'Tib the balance': the search for the optimal hormone replacement therapy.

In 1902, W. Bayliss and E. Starling formulated a new term intheir effort to prove the existence of internal secretions.The selected term ‘hormone’ was phrased after theGreek word for ‘I excite’.¹ Since these early observations about the physiological relevanceof sex hormone regulation, the excitement in this field of researchand related therapy has never really stopped. On the one hand,we have learnt a lot about the complex regulatory network ofsex hormones and their respective receptors in heart disease.²On the other, in parallel with the growing knowledge about hormones,     

Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity.

AIMS: Prophylactic administration of N-acetylcysteine (NAC) (600mg orally twice daily), along with hydration, prevents contrast agent-associated nephrotoxicity (CAN) induced by a low dose of non-ionic, low-osmolality contrast dye. We tested whether a double dose of NAC is more effective to prevent CAN. METHODS AND RESULTS: Two-hundred-twenty-four consecutive patients with chronic renal insufficiency (creatinine level > or =1.5mg/dl and/or creatinine clearance <60ml/min), referred to our institution for coronary and/or peripheral procedures, were randomly assigned to receive 0.45% saline intravenously and NAC at the standard dose (600mg orally twice daily; SD Group; n=110) or at a double dose (1200mg orally twice daily; DD Group; n=114) before and after a non-ionic, low-osmolality contrast dye administration. Increase of at least 0.5mg/dl of the creatinine concentration 48h after the procedure occurred in 12/109 patients (11%) in the SD Group and 4/114 patients (3.5%) in the DD Group (P=0.038; OR=0.29; 95% CI=0.09-0.94). In the subgroup with low (<140ml, or contrast ratio <=1) contrast dose, no significant difference in renal function deterioration occurred between the 2 groups. In the subgroup with high (> or =140ml, or contrast ratio >1) contrast dose, the event was significantly more frequent in the SD Group. Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent.     

A search for a transmissible agent in Crohn's disease.

Controversy exists as to whether a transmissible agent is responsible for Crohn's disease. Previous reports have suggested that sarcoid-like granulomas can develop in animals following inoculation of homogenates derived from bowel affected by Crohn's disease. This study involved the injection of Crohn's tissue homogenates into experimental animals under a variety of conditions which might be expected to favour the demonstration of such an agent. Homogenates have been inoculated into the ileum of rats, mice, and rabbits and also given inoculated into ileum and footpads of rats which have previously been rendered lymphoedematous by surgical interruption of the draining lymphatics. Bowel homogenates from a total of 17 patients with Crohn's disease have been injected into 91 experimental animals. No macroscopic or microscopic changes indicative of Crohn's disease were detected. Thus study does not support the suggestion that a transmissible agent is present in Crohn's disease.     

Neurological aspects of patent foramen ovale: in search of the optimal treatment

Although paradoxical embolism through a patent foramen ovale (PFO) has become an established cause of cerebral ischemia in younger patients without other obvious causes of stroke, the therapeutic options have not been investigated satisfactorily. There are still uncertainties about the natural history of PFO patients after suffering a stroke, and diagnostic criteria proving a causal and not incidental relation to the embolic event are not established. The stroke recurrence has been evaluated in several studies in a heterogeneous population and seems as low as 1.9% per year. Secondary prophylactic treatment has become a matter of discussion since efforts were made to close the PFO either surgically or by percutaneous transcatheter methods. Foramen closure seems to be effective in eliminating the mechanism of paradoxical embolism but its benefit-risk ratio has yet to be established. Following the goals of evidence-based medicine, none of the therapeutic options can be recommended. Fortunately, the issue has gone to trial and there are two studies underway to compare foramen closure to medical therapy.     

From the Cover: Efficient computation of optimal actions

Optimal choice of actions is a fundamental problem relevant to fields as diverse as neuroscience, psychology, economics, computer science, and control engineering. Despite this broad relevance the abstract setting is similar: we have an agent choosing actions over time, an uncertain dynamical system whose state is affected by those actions, and a performance criterion that the agent seeks to optimize. Solving problems of this kind remains hard, in part, because of overly generic formulations. Here, we propose a more structured formulation that greatly simplifies the construction of optimal control laws in both discrete and continuous domains. An exhaustive search over actions is avoided and the problem becomes linear. This yields algorithms that outperform Dynamic Programming and Reinforcement Learning, and thereby solve traditional problems more efficiently. Our framework also enables computations that were not possible before: composing optimal control laws by mixing primitives, applying deterministic methods to stochastic systems, quantifying the benefits of error tolerance, and inferring goals from behavioral data via convex optimization. Development of a general class of easily solvable problems tends to accelerate progress—as linear systems theory has done, for example. Our framework may have similar impact in fields where optimal choice of actions is relevant.     

From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization

There is a strong need for biomarkers to identify patients at risk for future cardiovascular events related with progressive atherosclerotic disease. Ideally, increasing knowledge of the mechanisms of atherosclerotic plaque destabilization should be translated in clinical practice. Currently, the following commonly followed strategies can be identified with the objective to detect either the local vulnerable plaque that is prone to rupture and gives rise to a thrombotic occlusion, or the systemic vulnerable patient, who has a high probability to suffer from an adverse clinical event. On the one hand, studies are ongoing to determine local atherosclerotic plaque characteristics to predict future local plaque rupture and subsequent vascular thrombosis. Newly developed imaging modalities are being developed and validated to detect these plaques in vivo. On the other hand, systemic approaches are pursued to discover serum biomarkers that are applicable to define patients at risk for future cardiovascular events. We propose a third original approach that is optional but yet unexplored, that is, to use local plaque characteristics as a biomarker not just for local plaque destabilization but for future cardiovascular events due to plaque progression in any vascular system. This review aims to provide an overview of the current standings of the identification of the vulnerable plaque and the vulnerable patient.     

Selection of a contrast agent in the cardiac catheterization laboratory

The evolution of contrast material for intravascular use has been directed toward the development of better-tolerated agents. Currently, a variety of such "dyes" are available for coronary angiography and left ventriculography. Considerable animal and human investigation suggests that significant differences exist between the families of contrast agents that relate to patient tolerance. The newer low osmolality agents (especially the nonionic agents) produce less perturbation of the homeostatic state, which is clinically manifested by a lessened incidence of side effects, including those of a hemodynamic and electrophysiologic nature. While controversy continues over the cost/benefit ratio of the low osmolality contrast agents compared to traditional high osmolality agents, the former are rapidly becoming the community standard for diagnostic and especially therapeutic cardiologic procedures. Accepting the advantages of the low osmolality contrast agents, differences between the ionic dimers and the nonionic agents have been examined. Both experimental and clinical data suggest superiority of the nonionic agents. Although controversy still surrounds the issue of thromboembolism with the nonionic agents, accumulating evidence fails to support a clinically significant relation. The choice of contrast material is the responsibility of the invasive cardiologist. While the benefits of low osmolality agents are most obvious in high-risk patients, experience with large-scale intravenous studies suggests that the choice of contrast agent is a better discriminator of adverse reaction than is preprocedural risk stratification.     

Magnetic resonance imaging of myocardial infarction using gadolinium-based contrast agent.

OBJECTIVES: To evaluate myocardial infarcts using a segmented inversion-recovery prepared gradient echo sequence on a 1.5 Tesla MR scanner after injection of a gadolinium-based contrast agent. METHODS: Fourteen patients were prospectively offered a cardiac MR exam between November 2003 and February 2004. Six patients had a history of anterior wall MI, six had a history of inferior wall MI and two patients had MI of undetermined location. RESULTS: Delayed enhancement indicating the presence of scarring was visualized in all fourteen patients. The scarring was transmural in ten patients and non-transmural in four patients. CONCLUSION: Delayed enhancement of infarcted areas in the myocardium after injection of gadolinium-based contrast agent represents scarring and adequate resolution exists to distinguish transmural from non-transmural scarring. This technique is useful in determining viability of infarcted myocardium, may detect infarcts missed by SPECT and may help in the selection of patients for implantation of defibrillators.     

Intrahepatic circulatory time analysis of an ultrasound contrast agent in liver cirrhosis.

OBJECTIVE: To assess the diagnostic accuracy and advantages of intrahepatic circulatory time analysis of an ultrasound contrast agent using pulse-inversion imaging as compared with recently reported noninvasive diagnostic tests for cirrhosis. METHODS: Forty patients divided into noncirrhotic (nonLC) (n = 20) and compensated cirrhotic (LC) (n = 20) groups were studied prospectively. After intravenous administration of a contrast agent, the arrival times at the hepatic artery (HA), portal vein (PV), and hepatic vein (HV) were measured by pulse-inversion imaging. Intrahepatic circulatory time was calculated as the difference between the HV and HA arrival times (HV-HA interval time) or the HV and PV arrival times (HV-PV interval time). RESULTS: The HV-HA and HV-PV interval times were significantly shorter in the LC group (7.4 +/- 1.7 and 1.9 +/- 1.5 s, respectively) compared with those in the nonLC group (normal: 15.6 +/- 2.1 and 11.1 +/- 1.7 s, respectively; P < 0.001 and P < 0.001, respectively, and hepatitis: 12.8 +/- 4.1 and 7.8 +/- 4.4 s, respectively; P < 0.001 and P < 0.002, respectively). Each intrahepatic circulatory time showed the highest accuracy rate for cirrhosis in other noninvasive diagnostic tests. CONCLUSIONS: This analysis, which is considered to reflect intrahepatic hemodynamic changes, is a useful noninvasive diagnostic test for compensated cirrhosis.     

经静脉心肌声学造影剂的研制

目的 :制备可经静脉注射产生心肌对比增强效果的声学对比造影剂 ,观察其心肌显影效果。方法 :1按不同比例将 5 0 g· L- 1 葡萄糖或 9g· L- 1 Na Cl,C3 F8气体与人血白蛋白混合后进行超声振荡。 Coulter’ s计数器对造影剂进行质量分析。 2经犬股静脉注射自制对比造影剂 0 .2 ml,经胸壁扫查犬左室乳头肌水平短轴切面。结果 :1造影剂微泡液的相对浓度为 4 .2 3 9× 10 9/m l,微泡平均直径 3 .789μm,小于 9.89μm微泡占 99.5 %。 2经静脉注射后 ,均产生不同程度的心肌对比增强效果 ,心肌显影持续时间 1～ 3 min。注射前后犬血流动力学无显著性改变。结论 :自制经静脉注射对比造影剂符合心肌声学造影的要求 ;初步动物实验表明经静脉注射可产生肉眼可辨的心肌显影 ;反复注射无明显血流动力学改变     

An approach to the performance of contrast studies in contrast material-reactive persons.

A method of carrying out contrast studies was considered for use in 124 persons with past histories of adverse reactions to contrast media. High-dosage steroid treatment was given before and during the contrast study to 37 patients with previous rash responses and 9 with prior anaphylactoid reactions; only 3 and 1 patients, respectively, of these groups had mild adverse reactions. Patients with past reactions deemed "vasomotor" underwent contrast study without preparative drug therapy without significant adverse effects. Although uncontrolled, this study suggests a possible protective role of steroids in patients with certain previous reactions to contrast media. We do not wish to imply that this is the only approach that can be used in the kind of patients reported here.