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Aims: Coronary endothelial dysfunction (CED) precedes atherosclerosis and is associated with cardiovascular events. Both CED and erectile dysfunction (ED) are partly mediated by impairment in the nitric oxide pathway. ED is associated with established coronary atherosclerosis, but its relationship with early coronary atherosclerosis and CED is unknown. This study was designed to test the hypothesis that CED is associated with ED in men with early coronary atherosclerosis. Moreover, the role of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) was investigated; ADMA is a novel endogenous competitive inhibitor of nitric oxide synthase and has been shown to be an independent marker for cardiovascular disease., Methods and Results: Fifty-six men without obstructive coronary artery disease (CAD) who underwent coronary endothelial function testing were studied. ADMA levels were determined and all men were asked to complete the International Index of Erectile Function-5 questionnaire to assess erectile function. Patients were divided according to the presence (n = 32) or absence (n = 24) of CED. Men with CED had significant impairment of erectile function (P = 0.008) and significantly higher ADMA levels (0.50 +/- 0.06 vs. 0.45 +/- 0.07 ng/mL, P = 0.017) compared with men with normal endothelial function. Erectile function positively correlated with coronary endothelial function. This correlation was independent of age, body mass index, high-density lipoprotein, C-reactive protein, homeostasis model assessment of insulin resistance index, and smoking status., Conclusion: CED is independently associated with ED and plasma ADMA concentration in men with early coronary atherosclerosis. This study further supports the role of the endothelium in systemic vascular diseases and the role of ADMA in the systemic manifestations of endothelial dysfunction.

Temperature and tissue stiffness are two indices that can be used to monitor MRI-guided focused ultrasound thermal therapy. It would be beneficial to have both measures available to monitor treatment progression during thermal therapy. MR Elastography (MRE) has already been shown to provide tissue stiffness information; the purpose of this work is to demonstrate how temperature can be derived from the same MRE data acquisition. MRE data were acquired from 1.5% agarose phantoms and ex vivo porcine muscle tissue (from a grocery store) while they were heated slowly. The temperatures were measured using a fluorescent thermometer. The phase average from the MRE acquisition was used to calculate the phase shift induced by the proton resonance frequency shift associated with the temperature change. The results show that the phase shift due to temperature extracted from MRE data correlate well with the temperature change recorded by thermometer, yielding a temperature coefficient of -0.0096 ppm/ degrees C for the agarose phantom, and -0.0103 ppm/ degrees C for the ex vivo porcine tissue. These results indicate that it is possible to simultaneously measure both temperature and tissue shear stiffness using a new method of MRE data reconstruction., (Magn Reson Med, 2006. (c) 2006 Wiley-Liss, Inc.)

Review of the trend in cardiovascular disease mortality for males and females clearly demonstrated that whereas the trend shows a decline in males this decline is not observed in females. Multiple important reports emerged from the initial phases of the Women's Ischemic Syndrome Evaluation (WISE) study that may have significant clinical implications for our approach to cardiovascular disease in women. The data derived from the WISE study certainly provided important information to our understanding of the approach to women with cardiovascular disease. The clinical presentation may be different, and a gender-oriented questionnaire may enhance our diagnosis. In a multivariable model, low hemoglobin was associated with significantly higher risk of adverse outcomes. The risk factor assessment and the risk factor profiles in women that are associated with coronary artery disease may be different. Based on the studies from the WISE study, metabolic syndrome is a leading and a major risk factor in women. Moreover, the data further support the concept that the mechanism of ischemia in women may be localized in the microvascular coronary arteries. Therefore, the diagnoses of coronary microvascular dysfunction or endothelial dysfunction should be considered in women with chest pain who do not have obstructive coronary artery disease. It may be advantageous to add such diagnostic tests when the conventional tests are nondiagnostic. A revised clinical approach to cardiovascular disease in women may be designed and tested based on these findings.

Chronic refractory angina is a term used to describe patients who, despite optimal medical therapy, have both angina and objective evidence of ischaemia. It is estimated that 5-15% of the 12 million patients with chronic angina in the US meet the criteria for having refractory angina. This review focuses on the following evolving pharmacological therapies for chronic refractory angina: L-arginine, ivabradine, ranolazine, nicorandil and trimetazidine. Evolving devices and invasive procedures including enhanced external counterpulsation, spinal cord stimulation, and transmyocardial revascularisation are also briefly discussed.

Precisely timed ubiquitin-mediated proteolysis of mitotic regulators by the anaphase-promoting complex (APC) governs the orderly passage of cells through mitosis. The established view is that Cdc20-activated APC (APC(Cdc20)) mediates the destruction of cyclin B and securin at the metaphase/anaphase transition, and that Cdh1-activated APC (APC(Cdh1)) has no role in this process. We recently reported that securin, but not cyclin B, is prematurely targeted for destruction by the APC in mutant mice that have low levels of the nuclear transport factors Rae1 and Nup98. We found that Rae1 and Nup98 assemble into a complex with APC(Cdh1) in prometaphase and act to delay APC(Cdh1)-mediated ubiquitination of securin until the metaphase/anaphase transition. Here we show that Rae1 and Nup98 not only form a complex with APC(Cdh1) in prometaphase but also with securin. This finding suggests that the Rae1-Nup98 complex does not inhibit early destruction of securin by preventing APC(Cdh1) from binding to securin, but by preventing ubiquitination of APC(Cdh1)-bound securin. We propose that the formation of APC(Cdh1)-securin complexes in prometaphase primes the cell for rapid securin degradation after release of the inhibitory Rae1-Nup98 complex at the metaphase/anaphase transition. We further report here that mutant mice with low levels of the Rae1-Nup98 complex are not prone to develop spontaneous tumors, despite massive aneuploidy. However, Rae1/Nup98 mutant mice are significantly more susceptible to DMBA-induced lung tumors than wild-type mice, indicating that combined Rae1/ Nup98 haplo-insufficiency does promote tumorigenesis when certain cancer-critical genes are also mutated.

Objective: The purpose of the current study was to determine whether lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with coronary endothelial dysfunction and is a predictor of endothelial dysfunction in humans., Methods and Results: Patients (172) with no significant coronary artery disease (<30% stenosis) undergoing assessment of coronary endothelial function were studied. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Plasma concentrations of Lp-PLA2 were measured, and patients were divided into tertiles. Patients in tertiles 2 and 3 had a significantly lower change in coronary blood flow (63.8+/-73.2 and 32.0+/-71.7 versus 78.4+/-73.2%; P<0.001) and greater epicardial coronary artery vasoconstriction (-14.1+/-14.7 and -23.3+/-25.1 versus -9.5+/-15.2% mean diameter change; P<0.001) in response to acetylcholine. Patients with coronary endothelial dysfunction had significantly higher serum concentrations of Lp-PLA2 than those with normal endothelial function (246.2+/-71.6 versus 209+/-56.7 ng/mL; P=0.001). The odds ratio for coronary endothelial dysfunction in patients with Lp-PLA2 in the highest tertile was 3.3 (95% CI, 1.6 to 6.6)., Conclusions: Lp-PLA2 is independently associated with coronary artery endothelial dysfunction and is a strong predictor of endothelial dysfunction in humans.

Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC > or = 500 cells/microl. Patients with an ALC > or = 500 cells/microl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC > or = 500 cells/microl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.

Health care providers that use electronic medical records maintain an administrative database of diagnoses generated by physicians in the course of medical care delivery. This database is subsequently used for billing and reimbursement but can also be used to identify patients for clinical research. In this paper we present a hybrid rule-based and machine learning technique for automatic determination of whether a diagnosis is confirmed, probable or represents a history of a disorder. The rule-based stage was able to classify 86% of test instances with an accuracy of 98.7%. The machine learning stage was able to classify the remaining 14% of the test instances with an accuracy of 91.61% using Perceptron neural network as the classification algorithm. A comparison between Naïve Bayes and Perceptron is also presented.

Objectives: The purpose of the current study was to evaluate the changes in incidence, clinical characteristics, and indications for emergency coronary artery bypass grafting (CABG) in patients undergoing percutaneous coronary intervention (PCI) from 1979 to 2003., Background: Emergency CABG after PCI is associated with significant morbidity and mortality., Methods: Data from 23,087 patients who underwent PCI at Mayo Clinic from 1979 to 2003 were analyzed. Patients were divided into three groups: the "pre-stent" era, 1979 to 1994 (n = 8,905); the "initial stent era," 1995 to 1999 (n = 7,605); and the "current stent era," 2000 to 2003 (n = 6,577)., Results: Although patients undergoing PCI in the recent time periods had more high-risk features, there was a significant decrease in the incidence of emergency CABG from 2.9% to 0.7% to 0.3% across the groups (p < 0.001). Patients requiring emergency surgery in the recent time periods had a higher prevalence of hypertension, prior revascularization, and left ventricular dysfunction (ejection fraction <40%), as well as more complex coronary lesions. Fewer patients in the current stent era had coronary artery dissections and abrupt vessel closure requiring emergency CABG. The in-hospital mortality rate for emergency CABG patients remains unchanged and ranges from 10% to 14%., Conclusions: The current study demonstrates that despite the increase in high-risk patients undergoing PCI, there has been a marked decrease in the incidence of patients requiring emergency CABG. However, the in-hospital mortality rate for those requiring emergency CABG remains high and unchanged.

Background: Hypochondriasis (HC) involves preoccupation with fears of having a serious illness. The preoccupation is persistent and based on misinterpretation of benign bodily sensations. In response, patients often resort to frequent checks with doctors, of their own body, and of medical references, to reassure themselves of their health status. Some authors have likened HC to obsessive-compulsive disorder (OCD) on the basis of similarities between obsessions and illness preoccupation and the ritualistic checking behavior observed in each condition., Methods: In this article, the phenomenology of HC is discussed in terms of factors that account for the development and persistence of this disorder. Treatment that is derived from this conceptual model is also described., Results: HC is best considered as an anxiety problem in which pathological fear is focused on innocuous bodily sensations and other health-relevant cues., Conclusions: Many of the psychological mechanisms of HC are similar to those present in OCD.

Objective: Atherosclerosis is a chronic and diffuse disease that affects all vascular beds. However, some vascular beds are more prone to atherosclerosis than others. Recent evidence suggests a role for the vasa vasorum in the atherosclerotic process. We hypothesized that there is a difference in adventitial vasa vasorum structure between the left internal thoracic artery and the coronary artery. Hence the current study was designed to characterize and compare the structure of the adventitial vasa vasorum in the left internal thoracic and coronary arteries., Methods: Samples of vessels were obtained from female crossbred domestic pigs maintained on a normal (n = 6) or high-cholesterol (n = 6) diet for 12 weeks. The samples were scanned with micro-computed tomography, and the tomographic images were reconstructed and analyzed to obtain lumen area, vessel wall area, vasa vasorum count, vasa vasorum density, mean diameter of first- and second-order vasa vasorum, and second-order/first-order vasa vasorum ratio., Results: Vasa vasorum density was significantly higher in the coronary arteries versus that seen in the left internal thoracic arteries in the normal group, as well as in the high-cholesterol group. The higher vasa vasorum density in the high-cholesterol group versus that in the normal group was significant for both vessels, being more pronounced in the left internal thoracic artery. Lumen area and second-order/first-order vasa vasorum ratio were higher in the high-cholesterol group than in the normal group only in the left internal thoracic artery., Conclusion: This study demonstrated that low vasa vasorum spatial density and higher lumen area observed in the left internal thoracic artery compared with that seen in the native coronary artery can be the structural background for the low incidence of atherosclerosis in this vessel.

Colorectal cancer (CRC) is among the most common human malignancies and remains a leading cause of cancer-related morbidity and mortality. Colorectal carcinogenesis is a multistep process characterized by molecular and cellular alterations that result in an identifiable precursor lesion, ie, the adenomatous polyp. The transition from normal mucosa to adenoma and its subsequent progression to carcinoma are protracted events that offer opportunities for preventive interventions. Suppression or reversal of the carcinogenic process in the colorectum with nonpharmacologic or pharmacologic agents, ie, chemoprevention, is an area of considerable research interest and activity. Interest in this field derives from multiple epidemiologic studies showing that regular and continued use of nonsteroidal anti-inflammatory drugs (NSAIDs), predominantly aspirin, is associated with significant reductions in both colorectal adenoma and carcinoma incidence. NSAIDs were first shown to be effective in patients with familial adenomatous polyposis (FAP). Subsequent randomized trials in FAP demonstrated that sulindac and the selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, can significantly regress existing adenomas, and resulted in Food and Drug Administration (FDA) approval of celecoxib for adjunctive management of these patients. Based on the aforementioned data, aspirin and coxibs have been or are currently being evaluated for the prevention of sporadic adenoma recurrence in high-risk patient populations. Evidence indicates that aspirin can reduce adenoma recurrence rates in patients with prior colorectal neoplasia; however, questions remain, including the optimal dosage, timing of initiation and duration of treatment, and clinical benefit versus potential harm to patients. These same issues apply to the nonpharmacologic agents such as calcium, folic acid, and selenium given as dietary supplements. Apart from aspirin, calcium carbonate is the only other agent that has been shown to modestly reduce sporadic adenoma recurrence rates in a randomized trial. Folate and selenium are being actively studied based on provocative preclinical data. In addition to demonstrating efficacy, chemopreventive agents must also be safe for long-term use, be well accepted by patients, and be cost-effective. In this review, the current status of CRC chemoprevention will be discussed, including the available evidence for selected pharmacologic and nonpharmacologic agents, particularly among high-risk populations.

Angina in the setting of a normal angiogram (NOCAD) occurs in 20-30% of patients undergoing coronary angiography. The etiologies of NOCAD can be anatomically classified into three groups: epicardial disease, coronary microvascular dysfunction, and noncoronary disease. Epicardial disease resulting in NOCAD includes endothelial dysfunction, coronary artery spasm, and coronary artery bridging. Microvascular dysfunction may be secondary to hypertension, cardiomyopathy, infiltrative disease, valvular disease, or idiopathic. Noncoronary artery disease states involving other organs systems such as the pulmonary, gastrointestinal, or musculoskeletal systems can also result in NOCAD. This review focuses on the coronary etiologies of NOCAD. The pathophysiology of disease is discussed as well as a systematic diagnostic strategy. Potential therapeutic options and prognosis are also reviewed.

Experimental and human data suggesting progenitor cells possess the capacity to regenerate tissue and augment repair in injured organs has generated widespread interest in the basic research and clinical communities. Nowhere have these findings been more tantalizing than in human cardiovascular disease, in which vasculogenesis and myocardial regeneration logically and understandably remain as attractive therapeutic targets. Burgeoning experimental evidence attests to the proangiogenic, vasculogenic and tissue reparative capabilities of a broad range of progenitor cells derived from the bone marrow, circulation and a number of other tissues in vivo. Studies demonstrating the most apparent therapeutic success are those implicated in revascularization and repair of acute or chronically ischemic tissues in the heart and the peripheral vascular system. Numerous small clinical trials have yielded promising preliminary results without clear evidence of a superiority for a specific cell type or clinical disease entity as the most suitable target for cell therapy. This review will evaluate the scientific rationale for use of a specific cell or cells, the cardiovascular disease states most appropriate for targeted cell therapy, and the patient-specific barriers to therapeutic success, including emerging hurdles such as cardiovascular risk factors and comorbidities in eligible subjects.

Use of abbreviations and acronyms is pervasive in clinical reports despite many efforts to limit the use of ambiguous and unsanctioned abbreviations and acronyms. Due to the fact that many abbreviations and acronyms are ambiguous with respect to their sense, complete and accurate text analysis is impossible without identification of the sense that was intended for a given abbreviation or acronym. We present the results of an experiment where we used the contexts harvested from the Internet through Google API to collect contextual data for a set of 8 acronyms found in clinical notes at the Mayo Clinic. We then used the contexts to disambiguate the sense of abbreviations in a manually annotated corpus.

The traditional view of the heart is of an organ incapable of self-renewal. Hypotheses on the genesis of pump dysfunction in heart failure include emerging concepts of myocyte deficiency due to attritional ischemia and chronic apoptotic cell loss. In the adult heart, inadequate regenerative capacity was presumed to exist to counterbalance such extensive myocyte depletion. Preliminary animal and human studies now challenge the paradigm of myocardial regenerative inadequacy, with findings suggesting that noncardiac cells implanted in the dysfunctional heart augment myocyte deficiency and contractile mass. Data from these studies remain inconclusive and have generated much debate in the basic science and clinical communities. Controversial issues center on the scientific basis for regeneration in the heart, the mechanism of cell-therapy benefit and the safety and appropriateness of clinical trials based on these concepts. This review will evaluate the scientific basis for myocardial-cell replacement, with emphasis on current experimental and human data. We will explore unresolved questions of experimental design, mechanism of action, therapeutic strategies and safety concerns in an era of rising numbers of human cell-therapy trials. Prospects for more widespread clinical application of myocardial-cell replacement and future hurdles to be overcome in this field will also be addressed.

Background: Increasing numbers of elderly patients are now referred for mitral valve operations. It has been unclear whether the results offset the risk of intervention in this patient population., Methods: We obtained clinical follow-up through May 2002 of 59 patients 80 years or older who underwent first-time isolated mitral valve repair (46 patients) or replacement (13 patients) for nonischemic, nonrheumatic mitral regurgitation from January 1990 to June 2000. The mean duration of follow-up was 68 +/- 33 months. Observed survival was compared with the expected survival of persons of the same age and gender in the general population., Results: Preoperatively 79% of patients were in New York Heart Association (NYHA) class III-IV. Operative mortality was 1.7%. Overall 1- and 5-year survival was 89% and 61%. One- and 5-year freedom from thromboembolic complications in hospital survivors was 97% and 84%. One- and 5-year freedom from heart-related hospitalization in hospital survivors was 89% and 78%. There were no reoperations. Twenty-nine patients underwent an echocardiographic follow-up; 31% of them exhibited moderate or more regurgitation. Of 37 surviving patients at follow-up, 78% were in NYHA functional class I-II. No statistically significant difference was noted between the observed survival postoperatively and the expected survival of persons of the same age and gender in the general population. In a univariate analysis, only preoperative left ventricular ejection fraction greater than 40% was significantly associated with freedom from late heart-related mortality (95% confidence interval 62%-92%, p = 0.01) and with freedom from heart-related hospitalization (95% CI 68%-95%, p < 0.01)., Conclusions: Native mitral valve surgery for isolated nonischemic, nonrheumatic disease in octogenarians resulted in a survival rate comparable with that of the general population. It also exhibited substantial improvement regarding the functional status of the patient. Reparative techniques did not result in a survival advantage compared with replacement but did prove to be a reliable approach. Surgery performed in an early stage, preceding the development of left ventricular dysfunction, was associated with an improved freedom from late cardiac complications.

The purpose of this study was to analyze coronary hemodynamics and determine a possible mechanism for microvascular dysfunction in patients with symptomatic hypertrophic cardiomyopathy (HC). Although patients with HC have been shown to have microvascular dysfunction and reduced coronary flow reserve (CFR), the mechanism by which this occurs is not well understood. We studied coronary hemodynamics in 8 patients with symptomatic HC and compared them with 8 matched controls. Compared with controls, patients with HC had higher coronary blood flow, lower coronary resistance, and lower CFR. Patients with HC also had abnormal phasic coronary flow characteristics. These results suggest that the reduction of CFR in patients with HC may be secondary to near maximal vasodilation of the microcirculation in the basal state., (Copyright 2004 Excerpta Medica, Inc.)

Advances in contrast echocardiography hold promise for the routine assessment of myocardial perfusion. Continued progress may ultimately position myocardial contrast echocardiography (MCE) as an imaging modality that can provide comprehensive cardiac assessment-anatomic, physiologic, and pathophysiologic. Vasodilator stress with adenosine can play an important role in conjunction with MCE, particularly as it relates to the noninvasive evaluation of myocardial perfusion and coronary blood flow reserve. Adenosine pharmacologic stress testing may provide improved test performance through perfusion detection when compared with traditional use of dobutamine assessments of regional wall motion abnormalities.

The field of radioimmunotherapy for the treatment of non-Hodgkin's lymphoma (NHL) has advanced significantly over the past decade, and several radioimmunoconjugates are being tested in clinical trials. Two of these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeled tositumomab (Bexxar). Other agents target either CD22 (Y-90 epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1), respectively. In February 2002, Y-90-labeled ibritumomab tiuxetan became the first radioimmunoconjugate to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Tositumomab/I-131 tositumomab was approved in June 2003. Thus, two radioimmunoconjugates have been approved for the treatment of NHL. Both agents, when administered as a single dose, have produced impressive tumor response rates with an acceptable toxicity profile. The main side effect is reversible myelosuppression. Radioimmunotherapy produces overall response rates of approximately 80% in patients with low-grade lymphomas, and 25% to 30% of patients achieve a complete remission. Lower response rates (approximately 40%) have been reported in patients with large-cell lymphomas. This review discusses the clinical trials of radioimmunotherapeutic agents for NHL that demonstrated their safety and efficacy and outlines the current status of these agents.

Congenital myasthenic syndromes are genetic disorders of neuromuscular transmission that should be considered in the differential diagnosis of seronegative myasthenia gravis and other neuromuscular disorders. They are present at birth but may not manifest until childhood or adult life. A classification system of congenital myasthenic syndromes based on molecular genetics is under evolution. Clinical and neurophysiological correlations with molecular studies have defined diagnostic criteria that assist the clinician in identifying specific clinical myasthenic syndromes. Some types of congenital myasthenia (e.g., slow-channel and fast-channel syndrome, acetylcholinesterase deficiency, and choline acetyltransferase deficiency) can be identified by clinical features, response to cholinesterase inhibitors, and standard electrodiagnostic studies. The molecular genetics, pathogenesis, clinical features, differential diagnosis, natural history, and treatment of well-characterized congenital myasthenic syndromes are discussed.

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials., (Copyright 2004 S. Karger AG, Basel)