Disruption of vitellogenesis and spermatogenesis by triclabendazole (TCBZ) in a TCBZ-resistant isolate of Fasciola hepatica following incubation in vitro with a P-glycoprotein inhibitor.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Sligo TCBZ-resistant fluke isolate was used for these experiments and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. In the first experiment, flukes were initially incubated for 2 h in R(+)-VPL (100 µ m), then incubated in R(+)-VPL+triclabendazole sulphoxide (TCBZ.SO) (50 µg mL-1, or 133·1 µ m) until flukes ceased movement (at 9 h post-treatment). In a second experiment, flukes were incubated in TCBZ.SO alone and removed from the incubation medium following cessation of motility (after 15 h). In the third experiment, flukes were incubated for 24 h in R(+)-VPL on its own. Changes to the testis tubules and vitelline follicles following drug treatment and following Pgp inhibition were assessed by means of light microscope histology and transmission electron microscopy. Incubation of the Sligo isolate in either R(+)-VPL or TCBZ.SO on their own had a limited impact on the morphology of the two tissues. Greater disruption was observed when the drugs were combined, in terms of the block in development of the spermatogenic and vitelline cells and the apoptotic breakdown of the remaining cells. Sperm formation was severely affected and abnormal. Large spaces appeared in the vitelline follicles and synthesis of shell protein was disrupted. The results of this study support the concept of altered drug efflux in TCBZ-resistant flukes and indicate that drug transporters may play a role in the development of drug resistance.

The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiovascular disorder. Although many HCM patients remain asymptomatic, sudden death (SD) can occur as the initial manifestation of the disease. It has been hypothesized that myocardial architectural disorganization and scarring represent an unstable electrophysiological substrate that creates susceptibility to malignant ventricular arrhythmias. Cardiovascular magnetic resonance imaging (CMR) is widely used for the diagnosis of HCM, especially in patients with an incomplete or inconclusive echocardiography study. CMR can provide precise non-invasive assessment of biventricular function, wall thickness, and assessment of myocardial fibrosis, using inversion recovery gadolinium-enhanced sequences. CMR is also one of the most promising avenues of research in HCM, and in recent years, has provided many new insights and identified a number of potential adverse prognostic indicators for SD. Future work is still needed to integrate CMR findings into traditional risk assessment algorithms. This paper reviews the evolving role of CMR for risk stratification in HCM including assessment of myocardial hypertrophy, fibrosis and ischaemia.

Increased susceptibility of a triclabendazole (TCBZ)-resistant isolate of Fasciola hepatica to TCBZ following co-incubation in vitro with the P-glycoprotein inhibitor, R(+)-verapamil.

A study was carried out to investigate whether the action of triclabendazole sulphoxide (TCBZ.SO) against the liver fluke, Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for this in vitro study and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. For experiments with the Oberon isolate, flukes were incubated for 24 h with either R(+)-VPL (1×10-4 m) on its own, TCBZ.SO (15 µg mL-1) alone, a combination of R(+)-VPL (1×10-4 m) plus TCBZ.SO (15 µg mL-1), TCBZ.SO (50 µg mL-1) on its own, or a combination of TCBZ.SO (50 µg mL-1) plus R(+)-VPL (1×10-4 m). They were also incubated in TCBZ.SO (50 µg mL-1) alone or in combination with R(+)-VPL (1×10-4 m) until they became inactive; and in TCBZ.SO (50 µg mL-1) alone for a time to match that of the combination inactivity time. Flukes from the Cullompton isolate were treated with either TCBZ.SO (50 µg mL-1) alone or in combination with R(+)-VPL (1×10-4 m) until they became inactive, or with TCBZ.SO (50 µg mL-1) alone time-matched to the combination inactivity time. Morphological changes resulting from drug treatment and following Pgp inhibition were assessed by means of scanning electron microscopy. Incubation in R(+)-VPL alone had a minimal effect on either isolate. TCBZ.SO treatment had a relatively greater impact on the TCBZ-susceptible Cullompton isolate. When R(+)-VPL was combined with TCBZ.SO in the incubation medium, however, the surface disruption to both isolates was more severe than that seen after TCBZ.SO treatment alone; also, the time taken to reach inactivity was shorter. More significantly, though, the potentiation of drug activity was greater in the Oberon isolate; also, it was more distinct at the higher concentration of TCBZ.SO. So, the Oberon isolate appears to be particularly sensitive to efflux pump inhibition. The results of this study suggest that enhanced drug efflux in the Oberon isolate may be involved in the mechanism of resistance to TCBZ.

Imaging of the aortic valve with MRI and CT angiography.

The aortic valve may be affected by a wide range of congenital and acquired diseases. Echocardiography is the main non-invasive imaging technique for assessing patho-anatomical alterations of the aortic valve and adjacent structures and in many cases is sufficient to establish a diagnosis and/or guide treatment decisions. Recent technological advances in magnetic resonance imaging (MRI) and multidetector computed tomography (MDCT) have enabled these techniques to play a complimentary role in certain clinical scenarios and as such can be useful problem-solving tools. Radiologists should be familiar with the indications, advantages, and limitations of MRI and MDCT in order to advise and direct an appropriate imaging strategy depending upon the clinical scenario. This article reviews the role of MRI and MDCT angiography for assessment of the aortic valve including relevant anatomy, scan acquisition protocols, and post-processing methods. An approach to interpretation and the key imaging features of commonly encountered aortic valvular diseases are discussed.

The emerging role of cardiovascular MRI for suspected cardioembolic stroke.

Stroke is a leading cause of morbidity and long-term disability worldwide and is often the result of embolic material from the heart or proximal aorta. These are referred to as cardioembolic sources of stroke. The investigation of patients with suspected cardioembolic stroke has traditionally been the mainstay of echocardiography. Cardiac magnetic resonance imaging (MRI) is a powerful imaging technique that has rapidly evolved over the last decade and is playing an ever increasing role in clinical cardiovascular imaging. This review of the literature aims to furnish the reader with an understanding of the role of cardiac MRI across the spectrum of causes of cardioembolic sources of stroke by providing the reader with an overview of the indications, technical considerations, a proposed imaging algorithm, and capabilities of this technology with selected illustrated examples of disease entities.

Increased action of triclabendazole (TCBZ) in vitro against a TCBZ-resistant isolate of Fasciola hepatica following its co-incubation with the P-glycoprotein inhibitor, R(+)-verapamil.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Sligo TCBZ-resistant fluke isolate was used for these experiments and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. In the first experiment, flukes were initially incubated for 2h in R(+)-VPL (1×10(-4) M), then incubated in R(+)-VPL + triclabendazole sulphoxide (TCBZ.SO) (50µg/ml) until flukes ceased movement (at 9h post-treatment). In a second experiment, flukes were incubated in TCBZ.SO alone and removed from the incubation medium following cessation of motility (after 15h). In the third experiment, flukes were incubated for 24h in R(+)-VPL on its own. Changes to the tegumental system and gut following drug treatment and following Pgp inhibition were assessed by means of light microscope histology and transmission electron microscopy. Incubation of the Sligo isolate in either R(+)-VPL or TCBZ.SO on their own had a limited impact on the tegumental syncytium and tegumental cells; the changes were consistent with a stress response by the fluke to drug action. Greater disruption was observed when the drugs were combined, in terms of the vacuolation and sloughing of the syncytium, spine disruption and the cessation of secretory activity in, and degradation of, the tegumental cells. In the gut, treatment with R(+)-VPL on its own did not lead to any cellular changes. Some limited changes to the mitochondria and the granular endoplasmic reticulum were observed after incubation in TCBZ.SO alone, together with reduced secretory activity and evidence of autophagy. However, these changes were far more pronounced in combination-treated flukes. The results of this study support the concept of altered drug efflux in TCBZ-resistant flukes and indicate that drug transporters may play a role in the development of drug resistance.

Pain management in spinal metastases: the role of percutaneous vertebral augmentation.

Recent technological advances combined with innovative interventional radiology techniques can now offer an alternative less invasive treatment option for many patients with malignant vertebral body infiltration. Percutaneous vertebral augmentation procedures offer less invasive but effective pain relief to many patients with symptomatic spinal metastatic disease. The procedures are image guided and involve the injection of polymethylmethacrylate bone cement into the effected vertebral body. This technique can also be combined with radiofrequency ablation, which may accelerate vertebral stability. In this review, we examine the recent literature surrounding this topic and provide an overview of these emerging techniques.

Population dynamics of the liver fluke, Fasciola hepatica: the effect of time and spatial separation on the genetic diversity of fluke populations in the Netherlands.

An evaluation of the genetic diversity within Fasciola hepatica (liver fluke) may provide an insight into its potential to respond to environmental changes, such as anthelmintic use or climate change. In this study, we determined the mitochondrial DNA haplotypes of > 400 flukes from 29 individual cattle, from 2 farms in the Netherlands, as an exemplar of fasciolosis in a European context. Analysis of this dataset has provided us with a measure of the genetic variation within infrapopulations (individual hosts) and the diversity between infrapopulations within a herd of cattle. Temporal sampling from one farm allowed for the measurement of the stability of genetic variation at a single location, whilst the comparison between the two farms provided information on the variation in relation to distance and previous anthelmintic regimes. We showed that the liver fluke population in this region is predominantly linked to 2 distinct clades. Individual infrapopulations contain a leptokurtic distribution of genetically diverse flukes. The haplotypes present on a farm have been shown to change significantly over a relatively short time-period.

Piperonyl butoxide enhances triclabendazole action against triclabendazole-resistant Fasciola hepatica.

A study has been carried out to determine whether the action of triclabendazole (TCBZ) against the liver fluke, Fasciola hepatica is altered by inhibition of the cytochrome P450 (CYP 450)-mediated drug metabolism pathway. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for these experiments, the basic design of which is given in the paper by Devine et al. (2010a). Piperonyl butoxide (PB) was the CYP P450 inhibitor used. Morphological changes resulting from drug treatment and following metabolic inhibition were assessed by means of transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with PB+TCBZ, but more particularly PB+TCBZ.SO, led to greater changes to the TCBZ-resistant isolate than with each drug on its own, with blebbing of the apical plasma membrane, severe swelling of the basal infolds and their associated mucopolysaccharide masses in the syncytium and flooding in the internal tissues. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis and production of secretory bodies were badly disrupted. The mitochondria were swollen throughout the tegumental system and the somatic muscle blocks were disrupted. With the TCBZ-susceptible Cullompton isolate, there was a limited increase in drug action following co-incubation with PB. The results provide evidence that the condition of a TCBZ-resistant fluke can be altered by inhibition of drug metabolism. Moreover, they support the concept that altered drug metabolism contributes to the mechanism of resistance to TCBZ.

Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 µM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ + NADPH + TCBZ (15 µg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15 µg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: in the syncytium, for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Erratum to: inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 µM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ + NADPH + TCBZ (15 µg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15 µg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Inhibition of cytochrome P450-mediated metabolism enhances ex vivo susceptibility of Fasciola hepatica to triclabendazole.

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP P450) system was inhibited using piperonyl butoxide (PB). The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP P450 system was inhibited by a 2 h pre-incubation in PB (100 mum). Flukes were then incubated for a further 22 h in NCTC medium containing either PB; PB+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nm); PB+NADPH+TCBZ (15 microg/ml); or PB+NADPH+TCBZ.SO (15 microg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater disruption to the TCBZ-susceptible than the resistant isolate. However, co-incubation with PB and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant Oberon isolate than with each drug on its own. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action, and only with TCBZ.SO. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Multi-technique imaging of sarcoidosis.

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. The diagnosis is suggested on the basis of wide ranging clinical and radiological manifestations, and is supported by the histological demonstration of non-caseating granulomas in affected tissues. This review highlights the multisystem radiological features of the disease across a variety of imaging methods including multidetector computed tomography (CT), magnetic resonance imaging (MRI) as well as functional radionuclide techniques, particularly 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT). It is important for the radiologist to be aware of the varied radiological manifestations of sarcoidosis in order to recognize and suggest the diagnosis in the appropriate clinical setting.

Transcatheter coil embolisation: a novel definitive treatment option for intralobar pulmonary sequestration.

Pulmonary sequestrations have been conventionally treated surgically with removal of the tissue mass and ligation of its feeding vessels. There is established evidence to support the use of transcatheter arterial coil embolisation as an effective definitive treatment option for extralobar sequestration especially in the paediatric literature describing good long-term clinical outcomes. We present a case of an adult with intralobar sequestration in whom the diagnosis was established with multi-detector computed tomography (MDCT) and in whom transcatheter arterial coil embolisation was successfully performed as a definitive treatment option to support the growing body of evidence of transcatheter arterial coil embolisation as a safe and effective treatment option for both form of pulmonary sequestrations.

Effect of the metabolic inhibitor, methimazole on the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica.

SUMMARY: A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered in the presence of a metabolic inhibitor. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-sensitive isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 microM). Flukes were then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 microg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 microg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater surface disruption to the triclabendazole-susceptible than -resistant isolate. However, co-incubation with MTZ and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant isolate than with each drug on its own; this was not seen for the TCBZ-susceptible Cullompton isolate. Results of this study support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

MRI and CT appearances of cardiac tumours in adults.

Primary cardiac tumours are rare, and metastases to the heart are much more frequent. Myxoma is the commonest benign primary tumour and sarcomas account for the majority of malignant lesions. Clinical manifestations are diverse, non-specific, and governed by the location, size, and aggressiveness. Imaging plays a central role in their evaluation, and familiarity with characteristic features is essential to generate a meaningful differential diagnosis. Cardiac magnetic resonance imaging (MRI) has become the reference technique for evaluation of a suspected cardiac mass. Computed tomography (CT) provides complementary information and, with the advent of electrocardiographic gating, has become a powerful tool in its own right for cardiac morphological assessment. This paper reviews the MRI and CT features of primary and secondary cardiac malignancy. Important differential considerations and potential diagnostic pitfalls are also highlighted.

Radiology errors: are we learning from our mistakes?

AIM: To question practising radiologists and radiology trainees at a large international meeting in an attempt to survey individuals about error reporting. MATERIALS AND METHODS: Radiologists attending the 2007 Radiological Society of North America (RSNA) annual meeting were approached to fill in a written questionnaire. Participants were questioned as to their grade, country in which they practised, and subspecialty interest. They were asked whether they kept a personal log of their errors (with an error defined as "a mistake that has management implications for the patient"), how many errors they had made in the preceding 12 months, and the types of errors that had occurred. They were also asked whether their local department held regular discrepancy/errors meetings, how many they had attended in the preceding 12 months, and the perceived atmosphere at these meetings (on a qualitative scale). RESULTS: A total of 301 radiologists with a wide range of specialty interests from 32 countries agreed to take part. One hundred and sixty-six of 301 (55%) of responders were consultant/attending grade. One hundred and thirty-five of 301 (45%) were residents/fellows. Fifty-nine of 301 (20%) of responders kept a personal record of their errors. The number of errors made per person per year ranged from none (2%) to 16 or more (7%). The majority (91%) reported making between one and 15 errors/year. Overcalls (40%), under-calls (25%), and interpretation error (15%) were the predominant error types. One hundred and seventy-eight of 301 (59%) of participants stated that their department held regular errors meeting. One hundred and twenty-seven of 301 (42%) had attended three or more meetings in the preceding year. The majority (55%) who had attended errors meetings described the atmosphere as "educational." Only a small minority (2%) described the atmosphere as "poor" meaning non-educational and/or blameful. CONCLUSION: Despite the undeniable importance of learning from errors, many radiologists and institutions do not engage in such practice. Radiologists and radiology departments must continue to improve the process of recording and addressing errors.

MDCT features of cardiothoracic sources of stroke.

Multidetector computed tomography (MDCT) is widely used in the assessment of cardiothoracic disease and provides high-resolution images of the heart, great vessels, and lungs. A range of cardiothoracic conditions can precipitate stroke, including intracardiac thrombus, right-to-left shunts, and diseases of the thoracic aorta. Many of these conditions may be identified on non-electrocardiogram (ECG)-gated studies, but the advent of high temporal resolution ECG-gated MDCT provides superior anatomical delineation. Radiologists should be familiar with the pathogenesis and CT features of cardiothoracic conditions that can precipitate stroke as their early identification to enables appropriate management and prognostic decisions.

Chronic left ventricular failure: the role of imaging in diagnosis and planning of conventional and novel therapies.

Heart failure is the leading cause of hospitalisation in the UK, and its prevalence is expected to increase further in the future due partly to an aging population. Although pharmacological agents remain the mainstay of therapy, an increasing number of surgical and novel minimally invasive interventions have been developed for the treatment of both acute and chronic heart failure. Imaging is essential for diagnosis, guiding therapeutic options, and monitoring therapy and its complications. As a result, radiologists should be familiar with the pathogenesis, treatment options, and imaging-related issues pertaining to the management of these patients.

CT appearances of pleural tumours.

Computed tomography (CT) is the imaging technique of choice for characterizing pleural masses with respect to their location, composition, and extent. CT also provides important information regarding invasion of the chest wall and surrounding structures. A spectrum of tumours can affect the pleura of which metastatic adenocarcinoma is the commonest cause of malignant pleural disease, while malignant mesothelioma is the most common primary pleural tumour. Certain CT features help differentiate benign from malignant processes. This pictorial review highlights the salient CT appearances of a range of tumours that may affect the pleura.