Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21Cip1 /p27Kip1 pathways and lead to renal fibrosis and dysfunction.

Cell-cycle regulatory proteins (p21Cip1 /p27Kip1 ) inhibit cyclin and cyclin-dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1 /p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) gene-knockout (0-copy; Npr1-/- ), 2-copy (Npr1+/+ ), and 4-copy (Npr1++/++ ) mice treated with GC inhibitor, A71915 and cGMP-dependent protein kinase (cGK) inhibitor, (Rp-8-Br-cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0-copy mice and A71915- and Rp-treated 2-copy and 4-copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1 , and p27Kip1 occurred in 0-copy and A71915-treated 2-copy and 4-copy mice, while Rp treatment caused minimal changes than controls. Pro-inflammatory (TNF-α, IL-6) and pro-fibrotic (TGF-ß1) cytokines were significantly increased in plasma and kidneys of 0-copy and A71915-treated 2-copy mice, but to lesser extent in 4-copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0-copy and A71915-treated 2-copy and 4-copy mice, but minimally occurred in Rp-treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21Cip1 and p27Kip1 .

Recent innovations in perfusion and cardiopulmonary bypass for neonatal and infant cardiac surgery.

The development and refinement of cardiopulmonary bypass (CPB) has made the repair of complex congenital heart defects possible in neonates and infants. In the past, the primary goal for these procedures was patient survival. Now that substantial survival rates have been achieved for even the most complex of repairs in these patients, focus has been given to the reduction of morbidity. Although a necessity for these complex neonatal and infant heart defect repairs, CPB can also be an important source of perioperative complications. Recent innovations have been developed to mitigate these risks and is the topic of this review. Specifically, we will discuss improvements in minimizing blood transfusions, CPB circuit design, monitoring, perfusion techniques, temperature management, and myocardial protection, and then conclude with a brief discussion of how further systematic improvements can be made in these areas.

Treatment of Premenstrual Breakthrough of Depression With Adjunctive Oral Contraceptive Pills Compared With Placebo.

PURPOSE/BACKGROUND: Two-thirds of women with depressive disorders report reemergence of depression premenstrually, or premenstrual exacerbation (PME), despite effective treatment of the underlying mood disorder during the remainder of the cycle. There is a paucity of studies that rigorously assess treatments targeting PME. Open-label data suggest that augmentation of antidepressants with the oral contraceptive pill (OCP) drospirenone and ethinyl estradiol (DRSP/EE) improves depressive symptoms that break through treatment premenstrually. We now report results of a randomized placebo-controlled OCP augmentation trial. METHODS: Women with unipolar depressive disorders in remission on stable antidepressant doses with a 30% increase in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from the follicular to luteal phase were randomized to double-blind augmentation of antidepressant with either DRSP/EE or placebo for 2 months. The MADRS and Daily Record of Severity of Problems (DRSP) measures were anchored to the menstrual cycle phase. FINDINGS/RESULTS: Of 32 women randomized, 25 (n = 12 DRSP/EE, n = 13 placebo) completed the trial. Premenstrual MADRS scores declined by a median of 43.6% and 38.9% (P = 0.59), and premenstrual DRSP scores declined by a median of 23.5% and 20.9% (P = 0.62) in the DRSP/EE and placebo groups, respectively. There was a trend toward greater improvement in premenstrual DRSP scores for women with fewer lifetime depressive episodes (r = -0.40, P = 0.06). IMPLICATIONS/CONCLUSIONS: Findings from this small randomized trial suggest that OCP augmentation of antidepressants may not be effective for treating premenstrual breakthrough of depression. Future studies should target women established to have hormonal sensitivity prior to antidepressant therapy and those with fewer lifetime depressive episodes.