Multimodality Imaging for Diagnosis and Characterization of a Cardiac Hydatid Cyst.

Here, we report the case of a young patient admitted to the emergency department because of abdominal pain. Computed tomography revealed a mass within her right heart. Through serial multimodality imaging testing, including computed tomography, three-dimensional (2D)- and three-dimensional echocardiography, as well as cardiac magnetic resonance, the diagnosis of cardiac involvement in the course of Echinococcus granulosus infection was hypothesized.

Prevalence of extramedullary hematopoiesis, renal cysts, splenic and hepatic lesions, and vertebral hemangiomas among thalassemic patients: a retrospective study from the Myocardial Iron Overload in Thalassemia (MIOT) network.

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report.

Multicenter validation of the magnetic resonance T2* technique for quantification of pancreatic iron.

OBJECTIVES: To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for pancreatic iron overload assessment. METHODS: Multiecho T2* sequences were installed on ten 1.5-T MRI scanners of the three main vendors. Five healthy subjects (n = 50) were scanned at each site. Five patients with thalassemia (n = 45) were scanned locally at each site and were rescanned at the reference site within 1 month. T2* images were analyzed using a previously validated software and the global pancreatic T2* value was calculated as the mean of T2* values over the head, body, and tail. RESULTS: T2* values of healthy subjects were above 26 ms and showed inter-site homogeneity. The T2* values measured in the MRI sites were comparable to the correspondent values observed in the reference site (12.02 ± 10.20 ms vs 11.98 ± 10.47 ms; p = 0.808), and the correlation coefficient was 0.978 (p < 0.0001). Coefficients of variation (CoVs) ranged from 4.22 to 9.77%, and the CoV for all the T2* values independently from the sites was 8.55%. The intraclass correlation coefficient (ICC) for each MRI site was always excellent and the global ICC was 0.995, independently from the sites. The mean absolute difference in patients with pancreatic iron (n = 39) was -0.15 ± 1.38 ms. CONCLUSION: The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron and may be transferred among MRI scanners by different vendors in several centers. KEY POINTS: • The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron. • The gradient-echo T2* MRI technique for the quantification of pancreatic iron may be transferred among MRI scanners by different vendors in several centers. • Pancreatic iron might serve as an early predictor of cardiac siderosis and is the strongest overall predictor of glucose dysregulation.

Relationship between Regional Fat Distribution and Hypertrophic Cardiomyopathy Phenotype.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, is characterized by heterogeneous phenotypic expression. Body mass index has been associated with LV mass and heart failure symptoms in HCM. The aim of our study was to investigate whether regional (trunk, appendicular, epicardial) fat distribution and extent could be related to hypertrophy severity and pattern in HCM. METHODS: Cardiovascular magnetic resonance was performed in 32 subjects with echocardiography-based diagnosis of HCM (22M/10F, 57.2±12.6 years) characterized by predominant hypertrophy at the interventricular septum (IVS). Regional fat distribution was assessed by dual-energy X-ray absorptiometry. RESULTS: Gender differences were detected in maximum IVS thickness (M: 18.3±3.8 mm vs. F: 14.3±4 mm, p = 0.012), right ventricle (RV) systolic function (M: 61.3±6.7%; F: 67.5±6.3%, p = 0.048), indexed RV end-diastolic (M: 64.8±16.3 ml/m2; F: 50.7±15.5 ml/m2, p = 0.04) and end-systolic volumes (M: 24.3±8.3 ml/m2; F: 16.7±7.4 ml/m2, p = 0.04). After adjusting for age and gender, maximum IVS thickness was associated with truncal fat (Tr-FAT) (ß = 0.43, p = 0.02), but not with either appendicular or epicardial fat. Epicardial fat resulted independently associated with NT-proBNP levels (ß = 0.63, p = 0.04). Late Gadolinium Enhancement-positive subjects displayed greater maximum IVS thickness (p = 0.02), LV mass index (p = 0.015) and NT-proBNP levels (p = 0.04), but no associations with fat amount or distribution were observed. CONCLUSION: Truncal, but not appendicular or epicardial fat amount, seems to be related with maximum IVS thickness, the hallmark feature in our cohort of HCM patients. Further prospective researches are needed to assess a potential causative effect of central adiposity on HCM phenotype.

Faster drug approval: challenges for safety.

INTRODUCTION: More rapid drug premarketing procedures pose a challenge for regulatory agencies in terms of innovation and improving real-world safety and effectiveness Areas covered: This review considers the blockbuster drugs used over the previous fifteen years with adverse reactions after marketing, the elements and time span of risk identification and the measures implemented or considered, based on the existing literature and reports from the agencies Expert opinion: Risk prediction is founded on several factors: randomization, sample size, a well-established endpoint for safety, use of a comparator rather than placebo and a longer Phase-III period, in which a serious illness may be identified by early signs of alteration in the primary parenchyma with the latest biochemical, instrumental and imaging techniques. In comparative non-inferiority evaluations, increased safety should be preferred, with the exception of drugs that may be useful in serious or life-threatening diseases for which there are few or no effective existing therapies. A period of restricted use may be required to test and dispense new drugs, as well as to implement specific methods for the early detection of adverse events. It is important not to regard a new medicine axiomatically as the best treatment before it comes into wide use.

Holmium Laser Enucleation of the Prostate and Iatrogenic Arteriovenous Fistula Treated by Superselective Arterial Embolization.

Iatrogenic pelvic pseudoaneurysm with concomitant arteriovenous fistula has been described as a rare and challenging complication, which may occur during transurethral resection of the prostate. We provide the first report of this complication after holmium laser enucleation of the prostate for the treatment of benign prostatic hyperplasia. The attempt to control the bleeding by conversion to open surgery and placement of haemostatic stitches into the prostatic fossa failed. Angiography with superselective arterial embolization proved to be a modern, quick, safe, and efficient treatment of this uncommon complication.

Age-related different relationships between ectopic adipose tissues and measures of central obesity in sedentary subjects.

Accumulation of fat at ectopic sites has been gaining attention as pivotal contributor of insulin resistance, metabolic syndrome and related cardiovascular complications. Intermuscular adipose tissue (IMAT), located between skeletal muscle bundles and beneath muscle fascia, has been linked to physical inactivity, ageing and body mass index, but little is known about its relationship with the other AT compartments, in particular with increasing age. To address this issue, erector spinae IMAT, epicardial (EAT), intraabdominal (IAAT) and abdominal subcutaneous adipose tissue (SAT) were simultaneously measured by Magnetic Resonance Imaging (MRI) and related to waist circumference measurements and age in 32 sedentary subjects without cardiovascular disease (18 men; 14 women; mean age 48.5 ± 14 years). Fasting glucose, triglycerides and HDL-cholesterol were also assessed. We observed that, after dividing individuals according to age (≤ or > 50 years), IMAT and EAT depots were significantly more expanded in older subjects (63.2 ± 8.3 years) than in the younger ones (38.4 ± 5.2 years) (p < 0.001). Overall, both IMAT and EAT showed stronger positive associations with increasing age (ß = 0.63 and 0.67, respectively, p < 0.001 for both) than with waist circumference (ß = 0.55 and 0.49, respectively, p < 0.01 for both) after adjusting for gender. In addition, the gender-adjusted associations of IMAT and EAT with waist circumference and IAAT were significant in individuals ≤ 50 years only (p<0.05 for all) and not in the older ones. In contrast, no age-related differences were seen in the relationships of IAAT and SAT with waist circumference. Finally, serum triglycerides levels turned out not to be independently related with ectopic IMAT and EAT. In conclusion, the expansion of IMAT and EAT in sedentary subjects is more strongly related to age than waist circumference, and a positive association of these ectopic depots with waist circumference and IAAT amount can be postulated in younger individuals only.

Cardiac magnetic resonance detection of left ventricular thrombus in acute myocardial infarction.

INTRODUCTION: Left ventricular thrombosis (LVT) is a possible complication of acute myocardial infarction. Aim of our study was to evaluate incidence and clinical characteristics of patients with LVT after ST elevation myocardial infarction (STEMI) using contrast- enhanced magnetic resonance (CMR). METHODS AND RESULTS: In a prospective cohort of 36 consecutive patients with STEMI acutely reperfused with primary percutaneous coronary intervention, CMR was performed within one week. LVT was found in 7 patients (19%), and was located in left ventricle apex or adherent to antero-septum. Compared to the rest of population patients with LVT have lower ejection fraction (38 ± 7% versus 51 ± 6%, P = 0.009), larger left ventricle end systolic volume (95.8 ± 19 ml versus 68.9 ± 19 ml, P = 0.02), higher time to reperfusion (9.3 ± 7.2 versus 5 ± 3.6, P = 0.03) and left anterior descending artery was constantly involved (100% versus 41 %, P = 0.06). In 5 cases the LVT was also detected by echocardiography, however, in 2 cases it was missed. CONCLUSIONS: The incidence of LVT after STEMI is not negligible and was accurately detected by CMR. Localization of myocardial infarction, time to reperfusion, ejection fraction and left ventricle end systolic volume are the most important predictors of left ventricle thrombus formation.

Inhibition of lipid peroxidation and protein oxidation by endogenous and exogenous antioxidants in rat brain microsomes in vitro.

Reactive oxygen and reactive nitrogen species oxidize and nitrate DNA, lipid and proteins thus leading to neuronal death. Both endogenous and dietary antioxidants were shown to afford neuroprotection either by scavenging free radicals or inducing antioxidant enzymes. That said, the differential contribution of endogenous versus nutritional antioxidants to prevent neurodegeneration is still debated. In this study the free radical scavenging activity of two endogenous antioxidants, such as bilirubin and its precursor biliverdin, was compared with that of the dietary antioxidant alpha-tocopherol in rat brain microsomes exposed to peroxyl radical or peroxynitrite in vitro. Bilirubin and biliverdin (1-200 µM) inhibited both peroxyl radical- and peroxynitrite-dependent lipid peroxidation with a greater potency and efficacy than alpha-tocopherol. However, both BV and BR displayed greater potency and efficacy in preventing peroxynitrite- than peroxyl radical-induced lipid peroxidation. The greater antioxidant effect of both bilirubin and biliverdin than alpha-tocopherol was also confirmed against peroxyl radical- and peroxynitrite-induced protein oxidation. In conclusion, both bilirubin and biliverdin exhibited a greater antioxidant activity than alpha-tocopherol in preventing oxidative stress damage in rat brain.

Percutaneous antegrade transarterial treatment of iatrogenic radial arteriovenous fistula.

Site of access vascular complications is infrequent after transradial interventions. We report the case of a 66-year-old man referred to our hospital because of right forearm swelling, oedema and pain with functional forearm disability, 1 year after a transradial primary percutaneous coronary intervention (PCI). The diagnostic and procedural issues are discussed. This is the first description of a successful and well-tolerated radial arteriovenous fistula (AVF) treatment by means of percutaneous antegrade approach with the use of a short introducer and a biocompatible covered stent.

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Pharmacologists and Alzheimer disease therapy: to boldly go where no scientist has gone before.

INTRODUCTION: Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Acetylcholinesterase inhibitors or NMDA glutamate receptor antagonists are currently used for the treatment of AD, but only the former have weak beneficial effects on cognitive function. AREAS COVERED: The aim of this review is to provide an overview of the main pharmacological features of both current drugs and new compounds which are still under clinical development for the treatment of AD. EXPERT OPINION: The discovery of new drugs acting at the early stage of AD could be considered as a 'medical need' and inhibitors of γ-secretase or monoclonal antibodies against Aß seemed good options. However, inhibitors of γ-secretase, that is, tarenflurbil or semagacestat, were discontinued due to their lack of cognitive improvement or unacceptable side effects. A careful evaluation of the risk:benefit ratio should be considered for monoclonal antibodies since, by increasing the disaggregation of fibrillar amyloid-ß-peptide (Aß), they could increase the neurotoxicity of soluble Aß oligomers. In conclusion, the discovery of new drugs efficacious in AD subjects is an ambitious goal, however, and one that will require close, active collaboration by pharmacologists, chemists and clinicians.

Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer's disease and amnestic mild cognitive impairment.

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders.

Influenza pharmacotherapy: present situation, strategies and hopes.

INTRODUCTION: Influenza is a serious health threat for people of all ages. The causative virus is evolving continuously and the risk of an unexpected mutant, which cannot be controlled by seasonal vaccination, is real. New and more effective antiviral drugs are needed. AREAS COVERED: This review examines the antiviral drugs with confirmed efficacy in combating influenza, as well as newer compounds that are currently undergoing testing and will hopefully be marketed in the near future. A comprehensive, state-of-the-art picture of drug therapy for influenza is presented, including novel solutions and effective strategies for prescribing currently available antiviral drugs, with emphasis on the importance of updated local epidemiological data, clinical assessment and laboratory testing. EXPERT OPINION: Current anti-influenza drug research is no longer tied solely to viral envelope protein targets like haemagglutinin and neuraminidase. New drugs act on the viral RNA polymerase complex, which is involved in transcription and replication of the viral genome, and can prevent the maturation, replication and dissemination of numerous viral subtypes. Combating this infection and reducing the duration of symptoms also has important socioeconomic implications related to health-care spending (including hospitalization for complications) and sick-leave pay for workers.

Biliverdin reductase--a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment.

Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment.

Roles of nitric oxide, carbon monoxide, and hydrogen sulfide in the regulation of the hypothalamic-pituitary-adrenal axis.

The importance of stress in modifying human behavior and lifestyle is no longer a matter of debate. Although mild stress enhances the immune response and prevents infections, prolonged stress seems to play pathogenic roles in depression and neurodegenerative disorders. The body has developed an adaptive stress response consisting of cardiovascular, metabolic, and psychological changes, which act in concert to eliminate stressors. One of the major components of this response is the hypothalamic-pituitary-adrenal axis, also known as the stress axis. Over the last 30 years, many studies have documented the integrated stress-axis regulation by neurotransmitters. They have also demonstrated that gaseous neuromodulators, such as NO, CO, and H(2)S, regulate the hypothalamic release of neuropeptides. The specific effects (stimulatory vs. inhibitory) of these gases on the stress axis varies, depending on the type of stress (neurogenic or immuno-inflammatory), its intensity (low or high), and the species studied (rodents or humans). This review examines the complex roles of NO, CO, and H(2)S in modulation of stress-axis activity, with particular emphasis on the regulatory effects they exert at the hypothalamic level.

Effects of olanzapine and quetiapine on corticotropin-releasing hormone release in the rat brain.

An altered regulation of the corticotropin-releasing hormone (CRH) system in the CNS is consistently associated with anxiety and depression; several drugs used to treat CNS disorders modulate--usually in a negative manner--CRH turnover in the brain, and it can be postulated that their effectiveness may be at least in part related to their effects on CRH. This study was aimed to investigate the effects of two atypical antipsychotics also employed in the treatment of bipolar disorders, i.e. quetiapine (QTP) and olanzapine (OLZ), on CRH release from isolated rat brain regions. Acute rat hypothalamic and hippocampal explants were exposed for 1 h to plain medium or medium containing the test drugs, either under baseline conditions or after stimulation of CRH release by veratridine or 56 mM KCl. CRH immunoreactivity present in the incubation medium and in the tissues was assessed by radioimmunoassay. QTP 10 microM but not OLZ inhibited baseline CRH secretion from the hypothalamus; neither drug affected basal CRH release from the hippocampus. Both QTP and OLZ, 1 and 10 microM, inhibited veratridine- or K(+)-stimulated CRH release from the hypothalamus, whereas OLZ only, when given at 10 microM, was able to inhibit stimulated CRH release from the hippocampus. In conclusion, two widely used atypical antipsychotics, QTP and OLZ are able to acutely reduce the release of CRH from isolated rat hypothalami and hippocampi.

Characterization of the S-denitrosylating activity of bilirubin.

Bilirubin-IX-alpha (BR) is an endogenous molecule with a strong antioxidant feature due to its ability to scavenge free radicals. In this paper, we demonstrated that BR, at concentrations close to those found within the cell (0.1-2.5 microM), acted as a denitrosylating agent and increased the release of nitric oxide from S-nitrosoglutathione (GSNO) and S-nitrosocysteine (SNOC) (2.5 microM). The complexation of BR with saturating concentrations of human serum albumin (HSA, 2.5 microM) did not further increase nitric oxide release from GSNO and SNOC. At concentrations similar to those reached in plasma (5-20 microM), BR denitrosylated S-nitroso-HSA (2.5 microM), the main circulating S-nitrosothiol, and this effect was potentiated by the complexation of BR with saturating HSA (20 microM). Furthermore, the product(s) of the reaction between nitric oxide and BR were identified. Ultraviolet and mass spectrometry analysis revealed that nitric oxide binds to BR forming a N-nitroso derivative (BR-nitric oxide) with extinction coefficients of 1.393 mM(-1)cm(-1) and 2.254 mM(-1)cm(-1) in methanol and NaOH, respectively. The formation of BR-nitric oxide did not occur only in a reconstituted system, but was confirmed in rat fibroblasts exposed to pro-oxidant stimuli. These results provided novel insights on the antioxidant characteristic of BR through its interaction with nitric oxide, a gaseous neurotransmitter with a well-known dual effect, namely neuroprotective under physiological conditions or neurotoxic if produced in excess, and proposed BR-nitric oxide as a new biomarker of oxidative/nitrosative stress.

Bilirubin as an endogenous modulator of neurotrophin redox signaling.

Bilirubin is neurotoxic upon excess accumulation in the brain, but it also plays important physiological roles related to its antioxidant properties. Here we report that exposure of PC12 and primary rat cerebellar granule neurons to bilirubin (0.5-10 microM) drastically decreases nerve growth factor (NGF)/brain-derived neurotrophic factor signaling to Akt and extracellular signal-regulated kinases (ERKs), indicating a direct interference of the molecule with crucial prosurvival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, the latter being able to inhibit, in PC12 cells, accumulation of intracellular reactive oxygen species and phosphorylation of Akt and ERKs in response to extracellular hydrogen peroxide. Interestingly, in the absence of exogenous growth factor, bilirubin elicited the phosphorylation of ERKs and of the cAMP responsive element binding (CREB) transcription factor, a signature of NGF-dependent survival signaling. These growth factor-like signaling effects were paralleled by the induction of the neuronal nitric oxide synthase (nNOS) and generation of nitric oxide (NO). Pharmacological dissection of the signaling cascade triggered by bilirubin revealed that phosphorylation of ERKs requires NO signaling through soluble guanylyl cyclase, and, further upstream, influx of extracellular calcium is necessary for nNOS induction and NO release, likely through calcium-dependent phosphorylation of CREB. Importantly, the cascade elicited by bilirubin through NO and ERK is cytoprotective, as revealed by exacerbated bilirubin toxicity in cultures treated by either NOS or MEK inhibitors. Taken together, these observations indicate an important action of bilirubin on redox signaling by neurotrophins, with either inhibitory or agonistic effects based on growth factor availability.