Reduced expression of THRß in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression.

PURPOSE: Down-regulation of thyroid hormone receptor beta (THRß) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRß mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical-biological features. METHODS: Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRß gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRß. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. RESULTS: THRß transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRß expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. CONCLUSIONS: Our results demonstrate that down-regulation of THRß is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis.

Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats.

BACKGROUND AND AIM: Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis. METHOD: Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5). RESULTS: Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril. CONCLUSION: Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Dilated cardiomyopathy due to thrombotic microangiopathy as the only manifestation of antiphospholipid syndrome: a case report.

Dilated cardiomyopathy due to thrombotic microangiopathy has been rarely reported as a clinical manifestation of antiphospholipid syndrome (APS). We describe the case of a 39-year-old woman affected by systemic lupus erythematosus (SLE) and positive antiphospholipid antibodies (aPL) who presented with orthopnea and peripheral oedema. Diagnosis of dilated cardiomyopathy due to myocardial thrombotic microangiopathy was made and treatment with anticoagulants prevented the worsening of the clinical condition. Interestingly, at variance with other cases, our patient showed no extracardiac signs of APS. The review of the current literature has confirmed that dilated cardiomyopathy due to thrombotic microangiopathy is a rare manifestation of APS.

Angiotensin II increases tissue-specific inhibitor of metalloproteinase-2 expression in rat aortic smooth muscle cells in vivo: evidence of a pressure-independent effect.

1. Angiotensin (Ang) II plays a major role in vascular remodelling. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the tissue remodelling processes. The aim of the present study was to investigate whether AngII modulates TIMP-2 expression in rat aortic smooth muscle cells in vivo. 2. Angiotensin II (200 ng/kg per min, s.c.) or AngII + losartan (10 mg/kg per day, s.c.) or normal saline was administered continuously by osmotic minipumps to Sprague-Dawley rats for 1 week. In addition, the effect of endogenous AngII on TIMP-2 expression was evaluated in renovascular hypertensive rats (two kidney, one clip (2K1C) and one kidney, one clip (1K1C) models). Control rats (sham 2K1C and sham 1K1C rats) underwent sham-clipping of the left renal artery. At the end of the treatment, plasma renin activity was measured by radioimmunoassay, aortic TIMP-2 mRNA expression was evaluated by real-time polymerase chain reaction and/or northern blotting and protein expression was evaluated by immunohistochemistry. Systolic blood pressure (SBP) was measured twice a week by the tail-cuff method. 3. Exogenous AngII administration produced the expected increase in SBP (P = 0.02) compared with the control saline-treated group. The increase in SBP was abolished in AngII + losartan-treated rats. Administration of AngII caused a significant increase in TIMP-2 expression (P = 0.01) in rat aortic smooth muscle cells that was abolished in AngII + losartan-treated rats. In renovascular hypertensive rats, SBP was higher (P < 0.0001) in 2K1C and 1K1C rats compared with the corresponding sham-operated rats. Plasma renin activity was higher (P < 0.01) in 2K1C rats compared with the other groups. The expression of TIMP-2 was significantly (P < 0.05) increased only in 2K1C rats. 4. Our in vivo data demonstrate that exogenous and endogenous AngII increases TIMP-2 expression in rat aortic smooth muscle cells. This effect is not dependent on the AngII-induced increase in blood pressure and is mediated by angiotensin AT1 receptors.

Functional anatomy of the human vagina.

Anatomy studies normally precede physiology. While the anatomy of the penis and the biochemical and molecular regulation of erection are largely known, the exact anatomical description of the human clitoris was produced in 1998, the taxonomy of female sexual dysfunctions classified in 1999, and biochemistry of female excitation described only in 2002. There are various reasons for this. Female sexual physiology is much more complex than that of the male, and cultural and religious considerations have discouraged the scientific study of female sexuality. However, it is now apparent that modern sexology cannot be truly 'medical' if female sexual anatomy and the physiology of female sexual response are unknown.