Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses a-, b-, and g-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1b expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1b expression in the macula densa affects sodium excretion and saltsensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1b mRNA and protein were 30-and five-fold higher, respectively, than those of NOS1a in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1a-knockout (NOS1aKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P,0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.

PurposeThis study seeks to present observations on the impact of Chinese culture traits on knowledge management practices in Chinese corporations.Design/methodology/approachThe paper presents an analysis of the authors' own experience as senior managers in implementing a globalization strategy for a leading Chinese domestic IT services company. It specifically focuses on key culture traits that have been proven to directly impact knowledge management practices.FindingsThere are deeply rooted culture traits that work counter to the objectives of a knowledge management program within a Chinese corporation. Information sharing is essential counter culture. The authors' experience is that incremental changes that rely on institutionalized systems of information transfer offer hope for the gradual transformation of corporate cultures that foster effective knowledge management practices and increase corporate competitiveness.Research limitations/implicationsThis study is by no means exhaustive, but is intended as a starting‐point to explore alternatives for overcoming culture traits that inhibit knowledge transfer.Originality/valueThe study provides a basis for companies including Chinese companies, joint ventures or multi‐national companies operating in China to assess obstacles to effective knowledge management and to consider various alternatives in adopting a knowledge management plan.

Males have higher prevalence of hypertension and renal injury than females, which may be attributed in part to androgen-mediated effects on renal hemodynamics. Tubuloglomerular feedback (TGF) is an important mechanism in control of renal microcirculation. The present study examines the role of testosterone in the regulation of TGF responses. TGF was measured by micropuncture (change of stop-flow pressure, ⌬P sf) in castrated Sprague-Dawley rats. The addition of testosterone (10 Ϫ7 mol/l) into the lumen increased the ⌬P sf from 10.1 Ϯ 1.2 to 12.2 Ϯ 1.2 mmHg. To determine whether androgen receptors (AR) are involved, mRNA of AR was measured in the macula dense cells isolated by laser capture microdissection from kidneys, and a macula densa-like cell line (MMDD1). AR mRNA was expressed in the macula densa of rats and in MMDD1 cells. We next examined the effects of the AR blocker, flutamide (10 Ϫ5 mol/l) on the TGF response. The addition of flutamide blocked the effects of testosterone on TGF. The addition of Tempol (10 Ϫ4 mol/l) or polyethylene glycol-superoxide dismutase (100 U/ml) to scavenge superoxide blocked the effect of testosterone to augment TGF. We then applied apocynin to inhibit NAD(P)H oxidase and oxypurinol to inhibit xanthine oxidase and found the testosterone-induced augmentation of TGF was blocked. In additional experiments in MMDD1 cells, we found that testosterone increased O 2 Ϫ generation. Apocynin or oxypurinol blocked the testosteroneinduced increases of O 2 Ϫ , while blockade of COX-2 with NS-398 had no effect. These findings suggest that testosterone enhances TGF response by stimulating O 2 Ϫ production in macula densa via an AR-dependent pathway.superoxide; testosterone; tubuloglomerular feedback THE KIDNEY PLAYS A CENTRAL role in long-term control of blood pressure. Tubuloglomerular feedback (TGF) is an important mechanism of the kidney in control of renal hemodynamics and salt and water balance. TGF is a negative feedback loop that senses changes in the delivery of NaCl to the macula densa (MD) and adjusts the tone of the afferent arteriole. Increases of luminal NaCl concentration activate TGF, which constricts the afferent arteriole and reduces single-nephron glomerular filtration rate. Together with other renal mechanisms that modulate salt and water balance, TGF controls the amount of NaCl delivery to the distal nephron and prevents excess salt excretion (31,43,49).Enhanced TGF responses have been reported in several models of hypertension, including spontaneous hypertensive rats (SHR) (5), Goldblatt hypertension (22, 35), and hypertensive ren-2 transgenic rats (27). These studies indicate that enhanced TGF responsiveness may contribute to the development of hypertension. There are also important sex differences in the severity of hypertension in these models, suggesting an important modulatory role of sex hormones. Hypertension is far more prevalent in men than in premenopausal women (38). After menopause, the incidence of hypertension in females rises to the same or even higher leve...

We present a case of refractory ileocolonic Crohn's disease in a 27-year-old female treated with dual ustekinumab and vedolizumab biologic therapy. She had mucosal healing for the first time in 13 years after a 10-month treatment of ustekinumab overlapped with 6 months of vedolizumab. No side effects were observed during the 6 months of dual biologic therapy. Short-term dual biologic therapy may be considered as a treatment option for induction of remission in refractory cases of Crohn's disease.