrenergic Stimulation of L-type Ca
2+
Channels in Cardiac Myocytes Requires the Distal Carboxyl Terminus of α
1C
but Not Serine 1928
Authors: Ganesan Anand N. , Maack Christoph , Johns David C. , Sidor Agnieszka , O’Rourke Brian
Published: January 2006

β-Adrenoceptor stimulation robustly increases cardiac L-type Ca
2+
current (
I
CaL
); yet the molecular mechanism of this effect is still not well understood. Previous reports have shown in vitro phosphorylation of a consensus protein kinase A site at serine 1928 on the carboxyl terminus of the α
1C
subunit; however, the functional role of this site has not been investigated in cardiac myocytes. Here, we examine the effects of truncating the distal carboxyl terminus of the α
1C
subunit at amino acid residue 1905 or mutating the putative protein kinase A site at serine 1928 to alanine in adult guinea pig myocytes, using novel dihydropyridine-insensitive α
1C
adenoviruses, coexpressed with β
2
subunits. Expression of α
1C
truncated at 1905 dramatically attenuated the increase of peak
I
CaL
induced by isoproterenol. However, the point mutation S1928A did not significantly attenuate the β-adrenergic response. The findings indicate that the distal carboxyl-terminus of α
1C
plays an important role in β-adrenergic upregulation of cardiac L-type Ca
2+
channels, but that phosphorylation of serine 1928 is not required for this effect.
Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator–Activated Receptor-α via Inhibition of the Protein Kinase C Signaling Pathway
Authors: Paumelle Réjane , Blanquart Christophe , Briand Olivier , Barbier Olivier , Duhem Christian , Woerly Gaëtane , Percevault Frédéric , Fruchart Jean-Charles , Dombrowicz David , Glineur Corine , Staels Bart
Published: January 2006

Statins are inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator–activated receptor (PPAR) α mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPARα-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPARα phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) α. A constitutive active form of PKCα inhibited nuclear factor κB transrepression by PPARα whereas simvastatin enhanced transrepression activity of wild-type PPARα, but not of PPARα mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPARα by a mechanism involving inhibition of PKCα inactivation of PPARα transrepression activity.
Hypercontractile Female Hearts Exhibit Increased
S
-Nitrosylation of the L-Type Ca
2+
Channel α1 Subunit and Reduced Ischemia/Reperfusion Injury
Authors: Sun Junhui , Picht Eckard , Ginsburg Kenneth S. , Bers Donald M. , Steenbergen Charles , Murphy Elizabeth
Published: January 2006

Mechanisms underlying gender differences in cardiovascular disease are poorly understood. We found previously that, under hypercontractile conditions, female hearts exhibit significantly less ischemia/reperfusion injury than males. Here we show that male wild-type (WT) mouse hearts pretreated with 10 nmol/L isoproterenol before ischemia exhibited increased injury versus female hearts, but this relative protection in females was absent in eNOS
−/−
and nNOS
−/−
hearts. In isoproterenol-treated female versus male hearts, there was also more endothelial NO synthase (eNOS) associated with cardiomyocyte caveolin-3, and more neuronal NOS (nNOS) translocation to caveolin-3 during ischemia/reperfusion.
S
-nitrosothiol (SNO) formation was increased in isoproterenol-treated ischemic/reperfused hearts in all mouse genotypes, but only in WT mice was SNO content significantly higher in females than males. Using the biotin switch method, we identified the L-type Ca
2+
channel α1 subunit as the predominant
S
-nitrosylated protein in membrane fractions, and following isoproterenol and ischemia/reperfusion male/female differences in SNO were seen only in WT hearts, but not in constitutive NOS
−/−
genotypes. The isoproterenol-induced increase in L-type Ca
2+
current (
I
Ca
) was smaller in females versus in males, but NOS blockade increased
I
Ca
in females. This gender difference in
I
Ca
in isoproterenol-treated myocytes (and abolition on NOS inhibition) was mirrored exactly in Ca
2+
transients and SR Ca
2+
contents. In conclusion, these data suggest that eNOS and nNOS both play roles in the gender differences observed in ischemia/reperfusion injury under adrenergic stimulation, and also demonstrate increased
S
-nitrosylation of the L-type Ca
2+
channels in female cardiomyocytes.
Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries
Authors: Bajolle Fanny , Zaffran Stéphane , Kelly Robert G. , Hadchouel Juliette , Bonnet Damien , Brown Nigel A. , Buckingham Margaret E.
Published: January 2006

Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the
y96-Myf5-nlacZ-16
transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in
Splotch
(
Pax3
) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in
Pitx2δc
mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in
Pitx2δc
mutants, which have transposition of the great arteries. Because Pitx2c is involved in left–right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.
LPP Expression During In Vitro Smooth Muscle Differentiation and Stent-Induced Vascular Injury
Authors: Gorenne I. , Jin L. , Yoshida T. , Sanders J.M. , Sarembock I.J. , Owens G.K. , Somlyo A.P. , Somlyo A.V.
Published: January 2006

Lipoma preferred partner (LPP) has been identified as a protein highly expressed in smooth muscle (SM) tissues. The aim of the present study was to determine mechanisms that regulate LPP expression in an in vitro model of SM cell (SMC) differentiation and in stent-induced pig coronary vessel injury. All
trans
-retinoic acid treatment of A404 cells induced a strong increase in LPP, as well as SM α-actin, SM myosin heavy chain, and smoothelin mRNA levels, in a Rho kinase (ROK)-dependent manner. Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression. Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid–treated A404 cells or human iliac vein SMCs. LPP silencing with short interfering RNA significantly decreased SMC migration. LPP expression was also markedly decreased in focal adhesion kinase (FAK)-null cells known to have impaired migration but rescued with inducible expression of FAK. LPP expression in FAK-null fibroblasts enhanced cell spreading. In stented pig coronary vessels, LPP was expressed in the neointima of cells lacking smoothelin and showed expression patterns identical to those of SM α-actin. In conclusion, LPP appears to be a myocardin-, RhoA/ROK-dependent SMC differentiation marker that plays a role in regulating SMC migration.
GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation
Authors: Xu Jian , Kimball Thomas R. , Lorenz John N. , Brown David A. , Bauskin Asne R. , Klevitsky Raisa , Hewett Timothy E. , Breit Samuel N. , Molkentin Jeffery D.
Published: January 2006

Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-β superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene–targeted mice through an endocrine effect. Conversely, examination of
Gdf15
gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation.
Gdf15
gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.
The Transforming Growth Factor-β Superfamily Member Growth-Differentiation Factor-15 Protects the Heart From Ischemia/Reperfusion Injury
Authors: Kempf Tibor , Eden Matthias , Strelau Jens , Naguib Marian , Willenbockel Christian , Tongers Jörn , Heineke Jörg , Kotlarz Daniel , Xu Jian , Molkentin Jeffery D. , Niessen Hans W. , Drexler Helmut , Wollert Kai C.
Published: January 2006

Data from the Women’s Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-β superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO–peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R,
Gdf-15
gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours.
Gdf-15
–deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury.
Classification and Pathogenesis of Cerebral Hemorrhages After Thrombolysis in Ischemic Stroke
Authors: Trouillas Paul , von Kummer Rüdiger
Published: January 2006

Background and Purpose—

Brain hemorrhage after ischemic stroke is a serious complication of treatment; however, its pathology is poorly understood. A classification based on brain imaging may help to better understand and avoid causal factors.

Methods—

Review of the results of controlled randomized trials and the available literature.

Results—

Hemorrhagic infarctions have no impact on clinical outcome and are probably not associated with the thrombolytic itself and the type of reperfusion strategy. They are associated with the extent of ischemic damage and most probably to an ischemic vasculopathy. Parenchymal hematomas are often clinically relevant. Their incidence is affected by the thrombolytic itself, the type, and probably the time point of reperfusion strategy. The loss of hemostatic control seems important in their pathogenesis. Extraischemic hematomas (remote from the infarct), unique or multiple, suggest pre-existing brain pathology, especially cerebral amyloid angiopathy.

Conclusions—

The radiological description of 3 different types of brain hemorrhage is useful to better understand the specific pathology and the impact on clinical outcome. It may help to avoid clinically relevant brain hemorrhages.
Modulation of Proline-Rich Akt Substrate Survival Signaling Pathways by Oxidative Stress in Mouse Brains After Transient Focal Cerebral Ischemia
Authors: Saito Atsushi , Hayashi Takeshi , Okuno Shuzo , Nishi Tatsuro , Chan Pak H.
Published: January 2006

Background and Purpose—

A proline-rich Akt substrate (PRAS) contributes to the regulation of apoptosis after a variety of cell death stimuli, as well as in an in vivo transient focal cerebral ischemia (tFCI) model. We reported previously that overexpression of copper/zinc-superoxide dismutase (SOD1) reduces apoptotic cell death after tFCI. Our present study was designed to clarify the relationship between the PRAS signaling pathway and oxidative stress in the regulation of apoptosis after tFCI.

Methods—

We used a tFCI model with SOD1 transgenic mice and wild-type littermates to examine the expression of phosphorylated PRAS (pPRAS) by Western blotting and immunohistochemistry and the interaction of pPRAS with phosphorylated Akt (pPRAS/pAkt) or the 14-3-3 protein (pPRAS/14-3-3) by coimmunoprecipitation. Direct oxidation of the carbonyl groups, an indication of oxidative injury to total and individual proteins caused by tFCI, was examined using a 2,4-dinitrophenylhydrazone reaction assay.

Results—

Expression of pPRAS, pPRAS/pAkt, and pPRAS/14-3-3 decreased 2 hours after tFCI. Oxidized hydroethidine did not colocalize with expression of pPRAS. Individual oxidized carbonyls in pPRAS remarkably increased 2 hours after tFCI but were significantly reduced by SOD1 2 hours after tFCI. Expression of pPRAS, pPRAS/pAkt, and pPRAS/14-3-3 was promoted by SOD1 during the same time course.

Conclusions—

These results suggest that overexpression of SOD1 may affect the PRAS pathway after tFCI by reducing the direct oxidative reaction to pPRAS after reperfusion injury.