Automated contrast painting for position verification in radiotherapy

The influence of information technology in medicine has been constantly rising and represents a central part in many medical disciplines, especially radio-oncology. For the proper delivery of radiation treatment, the correct position of the patient is essential. To verify the correct position of the patient radiological images are made. In order to compare positions, contours of structures (often bones) may be used, these need to be identified and painted. The software that was provided with the linear accelerator contains a bitmap paint program, where these structures are painted manually. This manual painting of structures could be replaced by automated algorithms. However, amendments, innovations or customization of the original software are costly and difficult to achieve due to copyright, license and certification issues. The concept described here aims to get around these issues by creating an automated algorithm on the user level, with no interference of the underlying original software. This system uses the Java platform; with the help of the Java Robot class user input can be simulated. The developed tool proved to be time-saving, functional and the development could easily be accomplished and individually tailored to users needs

Calcium Signaling and Contractility in Cardiac Myocyte of Wolframin Deficient Rats

Wolframin (Wfs1) is a membrane protein of the sarco/endoplasmic reticulum. Wfs1 mutations are responsible for the Wolfram syndrome, characterized by diabetic and neurological symptoms. Although Wfs1 is expressed in cardiac muscle, its role in this tissue is not clear. We have characterized the effect of invalidation of Wfs1 on calcium signaling-related processes in isolated ventricular myocytes of exon5-Wfs1 deficient rats (Wfs1-e5/-e5) before the onset of overt disease. Calcium transients and contraction were measured in field-stimulated isolated myocytes using confocal microscopy with calcium indicator fluo-3 AM and sarcomere length detection. Calcium currents and their calcium release-dependent inactivation were characterized in whole-cell patch-clamp experiments. At 4 months, Wfs1-e5/-e5 animals were euglycemic, and echocardiographic examination revealed fully compensated cardiac function. In field-stimulated isolated ventricular myocytes, both the amplitude and the duration of contraction of Wfs1-e5/-e5 animals were elevated relative to control Wfs1+/+ littermates. Increased contractility of myocytes resulted largely from prolonged cytosolic calcium transients. Neither the amplitude of calcium currents nor their voltage dependence of activation differed between the two groups. Calcium currents in Wfs1-e5/-e5 myocytes showed a larger extent of inactivation by short voltage prepulses applied to selectively induce calcium release-dependent inactivation of calcium current. Neither the calcium content of the sarcoplasmic reticulum, measured by application of 20 mmol/l caffeine, nor the expression of SERCA2, determined from Western blots, differed significantly in myocytes of Wfs1-e5/-e5 animals compared to control ones. These experiments point to increased duration of calcium release in ventricular myocytes of Wfs1-e5/-e5 animals. We speculate that the lack of functional wolframin might cause changes leading to upregulation of RyR2 channels resulting in prolongation of channel openings and/or a delay in termination of calcium release

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology

Key advances in antihypertensive treatment

Although various effective treatments for hypertension are available, novel therapies to reduce elevated blood pressure, improve blood-pressure control, treat resistant hypertension, and reduce the associated cardiovascular risk factors are still required. A novel angiotensin-receptor blocker (ARB) was approved in 2011, and additional compounds are in development or being tested in clinical trials. Several of these agents have innovative mechanisms of action (an aldosterone synthase inhibitor, a natriuretic peptide agonist, a soluble epoxide hydrolase inhibitor, and an angiotensin II type 2 receptor agonist) or dual activity (a combined ARB and neutral endopeptidase inhibitor, an ARB and endothelin receptor A blocker, and an endothelin-converting enzyme and neutral endopeptidase inhibitor). In addition, several novel fixed-dose combinations of existing antihypertensive agents were approved in 2010-2011, including aliskiren double and triple combinations, and an olmesartan triple combination. Upcoming fixed-dose combinations are expected to introduce calcium-channel blockers other than amlodipine and diuretics other than hydrochlorothiazide. Finally, device-based approaches to the treatment of resistant hypertension, such as renal denervation and baroreceptor activation therapy, have shown promising results in clinical trials. However, technical improvements in the implantation procedure and devices used for baroreceptor activation therapy are required to address procedural safety concerns

Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of “checks and balances”. It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the “crossroad” in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the “deleterious” Ang A as well as from the “protective” angiotensin 1–7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications

AT2 receptor agonists: hypertension and beyond

Research about the angiotensin AT2 receptor (AT2R) has been hampered in the past by the lack of a specific and selective agonist with in-vivo stability. Such an eagerly awaited agonist, compound 21, has recently become available, giving momentum to AT2R research which so far has resulted in 14 original publications. This article is intending to review those publications which address AT2R function by direct in-vivo stimulation instead of indirect approaches such as receptor blockade or genetic alteration of AT2R expression.Studies reviewed in this article looked at the effect of AT2R stimulation in disease models of hypertension, renal disease, stroke, Alzheimer's disease and myocardial infarction. AT2R stimulation does not have an antihypertensive effect, but promoted tissue protection in all models in which it was tested. Antiinflammation and antiapoptosis seem important features of the AT2R underlying improved outcome in experimental disease models.Availability of nonpeptidic, orally active AT2R agonists will facilitate future AT2R research and hopefully contribute to the clarification of many still open questions regarding AT2R signalling and function. Furthermore, AT2R agonists represent a potential novel class of drugs and are expected to enter a phase I clinical study in 2012

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases

Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin–angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired