Development of bioluminescence resonance energy transfer (BRET) based genetic sensors for sensing biological functions such as protein–protein interactions (PPIs) in vivo has a special value in measuring such dynamic events at their native environment. Since its inception in the late nineties, BRET related research has gained significant momentum in terms of adding versatility to the assay format and wider applicability where it has been suitably used. Beyond the scope of quantitative measurement of PPIs and protein dimerization, molecular imaging applications based on BRET assays have broadened its scope for screening pharmacologically important compounds by in vivo imaging as well. In this mini-review we focus on an in-depth analysis of engineered BRET systems developed and their successful application to cell-based assays as well as in vivo non-invasive imaging in live subjects.
bioluminescence resonance energy transfer; luciferase; fluorescent proteins; optical imaging; protein–protein interactions; cell-based assay
Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors—raltegravir (RAL), elvitegravir (ELV) and L731,988—were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Our in silico and in vitro studies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.
Studies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel.
19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed.
CYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06–1.54; p = 0.009], CV death [RR: 3.21, CI: 1.65–6.23; p = 0.001], MI [RR: 1.36, CI: 1.12–1.65; p = 0.002], ST [RR: 2.41, CI: 1.69–3.41; p < 0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86–1.20; p = 0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01–1.76; p = 0.03], and PCI with DES [RR: 1.53, CI: 1.029–1.269; p = 0.03]. CYP2C19*2 polymorphism has very low sensitivity (28–58%), specificity (71–73%), positive predictive value (3–10%) but good negative predictive value (92–99%). ABCB1-C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99–1.29; p = 0.06], ST [RR: 0.88, CI: 0.52–1.47; p = 0.63] and major bleeding [RR: 1.04, CI: 0.87–1.25; p = 0.62] in both groups.
In CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present.
Genetic testing; CYP2C19*2 polymorphisms; ABCB1-C3435T polymorphisms
There are a handful of studies that have been done investigating the effect of music on various vital signs, namely systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Many studies have also assessed effects of music on self-reported anxiety level, attributing some degree of music-induced anxiety relief to the beneficial impacts of music on vital signs. Several randomised studies have shown varying effects of music on these vital parameters and so a metaanalysis was done to compare the effect of music on them. The fixed effects model was used as studies were homogenous. A two-sided alpha error < 0.05 was considered to be statistically significant. Compared to those who did not receive music therapy, those who did receive music therapy had a significantly greater decrease in SBP before and after (difference in means, −2.629, confidence interval (CI), −3.914 to −1.344, P < 0.001), a significantly greater decrease in DBP (difference in means, −1.112, CI, −1.692 to −0.532, P < 0.001), and a significantly greater decrease in HR (difference in means, −3.422, CI, −5.032 to −1.812, P < 0.001).
Blood pressure; Diastolic; Heart rate; Music; Systolic
The endodontic treatment of a mandibular molar with aberrant canal configuration can be diagnostically and clinically challenging. This case report presents the treatment of a mandibular first molar with six root canals, of which three canals were located in the mesial root and three in distal root. Third canals were found between the two main root canals. This case presents a rare anatomic configuration and points to the importance of expecting and searching for additional canals.
Cone beam computed tomography; mandibular first molar; middle distal canal; middle mesial canal
Diatal radius fractures (DRFs) are typical fractures of relatively fit persons with osteoporotic bone who remain active into older age. Traditionally, DRFs in older patients have been treated with closed reduction and cast immobilization. Considering the increasing life expectancy of the elderly population, appropriate management of these fractures is of growing importance. Decision making for surgical or nonsurgical approach to osteoporotic DRFs is difficult. These decisions are often made based on the data from treatments of much younger patients. The current literature concerning the treatment of DRFs in the elderly individuals is more controversial. Some investigators have recommended open reduction internal fixation (ORIF) as treatment for unstable DRFs in older patients, while others have suggested that elderly patients should be treated nonsurgically even if there is an unstable fracture situation because fracture reduction is not associated with functional outcomes as in younger patients. This article reviews the different treatment options for DRFs in the elderly individuals reported in the recent literature.
distal radius fracture; osteoporosis; elderly; treatment; geriatric trauma
Revascularization after myocardial infarction is often achieved via percutaneous coronary intervention, which often entails stenting. Drug-eluting stents have shown benefits over bare metal stents in this setting, and a variety of drug-eluting stents are now available, including sirolimus-, paclitaxel-, and zotarolimus-eluting stents. There are studies that have compared the various drug-eluting stents and this meta-analysis pools data comparing 12-month clinical outcomes of zotarolimus- and paclitaxel-eluting stents. End points studied were myocardial infarction, major adverse cardiac events, cardiac death, all-cause death, stent thrombosis, target vessel revascularization, and target lesion revascularization.There was a statistically significant reduction in risk of myocardial infarction (odds ratio, 0.250, confidence interval, 0.160 to 0.392) and statistically insignificant reductions in major adverse cardiac events (odds ratio, 0.813, confidence interval, 0.656 to 1.007), cardiac death (odds ratio, 0.817, confidence interval, 0.359 to 1.857), all cause death (odds ratio, 0.820, confidence interval, 0.443 to 1.516), and target lesion revascularization (odds ratio, 0.936, confidence interval 0.702 to 1.247). There was a statistically significant increase in target vessel revascularization (odds ratio, 1.336, confidence interval, 1.003 to 1.778) and a statistically insignificant increase in stent thrombosis (odds ratio, 1.174, confidence interval, 0.604 to 2.280). These findings are similar to the individual studies although other studies have noted increased late loss with zotarolimus-eluting stents and this current data associated with late loss should be kept in mind when makimg clinical decisions regarding sent selection.
Although diabetic patients constitute an increasing number of individuals undergoing percutaneous coronary intervention (PCI) and surgical revascularization, they experience worse outcomes than nondiabetic patients. The optimal coronary revascularization strategy in the diabetic population remains unclear in view of advancements in pharmacotherapy and technology of both PCI and surgical revascularization. Data to guide decision making are limited regarding the current choice between coronary artery bypass graft surgery and PCI using drug-eluting stents and newer antiplatelet agents in diabetic patients with multivessel coronary artery disease. The present article summarizes the current state of evidence for coronary revascularization in the diabetic population.
CABG; Coronary revascularization; Diabetes mellitus; PCI
We sought to assess vascularity in wrist tenosynovitis by using power Doppler ultrasound (PDUS) and to compare detection of intra- and peritendinous vascularity with that of contrast-enhanced grey-scale ultrasound (CEUS).
Twenty-six tendons of 24 patients (nine men, 15 women; mean age ± SD, 54.4 ± 11.8 years) with a clinical diagnosis of tenosynovitis were examined with B-mode ultrasonography, PDUS, and CEUS by using a second-generation contrast agent, SonoVue (Bracco Diagnostics, Milan, Italy) and a low-mechanical-index ultrasound technique. Thickness of synovitis, extent of vascularized pannus, intensity of peritendinous vascularisation, and detection of intratendinous vessels was incorporated in a 3-score grading system (grade 0 to 2). Interobserver variability was calculated.
With CEUS, a significantly greater extent of vascularity could be detected than by using PDUS (P < 0.001). In terms of peri- and intratendinous vessels, CEUS was significantly more sensitive in the detection of vascularization compared with PDUS (P < 0.001). No significant correlation between synovial thickening and extent of vascularity could be found (P = 0.089 to 0.097). Interobserver reliability was calculated to be excellent when evaluating the grading score (κ = 0.811 to 1.00).
CEUS is a promising tool to detect tendon vascularity with higher sensitivity than PDUS by improved detection of intra- and peritendinous vascularity.
Not long after coronary artery bypass grafting surgery was described, several reports presented follow-up angiographic data on large cohorts of patients, demonstrating that approximately one-half of saphenous vein grafts fail within 10 to 15 years of surgery and that graft failure is associated with worse clinical outcomes. Three processes are responsible for vein graft failure. Thrombosis, intimal hyperplasia and accelerated atherosclerosis contribute to graft failure in the acute, subacute and late postoperative periods, respectively. Studies have shown that perioperative antiplatelet therapy can reduce early thrombosis and graft failure. As in native coronaries, intensive lipid lowering can attenuate the process of atherosclerosis in vein grafts. Intimal hyperplasia in the vein graft is thought to be an adaptation of the vein to higher pressures in the arterial circulation. This process is further promoted by the loss of inhibition from the endothelial layer, which is injured during surgery. A new ‘no-touch’ technique for harvesting grafts may be effective in preventing disruption to the endothelial layer, and subsequent intimal hyperplasia and graft loss. Off-pump surgery and endoscopic vein harvesting, which are known to reduce surgical morbidity, have been shown to be no worse than on-pump surgery and open vein harvesting, respectively, in terms of vein graft patency. Various gene therapies can prevent intimal hyperplasia in animal models, but human data obtained so far have been disappointing. Placing an external stent around a vein graft may reduce tangential wall stress and subsequent intimal hyperplasia.
Coronary artery bypass surgery; Endoscopic vein harvesting; External stenting; Gene therapy; No-touch technique; Off-pump bypass surgery; Vein graft disease
Atrial fibrillation is the most common of the serious cardiac rhythm disturbances and is responsible for substantial morbidity and mortality. Amiodarone is currently one of the most widely used and most effective antiarrhythmic agents for atrial fibrillation. But during chronic usage amiodarone can cause some serious extra cardiac adverse effects, including effects on the thyroid. Dronedarone is a newer therapeutic agent with a structural resemblance to amiodarone, with two molecular changes, and with a better side effect profile. Dronedarone is a multichannel blocker and, like amiodarone, possesses both a rhythm and a rate control property in atrial fibrillation. The US Food and Drug Administration approved dronedarone for atrial fibrillation on July 2, 2009. In this review, we discuss the role of dronedarone in atrial fibrillation.
dronedarone; amiodarone; atrial fibrillation
Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV).
We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an α1-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the α1-agonist was discontinued; and 61 (45 female) who were on an α1-agonist, but for whom no drug changes were made. The tests averaged 3.1 ± 1.4 months apart; midodrine (ProAmatine) was the α1-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension.
Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term α1-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed.
The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA.
The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.
autonomic nervous system; cardiovascular autonomic neuropathy; orthostatic hypotension; postural orthostatic tachycardia syndrome; respiratory activity analysis; vasopressor
The case of a 78-year-old African American woman who presented at the Mount Sinai Medical Center (Chicago, USA) with excruciating backache is presented. Computed tomography of the chest at the time of admission showed dissection of the aortic arch, descending aorta and dissection of an aberrant right subclavian artery. She was managed medically for Stanford type B acute aortic dissection. The patient was asymptomatic at presentation, but started complaining of new-onset dysphagia during her stay in the hospital. An esophagogram was performed and suggested posterior impingement of the esophagus, a classic sign of an aberrant right subclavian artery. Because the patient had multiple underlying comorbidities and the dysphagia was mild and intermittent, surgery was deferred. The patient was discharged home after complete stabilization and was scheduled for a follow-up appointment.
Aortic arch syndromes; Dysphagia; Subclavian artery
Chronic stable angina is a debilitating illness affecting at least 6.6 million US residents. Despite being optimally treated by pharmacotherapy and revascularization up to 26% of patients still experience angina. Diabetes mellitus is a common co-morbid condition in angina patients. Several new investigational medications are being tested for chronic angina. Advances in understanding of myocardial ischemia have prompted evaluation of a number of new antianginal strategies. In this review we discuss the utility of ranolazine, a recently approved novel antianginal agent and its efficacy in the diabetic patient population. In addition to its antianginal action in diabetic patients with chronic angina, ranolazine may have favorable effects on glycated hemoglobin levels.
chronic stable angina; antianginal; ranolazine; diabetes mellitus; glycated hemoglobin
To compare the demographics, inpatient mortality and short-term survival following hospital discharge between cocaine-using and non-cocaine-using patients presenting with acute aortic dissection.
Retrospective analysis of 46 consecutive patients admitted with the diagnosis of acute aortic dissection at the Mount Sinai Hospital (Chicago, USA) between 1996 and 2005. Among these 46 patients, cocaine use was temporally related to the presenting symptom in 13 patients (28%, group 1). Patients who were not cocaine users were grouped into group 2 (33 patients [72%]).
Patients in group 1 were younger than those in group 2 (mean age 38±9 years versus 63±17 years, P=0.001), more likely to be smokers (13 of 13 patients [100%] versus 15 of 33 patients [45%], P=0.001) and had a higher prevalence of accelerated hypertension (mean blood pressure 210/130 mmHg) compared with group 2 (10 of 13 patients [77%] versus 11 of 33 patients [33%]) (P=0.01). Group 1 patients had a higher prevalence of type B dissection than group 2 (nine of 13 patients [69%] versus one of 33 patients [3%]). After hospital discharge, eight of 13 patients (62%) in the cocaine group continued to use cocaine. Mortality following hospital discharge was significantly higher in cocaine users (nine of 13 patients [69%]) compared with the non-cocaine users (four of 33 patients [12%], P=0.01). Recurrent dissection was the cause of death in five of the 13 deaths (42%) in the cocaine group.
Patients presenting with acute aortic dissection temporally related to cocaine use are more likely to be younger, smokers, have higher prevalence of hypertensive crises, more likely to have type B aortic dissection and may have a higher mortality following hospital discharge, possibly due to continued cocaine use and recurrent aortic dissection.
Aortic dissection; Clinical outcome; Cocaine; Mortality
The incidence of cardiorenal syndrome is increasing; however, its pathophysiology and effective management are still not well understood. For many years, diuretics have been the mainstay of treatment for cardiorenal syndrome, although a significant proportion of patients develop resistance to diuretics and even deteriorate while on diuretics. Trials on different ways to counteract diuretic resistance and newer treatment modalities, such as nesiritide, arginine vasopressin receptor antagonists, adenosine receptor antagonists and ultrafiltration, have shown promising results.
Cardiorenal syndrome; Diuretic resistance; Diuretics; Nesiritide; Tolvaptan; Ultrafiltration
Peripheral arterial disease (PAD) is a common manifestation of atherosclerotic vascular disease. Its incidence increases with age and in the presence of known cardiovascular risk factors (eg, smoking and diabetes). PAD frequently coexists with coronary and/or cerebrovascular disease, probably because of common risk factors. Asymptomatic PAD of the lower limbs (defined as an ankle-brachial index of less than 0.9) is believed to be approximately three to four times more common than symptomatic PAD. Both symptomatic and asymptomatic diseases are associated with high risk of cardiovascular mortality and morbidity. Therefore, patients with PAD are candidates for preventive strategies for cardiovascular events. Platelet activation and aggregation is believed to significantly contribute to atherothrombotic events. Thus, patients with PAD can benefit from antiplatelet therapy. Both acetylsalicylic acid and clopidogrel decrease serious cardiovascular events in patients with PAD. However, acetylsalicylic acid is the preferred agent because of its low cost and wide availability. Cilostazol is recommended for use in patients with severe and disabling symptoms but not for asymptomatic or less disabling disease. Currently, there is insufficient evidence to recommend routine use of newer agents such as picotamide in patients with PAD.
Antiplatelet agents; Cardiovascular risk; PAD
As the incidence of angina and heart failure continue to rise, new therapeutic options will be needed to treat patients who remain symptomatic or who are intolerant to current treatment. Enhanced external counterpulsation (EECP) is a noninvasive modality being investigated in both angina and congestive heart failure patients. It has been proven to provide symptomatic benefit in angina patients, but has not been proven to show an increase in life expectancy or decrease in cardiovascular events. EECP in heart failure has been proven to be safe, but its efficacy is still uncertain. The present paper summarizes the current literature on the clinical use of EECP in angina and heart failure.
Angina; Congestive heart failure; EECP; Prognosis
Stress cardiomyopathy is increasingly being described as a form of reversible left ventricular systolic dysfunction, with a characteristic shape on left ventriculography. The acute clinical, electrocardiographic and laboratory abnormalities are reminiscent of acute coronary syndrome, with nonobstructive coronary arteries on angiography. Wall motion abnormalities typical of this disease exhibit apical akinesis with compensatory basal hyperkinesis, resulting in the characteristic systolic apical ballooning. Stress cardiomyopathy is much more common in women than men, especially postmenopausal women, and it is typically triggered by intense medical, emotional or physical stress. The pathogenesis of the disease is not well understood, with current evidence favouring catecholamine myocardial injury. Until prospective distinction can be made between stress car-diomyopathy and acute coronary syndrome, the diagnosis should be that of exclusion. In addition to long-term beta-blockers, angiotensin-converting enzyme inhibitors and diuretics as needed, treatment is generally supportive, with recovery of baseline left ventricular function within a few weeks to a month.
Reversible left ventricular systolic dysfunction; Stress cardiomyopathy; Takotsubo cardiomyopathy
Posttraumatic stress disorder (PTSD) involves the onset of psychiatric symptoms after exposure to a traumatic event. PTSD has an estimated lifetime prevalence of 7.8% among adult Americans, and about 15.2% of the men and 8.5% of the women who served in Vietnam suffered from posttraumatic stress disorder (PTSD) > or =15 years after their military service. Physiological responses (increase in heart rate, blood pressure, tremor and other symptoms of autonomic arousal) to reminders of the trauma are a part of the DSM-IV definition of PTSD. Multiple studies have shown that patients suffering from PTSD have increased resting heart rate, increased startle reaction, and increased heart rate and blood pressure as responses to traumatic slides, sounds and scripts. Some researchers have studied the sympathetic nervous system even further by looking at plasma norepinephrine and 24-hour urinary norepinephrine and found them to be elevated in veterans with PTSD as compared to those without PTSD. PTSD is associated with hyperfunctioning of the central noradrenergic system. Hyperactivity of the sympathoadrenal axis might contribute to cardiovascular disease through the effects of the catecholamines on the heart, the vasculature and platelet function. A psychobiological model based on allostatic load has also been proposed and states that chronic stressors over long durations of time lead to increased neuroendocrine responses, which have adverse effects on the body. PTSD has also been shown to be associated with an increased prevalence of substance abuse. With this review, we have discussed the effects of PTSD on the cardiovascular system.