Placental antiangiogenic prolactin fragments are increased in human and rat maternal diabetes.

INTRODUCTION/OBJECTIVES: The role of the placenta in diabetic mothers on fetal development and programming is unknown. Prolactin (PRL) produced by decidual endometrial cells may have an impact. Although full-length PRL is angiogenic, the processed form by bone morphogenetic protein-1 (BMP-1) and/or cathepsin D (CTSD) is antiangiogenic. The objectives were to investigate the involvement of decidual PRL and its antiangiogenic fragments in placentas from type-1 diabetic women (T1D) and from pregnant diabetic rats with lower offspring weights than controls. METHODS: PRL, BMP-1, and CTSD gene expressions and PRL protein level were assessed in T1D placentas (n=8) at delivery and compared to controls (n=5). Wistar rats received, at day 7 of pregnancy, streptozotocin (STZ) (n=5) or nicotinamide (NCT) plus STZ (n=9) or vehicle (n=9). Placental whole-genome gene expression and PRL western blots were performed at birth. RESULTS: In human placentas, PRL (p<0.05) and BMP-1 (p<0.01) gene expressions were increased with a higher amount of cleaved PRL (p<0.05) in T1D than controls. In rats, diabetes was more pronounced in STZ than in NCT-STZ group with intra-uterine growth restriction. Decidual prolactin-related protein (Dprp) (p<0.01) and Bmp-1 (p<0.001) genes were up-regulated in both diabetic groups, with an increased cleaved PRL amount in the STZ (p<0.05) and NCT-STZ (p<0.05) groups compared to controls. No difference in CTSD gene expression was observed in rats or women. CONCLUSIONS: Alterations in the levels of the PRL family are associated with maternal diabetes in both rats and T1D women suggesting that placental changes in these hormones impact on fetal development.

Clenbuterol favorably remodels neonatal cardiac cells via activation of p38 MAPK signalling pathway.

AIM: Pharmacologic treatments which aim to induce physiological hypertrophy are now thought as novel treatments for heart failure. Thus, clenbuterol, a beta-2 adrenergic agonist has recently been shown to partially reverse cardiac remodeling by inducing physiological hypertrophy. The present study further investigated potential underlying mechanisms of this effect in a neonatal cardiomyocytes cell based model. METHODS: Neonatal cardiomyocytes obtained from newborn rats were exposed to clenbuterol (CLEN, 1µM) for five days, while untreated cells served as controls. CLEN administration resulted in well organized orientation of cytoskeletal fibers manifesting as a longitudinal cell shape, while had no effect on myosin heavy chain (MHC) isoform expression. CLEN increased cell growth as indicated by protein content: total protein per cell (pg/cell) was 116 (6.0) for CLEN and 77 (5.0) for the untreated cells, P<0.05. This response was accompanied by a 2.2 fold increase in phospho-p38 MAPK levels as compared to untreated cells, P<0.05 while no changes were observed in ERK, JNK and Akt. Administration of SB203580 (a p38 MAPK inhibitor) abrogated the CLEN induced changes in cardiomyocyte morphology, while it had no effect on protein content. CONCLUSION: Clenbuterol induces favorable changes in neonatal cardiomyocyte shape and geometry without affecting MHC isoform expression. Activation of p38 MAPK signaling seems, at least in part, to be implicated in this response.

Solitary fibrous tumor of the kidney with massive retroperitoneal recurrence. A case presentation.

Solitary fibrous tumor is an unusual spindle cell neoplasm that usually occurs in the pleura but has also been described in other sites. Renal presentation is rare and only 38 cases of SFT of the kidney have been described until now. Up to 90% of the tumors have benign characteristics. Local retroperitoneal recurrence is extremely rare. We report a case of a large malignant solitary fibrous tumor recurrence after the surgical excision of the primary tumor. Histological examination of the specimen confirmed the diagnosis by revealing highly positive reaction of the neoplasmatic cells for vimentin, CD34, bcl-2 and moderately positive for actin. The rate of Ki67 lied between 2-7%. No adjuvant therapy was given to the patient and he is disease-free with no imaging findings of recurrence or metastasis 9 months after the re-operation.

Implication of high grade intraepithelial neoplasia in adverse pathology after radical prostatectomy.

The implication of high grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer aggressiveness and prognosis is conflicted. The aim of the present study was to evaluate the role of HGPIN in prediction of adverse pathology in patients undergoing a radical prostatectomy. We retrospectively analysed patients who underwent a radical prostatectomy between January 2005 and December 2010. The relationship between HGPIN and the presence of upgrade, positive surgical margins (PSM), extracapsular disease (ECD), seminal vesicle invasion (SVI) and lymph node invasion (LNI) was analysed. HGPIN predictive ability was estimated by using receiver operating characteristic curves. HGPIN was found in 160 (53.3%) specimens. A statistically significant correlation was found between HGPIN and preoperative prostate specific antigen (p=0.020) and patients' age (p=0.025). No significant differences were found, regarding the presence of adverse pathological findings, between the patients with or without HGPIN, irrespective of the preoperative risk stratification. HGPIN did not reach significance for the prediction of upgrade, PSM, ECD, SVI and LNI. The presence of concomitant HGPIN and prostate cancer found not to be related with tumor aggressiveness in patients undergoing a radical prostatectomy and should not be considered as a parameter for the operative outcome prediction.

Clinical and pathological parameters predicting extracapsular disease in patients undergoing a radical prostatectomy for clinically localized prostate cancer.

To determine the epidemiological, clinical and pathological factors that can potentially predict extracapsular extension of prostate cancer in patients undergoing radical prostatectomy for clinically localized disease. We retrospectively analyzed the medical records of patients who undergone radical prostatectomy from January 2001 until November 2010. Patients age, prostate volume, PSA, PSA density, percent of cancer in prostate biopsy material, presence of cancer in biopsy cores of the right lobe or the left lobe or both lobes, Gleason summary, 1st Gleason pattern and 2nd Gleason pattern were analyzed for their predictive ability. From 187 studied patients, 44 of them (23.5%) had extracapsular disease. Multivariate analyses revealed that smaller prostate volumes and the presence of malignancy in both lobes after prostate biopsy were significant predictors for non-organ confined disease in the total population and in patients with Gleason score ≥ 7. Presence of malignancy in both lobes was the only significant predictive factor in patients with PSA ≤ 10 and in those with Gleason score ≤ 6. Prostate volume and positive cores for malignancy from both lobes after prostate biopsy are preoperative data that can be used for prediction of extracapsular disease. This information can be valuable in cases a nerve sparing radical prostatectomy is planned.

Preoperative prostate specific antigen and prostate volume are significant predictors of seminal vesicle invasion in patients with prostate cancer.

To evaluate the potential role of several clinical and pathological parameters in prediction of seminal vesicle invasion in patients with clinically localized prostate cancer undergoing radical prostatectomy. We retrospectively analyzed the medical records of patients who undergone radical prostatectomy from January 2005 until November 2010. Patients age, prostate volume, PSA, PSA density, percent of cancer in prostate biopsy material, Gleason summary, 1st Gleason pattern, 2nd Gleason pattern and the presence of high grade prostatic intraepithelial neoplasia were studied for their predictive ability. Two hundred and seventeen patients analyzed and 13.8% of them had seminal vesicle invasion in the final histopathological examination of the surgical specimen. A significant difference in PSA values, PSA density, percentage of cancer in biopsy material, biopsy Gleason score and 1st Gleason pattern was noticed between patients with and without seminal vesicle invasion. In univariate analysis, PSA, PSA density, prostate volume, percentage of cancer in biopsy material, biopsy Gleason score and 1st Gleason pattern found significant. However, in multivariate analysis, only PSA (p=0.008) and prostate volume (p=0.027) were found to be significant predictors. PSA ≥ 10 ng/ml and prostate volume ≤ 41 ml was shown to be the optimal cut-off values for seminal vesicle invasion in receiver operating curve analysis. PSA and prostate volume should be considered significant predictors for adverse pathology of the seminal vesicles in patients planned for surgical treatment of prostate cancer. This is of great concern especially in cases that a seminal vesicle sparing technique is planned.

A comparative analysis of primary and secondary Gleason pattern predictive ability for positive surgical margins after radical prostatectomy.

To compare the predictive ability of primary and secondary Gleason pattern for positive surgical margins in patients with clinically localized prostate cancer and a preoperative Gleason score ≤ 6. A retrospective analysis of the medical records of patients undergone a radical prostatectomy between January 2005 and October 2010 was conducted. Patients' age, prostate volume, preoperative PSA, biopsy Gleason score, the 1st and 2nd Gleason pattern were entered a univariate and multivariate analysis. The 1st and 2nd pattern were tested for their ability to predict positive surgical margins using receiver operating characteristic curves. Positive surgical margins were noticed in 56 cases (38.1%) out of 147 studied patients. The 2nd pattern was significantly greater in those with positive surgical margins while the 1st pattern was not significantly different between the 2 groups of patients. ROC analysis revealed that area under the curve was 0.53 (p=0.538) for the 1st pattern and 0.60 (p=0.048) for the 2nd pattern. Concerning the cases with PSA <10 ng/ml, it was also found that only the 2nd pattern had a predictive ability (p=0.050). When multiple logistic regression analysis was conducted it was found that the 2nd pattern was the only independent predictor. The second Gleason pattern was found to be of higher value than the 1st one for the prediction of positive surgical margins in patients with preoperative Gleason score ≤ 6 and this should be considered especially when a neurovascular bundle sparing radical prostatectomy is planned, in order not to harm the oncological outcome.

The angiogenic switch for vascular endothelial growth factor-A and cyclooxygenase-2 in prostate carcinoma: correlation with microvessel density, androgen receptor content and Gleason grade.

OBJECTIVE: Angiogenesis is essential for tumor growth and metastasis; however, angiogenic factors are not uniformly expressed in prostate carcinoma. Our aim was to determine the expression of vascular endothelial growth factor-A (VEGF-A) and cyclooxygenase-2 (COX-2) in prostate carcinomas in relation to intratumoral microvessel density (MVD), tumor grade and androgen receptor (AR) status. MATERIALS AND METHODS: The expression of AR, VEGF-A and COX-2 was immunohistochemically evaluated in 24 benign prostatic hyperplasia (BPH) and 139 prostate carcinoma cases. MVD was evaluated by CD34 immunostaining. RESULTS: Nuclear AR expression was inversely related to tumor grade (p < 0.001). MVD was strongly related to tumor grade, VEGF-A and COX-2 (p < 0.001 in all comparisons). VEGF-A expression increased with tumor grade (p < 0.01) and was inversely related to stromal AR expression. COX-2 was present in both BPH and prostate carcinoma, but its expression increased with tumor grade (p < 0.01). High-grade neoplasms presented low-to-moderate VEGF staining intensity compared to strong COX-2 expression. CONCLUSIONS: Both VEGF-A and COX-2 expression is positively correlated with tumor grade and MVD. However, in Gleason 8-10 tumors, VEGF expression is moderate while COX-2 immunostaining is intense, suggesting a possible switch in the role of these two angiogenic factors in poorly differentiated neoplasms.

Schwannoma of the kidney with magnetic resonance images of non-homogenous renal mass--a case presentation.

Schwannomas are rare tumours that originate from the neural sheath and are usually located in the head and neck, extremities, and posterior mediastinum. Although 3% of schwannomas occur in the retroperitoneum, involvement of visceral organs is extremely uncommon. Schwannomas of the kidney are rare, with only a few reported cases. A 55-year-old woman was referred to our hospital with an abdominal sonography showing a spherical lesion in the upper pole of the left kidney that did not have the characteristics of a cortical cyst. The ultrasound had been recommended from her family doctor, due to a non specific pain in the hypogastrium in the previous 10 days. The final pathologic diagnosis was intrarenal benign schwannoma. Schwannomas are rare renal tumours with usually benign behaviour. Due to nonspecific symptoms and limited radiologic features for the diagnosis and assessment of the benign or malignant character of the tumour, the therapeutic approach is similar to other renal tumours. The definitive diagnosis is achieved with the help of immunohistochemistry.

Thyroid hormone receptor alpha1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism.

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.

Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction.

Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. Acute myocardial infarction was induced in male Wistar rats by ligating left coronary artery (AMI, n=8), while sham operated animals served as control (SHAM, n=8). 13 weeks after AMI, TH was administered in a group of animals for 4 weeks (AMI-THYR, n=9). TH significantly increased beta-MHC and decreased alpha-MHC expression in the myocardium. This response was accompanied by changes in cardiac geometry: sphericity index, (SI, long to short axis ratio) was found to be 1.95 (SEM, 0.02) in SHAM, 1.51(0.03) in AMI and 1.64(0.03) in AMI-THYR, p<0.05. As a consequence, cardiac function was significantly improved: left ventricular ejection fraction (EF%) was 74.5% (SEM, 2.8) in SHAM vs 29.5% (2.1) in AMI, and 40.0% in AMI-THYR, p<0.05. Furthermore, +dp/dt and -dp/dt were 4250 (127) and 2278 (55) in SHAM vs 2737(233) and 1508 (95) in AMI vs 3866 (310) and 2137(111) in AMI -THYR, respectively, p<0.05. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure.

Effect of alfuzosin on female primary bladder neck obstruction.

Our objective was to assess the effect of the selective alpha(1)-blocker alfuzosin on urodynamic parameters and quality of life in female patients with primary bladder neck obstruction (PBNO). Twenty-five women identified as having PBNO were included in the study. After the initial assessment of urodynamic parameters and bother score index, all patients were treated with alfuzosin 5 mg twice daily for 8 weeks. After this period of time, the patients were reassessed with the same methodology as pretreatment. Symptoms subjectively improved, and patients' satisfaction significantly increased in 64% of the patients (16 out of 25). Most urodynamic parameters were also significantly improved after treatment with alfuzosin. Alfuzosin significantly improved urodynamic parameters and alleviated bother score in almost two thirds of patients with PBNO and can be an effective first-line treatment of this situation.

Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"?

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechanisms and physiological consequences, as well as the role of TRalpha1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an alpha1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of beta-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRalpha1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRalpha1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRalpha1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRalpha1 seems to be critical in cardiac myoblast differentiation.

Doxazosin for the management of distal-ureteral stones.

PURPOSE: To evaluate the efficacy of doxazosin in inducing spontaneous passage of stones in the distal ureter and to compare its efficacy according to the size of the stone. PATIENTS AND METHODS: Seventy-three patients with a mean age of 46.38 +/- 10.17 years who presented with a distal-ureteral stone were divided into four groups according to stone size and drug treatment: <5 mm without doxazosin (group A; n=15); 5-10 mm (group B; n=16); <5 mm with doxazosin 4 mg/day for 4 weeks (group C; n=20); and 5-10 mm with doxazosin 4 mg/day for 4 weeks (group D; n=22). Groups A and B served as controls for groups C and D, respectively. RESULTS: Spontaneous stone passage was documented in 9 patients (60%) in group A v 17 (85%) in group C (P=0.047) and 7 (43.75%) in group B v 16 (72.73%) in group D (P=0.036). The average expulsion time was 8.78 +/- 1.09 days in group A v 7.59 +/- 0.80 days in group C (P=0.004) and 12.14 +/- 1.35 days in group B v 7.06 +/- 1.29 days in group D (P<0.0001). The number of pain episodes in group D patients was significantly lower than in group B (P +/- 0.0078). CONCLUSIONS: Doxazosin treatment proved to be safe and effective for distal-ureteral stones, as determined by earlier expulsion, decreased colic frequency, and absence of side effects. The efficacy of doxazosin was significantly higher for 5-to 10-mm stones than for smaller ones.

Does CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome?

OBJECTIVE: The aim of the study was to examine the quality of the characteristics of Erectile Dysfunction (ED) in men with Obstructive Sleep Apnea Syndrome (OSAS) and to investigate whether there is an improvement with the use of continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHODS: Fifteen men with OSAS and sexual dysfunction have been investigated in this follow-up study. The treatment period was for 12 weeks and the therapeutic CPAP levels were determined during the full night of the therapeutic titration. RESULTS: In our 15 treated patients, the International Index Erectile Function (IIEF) total and all domain scores had increased after the CPAP treatment compared to the baseline, except for that of sexual desire domain. CONCLUSIONS: CPAP therapy can improve the sexual function in ED patients with OSAS.

Versican but not decorin accumulation is related to metastatic potential and neovascularization in testicular germ cell tumours.

AIMS: To investigate the expression of versican and decorin in patients with testicular germ cell tumours (GCTs) and to correlate this with the clinicopathological findings. Matrix proteoglycans versican and decorin are frequently overexpressed in various malignancies and are involved in the progression of cancer. METHODS AND RESULTS: Overexpression of versican and decorin was detected in GCTs by immunoblotting. Immunohistochemical staining for proteoglycans was performed on 71 cases of paraffin-embedded tissues. In most of the cases increased decorin and versican stromal staining was demonstrated. In both seminomas and non-seminomatous germ cell tumours (NSGCTs) strong staining of decorin was not found to be related to any of the clinicopathological variables. Accumulation of versican was found to be associated with vascular and lymphatic invasion, nodal metastasis and disease stage in seminomas and NSGCTs and, in addition, with tumour size and distant metastasis only in NSGCTs. Additionally, only the deposition of versican was linearly correlated with the number of microvessels in the tumour stroma in GCTs. CONCLUSIONS: Ectopic versican and decorin expression is a frequent feature in GCTs. Versican but not decorin accumulation in GCTs is related to metastatic potential and neovascularization and might be a useful marker for testicular malignancy.

Primary adrenal tuberculosis: role of computed tomography and CT-guided biopsy in diagnosis.

A case of isolated, bilateral, adrenal tuberculosis is presented. A 25-year-old male was admitted to the hospital due to lumbar pain, fever, weight loss and anorexia. Abdominal ultrasonography and computed tomography demonstrated bilateral adrenal enlargement. Laboratory investigations were remarkable for adrenal insufficiency. The Mantoux reaction was positive but there was no evidence of lung or urinary infection. CT-guided biopsy of the left adrenal gland was performed and established the diagnosis of adrenal tuberculosis.

Long-term treatment with intracavernosal injections in diabetic men with erectile dysfunction.

AIM: To assess the behavior of patients with diabetes mellitus (DM) and erectile dysfunction (ED) during 10 consecutive years of treatment with self-injection of vasoactive drugs. METHODS: Thirty-eight diabetic men, including 12 with type I and 26 with type II diabetes, were followed up regularly for 10 years after they began self-injecting for severe ED. Real time rigidity assessment was used for the objective determination of the initial dosage and then doses were regulated in order to introduce an erection suitable for penetration and maintenance of erection for approximately 30 min. Patients were followed up every two months, and doses were increased only when the treatment response was not satisfactory. RESULTS: The number of injections used per year by the patients was reduced each year (mean numbers: 50 in the first year and 22.5 in the 10th) and treatment shifted towards stronger therapeutic modalities (mixtures of vasoactive drugs instead of prostaglandin E1 alone). Type I diabetic men were standardized to a level of treatment as early as 5 years after the initiation of treatment. That level was finally reached by type II patients after another 4-5 years. CONCLUSION: Treatment with self-injections of vasoactive drugs in diabetic men with severe ED is a safe and effective alternative in the long term. Diabetic men of both types show the same preferences in quality and quantity of treatment after 10 years. The key point for maintenance in treatment is the adjustment of the therapeutic method and dosage to optimal levels for satisfactory erections.

Ureteral injuries during gynecologic surgery: treatment with a minimally invasive approach.

PURPOSE: To report the safety and efficacy of percutaneous nephrostomy and primary antegrade recanalization for treatment of iatrogenic ureteral strictures after gynecologic surgery. PATIENTS AND METHODS: Ten women had symptoms suggestive of ureteral obstruction during the immediate postoperative period (5 days-1 week after surgery). Under analgesia and conscious sedation, standard percutaneous nephrostomy was performed, and a long 7F sheath was placed in the upper ureter. The obstructions were traversed with the aid of a 0.0035-inch Glidewire and a 5F angled Glide catheter (Terumo, Japan). Subsequently, the areas were dilated with angioplasty balloons to a maximum diameter of 7 mm. Finally, an 8F percutaneous internal/external nephroureteral drainage stent was inserted to secure ureteral patency. Follow-up was carried out by serial nephrostomography until removal of the stent and by renal ultrasonography thereafter. RESULTS: Twelve obstructions with a mean length of 1.4 cm (range 0.4-1.9 cm) were managed. The technical success rate was 100%. No major complications occurred, and normal renal function was restored. The mean follow-up was 12 months. In 60% of the patients, a patent ureter was depicted at 1 week, whereas in four patients, repeat dilation of the obstructed segment was required. The stents were removed after a mean period of 4.8 weeks. CONCLUSION: Percutaneous nephrostomy and primary antegrade ureteral balloon dilation is safe and efficacious for treating ureteral injury after pelvic surgery and obviates open surgical manipulations.