Evaluating patient perspectives of endovascular created arteriovenous fistulas for dialysis access (EndoAVF).

BACKGROUND: Patient reported experience measures are contemporary quality indicators that focus on evaluation of healthcare delivery processes. While surgical arteriovenous fistulas (otherAVF) are preferred for haemodialysis vascular access, fears about surgery and complications often result in refusal/delays. A new technique of endovascular arteriovenous fistula creation (EndoAVF) has been developed and as part of it's ongoing introduction into our unit, the patient perspective was felt critical to its evaluation. The Vascular Access Questionnaire (VAQ) provides a mechanism for identifying and scoring perceptions in this setting. METHOD: Patients who had previously undergone EndoAVF formation were approached to undertake the VAQ as part of a service evaluation of their experience. In addition to the components of the VAQ, data questions relating to the patient's perception of their access were gathered. Results were compared with a matched historical cohort of surgically created fistulas (otherAVF) patients. RESULTS: Patient satisfaction and self-reported ease of use with EndoAVF were high. Overall VAQ scores were similar between the EndoAVF and the surgically created cohort. Functionally, there was no significant difference in perception of their fistula by patients, irrespective of them being created surgically or radiologically. CONCLUSION: Although numbers in this report are small limiting exploration of preserved inherent heterogeneity, we provide a useful initial patient reported experience and perspectives on comparative functional use of radiologically and surgically created AVFs. As real world experience gathers, future larger cohorts with adequate sampling may allow exploration of patient reported experiences and outcome measures.

LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis.

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

A Review on the Hemodialysis Reliable Outflow (HeRO) Graft for Haemodialysis Vascular Access.

OBJECTIVES: With improved dialysis survival there are increasing numbers of patients who have exhausted definitive access options due to central venous stenosis and are maintaining dialysis on a central venous catheter. The Hemodialysis Reliable Outflow (HeRO) allows an alternative by providing a definitive access solution. The aim of this study is to systematically review the published outcomes of the HeRO graft and discuss the role in complex haemodialysis patients. METHODS: Electronic databases were searched for studies assessing the use of the HeRO graft for dialysis in accordance with PRISMA published up to December 31 2014. The primary outcomes for this study were 1-year primary and secondary patency rates. Secondary outcomes were rates of dialysis access associated steal syndrome, HeRO-related bacteraemia rates and rates of interventions. RESULTS: Following strict inclusion/exclusion criteria, eight studies including 409 patients were included in our review. Primary and secondary pooled patency rates in this complex cohort of dialysis patients were found to be 21.9% (9.6-37.2%) and 59.4% (39.4-78%). The rate of dialysis access associated steal syndrome was low at 6.3% (1-14.7%) as was the range of HeRO-related bacteraemia (0.13-0.7 events per 1000 days). CONCLUSIONS: This literature review shows that the HeRO graft is an acceptable option for complex dialysis patients who are catheter dependent. Owing to device availability, published data are predominantly North American and further longer-term studies in other populations may be necessary. In this challenging patient group, randomized controlled trials are required to allow comparisons with alternative access options.

Central venous obstruction in the thorax.

Central venous stenosis and occlusion can occur secondary to a spectrum of conditions ranging from aggressive malignancy to benign extrinsic anatomical compression in otherwise healthy individuals. Irrespective of aetiology, significant morbidity in the acute setting and long term can occur unless prompt accurate diagnosis and appropriate management is initiated, the radiologist being central to both. The present review will provide radiologists with a thorough illustration and explanation of the range of central venous conditions in the thorax (including deep vein thrombosis, thoracic outlet syndrome, haemodialysis, and malignancy related causes), the salient imaging findings and interventional management using case examples from the authors' practice.

Emergency treatment of haemorrhaging coeliac or mesenteric artery aneurysms and pseudoaneurysms in the era of endovascular management.

OBJECTIVES: Patients requiring emergency treatment of visceral artery aneurysms (VAAs) can be treated by endovascular or surgical techniques. Outcomes after failed attempts at endovascular control are unclear as is the present role of surgery. This study reviewed treatment and outcomes of a contemporary cohort of patients with symptomatic VAAs at a tertiary referral centre. METHODS: Patients undergoing emergency treatment of a VAA of the coeliac, mesenteric arteries, or their branches were identified over a 5-year period. Patient variables, treatments, and outcomes were assessed. RESULTS: Forty-eight patients underwent 65 radiological and two surgical procedures. Pseuodaneuryms were present in 45 (94%) of patients. Interventional radiology procedures were the initial treatment in every patient. The initial success was 40 out of 48 (83%). Patients requiring more than one procedure were all successfully treated. Regarding initial failures, if the VAA sac could not be accessed at angiography an alternative procedure to control the VAA was required in every case. If initial endovascular treatment failed, repeating the same procedure was successful in half of the patients. Ultrasound-guided percutaneous VAA embolisation was used in four patients. The 30-day mortality was eight out of 48 (17%). There were four recorded complications including one death directly attributable to VAA treatment. CONCLUSIONS: Patients needing emergency treatment of a VAA could be well served by non-surgical management. When the initial attempt at control of bleeding is unsuccessful it is important to consider non-conventional means of accessing these arteries. The need for surgery, in selected centres, may exist for a small group of patients after initial failed radiological treatment only.

Differential effects of AMPK agonists on cell growth and metabolism.

As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK dependence of six commonly used AMPK agonists (metformin, phenformin, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), 2-deoxy-D-glucose (2DG), salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity. Finally, contrary to the view of AMPK activity being tumor suppressive, we find that A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the antigrowth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution not only regarding the type of AMPK agonist proposed for cancer treatment but also the context in which they are used.

Inferior vena cava filters: what radiologists need to know.

Inferior vena cava (IVC) filters are a controversial mechanical adjunct in the prevention of pulmonary embolism, the most serious result of venous thromboembolism. Despite modern IVC filters being in clinical use for more than 45 years, there is still uncertainty amongst many radiologists about the indications for IVC filter placement and their removal, particularly the more recent prophylactic use in patients without confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). Recently published guidelines on filter use from the National Institute of Health and Clinical Excellence (NICE) and other professional bodies are discussed. The vast majority of IVC filters in the UK are inserted by interventional radiologists, so radiologists may be the first point of contact for information requested by other clinicians. The increasing use of filters means that radiologists will encounter filters increasingly often during abdominal cross-sectional imaging. Awareness of common filter-related complications, such as tilting, thrombosis, and caval perforation, is useful to reassure or alert other clinicians. The potential role of filters in upper extremity DVT and requirement for concomitant anticoagulation is discussed.

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model.

Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.

The TGF-ß-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells.

Transforming growth factor-ß (TGF-ß) maintains self-tolerance through a constitutive inhibitory effect on T-cell reactivity. In most physiological situations, the tolerogenic effects of TGF-ß depend on the canonical signaling molecule Smad3. To characterize how TGF-ß/Smad3 signaling contributes to maintenance of T-cell tolerance, we characterized the transcriptional landscape downstream of TGF-ß/Smad3 signaling in resting or activated CD4 T cells. We report that in the presence of TGF-ß, Smad3 modulates the expression of >400 transcripts. Notably, we identified 40 transcripts whose expression showed Smad3 dependence in both resting and activated cells. This 'signature' confirmed the non-redundant role of Smad3 in TGF-ß biology and identified both known and putative immunoregulatory genes. Moreover, we provide genomic and functional evidence that the TGF-ß/Smad3 pathway regulates T-cell activation and metabolism. In particular, we show that TGF-ß/Smad3 signaling dampens the effect of CD28 stimulation on T-cell growth and proliferation. The impact of TGF-ß/Smad3 signals on T-cell activation was similar to that of the mTOR inhibitor Rapamycin. Considering the importance of co-stimulation on the outcome of T-cell activation, we propose that TGF-ß-Smad3 signaling may maintain T-cell tolerance by suppressing co-stimulation-dependent mobilization of anabolic pathways.

Congenital anomalies of the inferior vena cava.

Congenital anomalies of the inferior vena cava (IVC) and its tributaries are increasingly recognized in asymptomatic patients due to the more frequent use of cross-sectional imaging and computed tomography (CT) in particular. IVC development is a complex process involving formation of anastomoses between three pairs of embryonic veins in the 4th to 8th week of gestation. Various permutations occur in the basic venous plan of the abdomen and pelvis resulting in variants such as isolated left IVC, double IVC, and retroaortic left renal vein. The majority of these anomalies are asymptomatic but occasionally present clinically with thromboembolic complications. However, awareness of their existence is important to avoid important diagnostic pitfalls and in preoperative surgical and interventional radiological planning.

Imaging and management of vascular malformations.

Vascular malformations are a diffuse collection of abnormalities that are usually present at birth but may present any time during childhood or as an adult. Historically terminology has been complicated and used interchangeably causing confusion to patients and clinicians alike; however, a structured internationally agreed classification system exists. It is not uncommon for patients with vascular malformations to be referred to various specialties without obtaining a correct diagnosis and appropriate treatment. Vascular malformations can occur anywhere within the body and all patients will require imaging at some stage; therefore, it is important for all radiologists to be aware of the correct terminology and imaging characteristics. This review discusses classification and illustrates salient imaging findings and the modern approach to treatment of vascular malformations.

The vapour of imidazolium-based ionic liquids: a mass spectrometry study.

Eight common dialkylimidazolium-based ionic liquids have been successfully evaporated in ultra-high vacuum and their vapours analysed by line of sight mass spectrometry using electron ionisation. The ionic liquids investigated were 1-alkyl-3-methylimidazolium bis[(trifluoromethane)sulfonyl]imide, [C(n)C(1)Im][Tf(2)N] (where n = 2, 4, 6, 8), 1-alkyl-3-methylimidazolium tetrafluoroborate, [C(n)C(1)Im][BF(4)] (where n = 4, 8), 1-butyl-3-methylimidazolium octylsulfate, [C(4)C(1)Im][C(8)OSO(3)] and 1-butyl-3-methylimidazolium tetrachloroferrate, [C(4)C(1)Im][FeCl(4)]. All ionic liquids studied here evaporated as neutral ion pairs; no evidence of decomposition products in the vapour phase were observed. Key fragment cations of the ionised vapour of the ionic liquids are identified. The appearance energies, E(app), of the parent cation were measured and used to estimate the ionisation energies, E(i), for the vapour phase neutral ion pairs. Measured ionisation energies ranged from 10.5 eV to 13.0 eV. Using both the identity and E(app) values, the fragmentation pathways for a number of fragment cations are postulated. It will be shown that the enthalpy of vaporisation, Δ(vap)H, can successfully be measured using more than one fragment cation, although caution is required as many fragment cations can also be formed by ionisation of decomposition products.

Phrenic nerve-hemidiaphragm as a highly sensitive replacement assay for determination of functional botulinum toxin antibodies.

Botulinum neurotoxins induce a prolonged muscle paralysis by specifically blocking the release of neuronal transmitters from peripheral nerve junctions. Potency testing of toxin and antitoxin therapies is entirely dependent on mouse lethality bioassay which is associated with extreme suffering of large numbers of animals to ensure high precision. The mouse phrenic nerve-diaphragm assay is an ex vivo assay that closely mimics in vivo respiratory paralysis offering substantial refinement and reduction in the number of animals used. A range of botulinum antitoxin standards, one licenced product and experimental antitoxins were tested for neutralising potency using ex vivo hemidiaphragm assay and compared with in vivo determined activities. Overall, there was an excellent agreement between neutralising activity detected by the two assay systems and for each toxin serotype using only 4-7 replicates for each product (almost perfect concordance for type A antitoxins: ρ = 0.997, and substantial concordance for type B antitoxins: ρ = 0.991 and type E antitoxins: ρ = 0.964, respectively). These findings confirm that the mouse nerve-diaphragm preparation can provide a functional ex vivo replacement assay for specific, sensitive and precise assessment of toxin and antitoxin activity.

Imaging of thoracic aortic disease.

Aortic pathology can be more complex to understand on imaging than is initially appreciated. There are a number of imaging modalities that provide excellent assessment of aortic pathology and enable the accurate monitoring of disease. This review discusses the imaging of the most common disease processes that affect the aorta in adults, with the primary focus being on CT and MRI.

Intravascular embolisation and surgical resection of a giant neurofibroma with intratumoural haemorrhage.

The use of pre-operative embolisation has been described for small neurofibromas, but not for giant lesions. Advances in embolisation techniques are extending the indications for this procedure, in particular to assist with operative intervention on a range of lesions. This case report describes a 45-year-old male with a giant neurofibroma who underwent embolisation to stabilise intratumoural haemorrhage and to assist with haemostasis during the subsequent surgical resection. Minimal transfusion was required and the patient has made a good recovery. This case demonstrates that pre-operative embolisation of these large and challenging lesions is technically feasible and appears to be beneficial in reducing perioperative blood loss and morbidity.

Measurement of botulinum types A, B and E neurotoxicity using the phrenic nerve-hemidiaphragm: improved precision with in-bred mice.

Botulinum neurotoxins induce a prolonged muscle paralysis by specifically blocking the release of neuronal transmitters from peripheral nerve junctions. The current method for assessing the potency of botulinum toxin and antitoxins is the mouse LD50 assay. The mouse phrenic nerve-diaphragm assay is an in vitro assay that closely mimics in vivo respiratory paralysis. In this study, we have further improved the assay by using gelatin as a non-frothing alternative to albumin and investigated the effects of botulinum toxin serotypes A, B and E on phrenic nerve-hemidiaphragms from out-bred MF1 and in-bred Balb/c mice. Improved reproducibility was found with in-bred mice. Balb/c mice were also found to be much less sensitive to type B toxin perhaps indicating differences in the expression of receptor components. Hemidiaphragm preparations from Balb/c mice were approximately 7 times more sensitive to type A toxin and 7-12 times more sensitive to type E toxin relative to type B toxin. These findings indicate that when fully optimised the mouse nerve-diaphragm preparation can provide a functional in vitro model for accurate and reproducible assessment of toxin activity.

The structure of the Au(111)/methylthiolate interface: new insights from near-edge x-ray absorption spectroscopy and x-ray standing waves.

The local structure of the Au(111)(square root(3) x square root(3))R30 degrees-methylthiolate surface phase has been investigated by S K-edge near-edge s-ray absorption fine structure (NEXAFS) both experimentally and theoretically and by experimental normal-incidence x-ray standing waves (NIXSW) at both the C and S atomic sites. NEXAFS shows not only excitation into the intramolecular sigma(*) S-C resonance but also into a sigma(*) S-Au orbital perpendicular to the surface, clearly identifying the local S headgroup site as atop a Au atom. Simulations show that it is not possible, however, to distinguish between the two possible adatom reconstruction models; a single thiolate species atop a hollow-site Au adatom or a dithiolate moiety comprising two thiolate species bonded to a bridge-bonded Au adatom. Within this dithiolate moiety a second sigma(*) S-Au orbital that lies near parallel to the surface has a higher energy that overlaps that of the sigma(*) S-C resonance. The new NIXSW data show the S-C bond to be tilted by 61 degrees relative to the surface normal, with a preferred azimuthal orientation in <211>, corresponding to the intermolecular nearest-neighbor directions. This azimuthal orientation is consistent with the thiolate being atop a hollow-site Au adatom, but not consistent with the originally proposed Au-adatom-dithiolate moiety. However, internal conformational changes within this species could, perhaps, render this model also consistent with the experimental data.

Abciximab for treatment of thromboembolic complications during endovascular coiling of intracranial aneurysms.

BACKGROUND AND PURPOSE: Thromboembolism is a recognized complication occurring during endovascular coil embolization of intracranial aneurysms. Recently, there has been much interest in glycoprotein IIb/IIIa inhibitors to treat such complications, but the evidence is limited. We reviewed our use of one such agent, abciximab, which we commonly administer and believe to be a safe and suitable rescue agent in this setting. MATERIALS AND METHODS: We retrospectively reviewed cases in which abciximab was administered in our institution between 2001 and 2007. Clinical outcome was assessed by the modified Rankin Scale (mRS) at 6 months. Good outcome was defined as no significant clinical sequelae compared with baseline status or clinical improvement (mRS < 2). Poor outcome was defined as no resolution of a new clinical deficit that developed postprocedure at 6 months (mRS > 2). Angiographic appearance of thromboembolic phenomena and posttreatment outcome was assessed with the Thrombolysis in Myocardial Infarction (TIMI) scale. RESULTS: Thirty-eight patients were included, with good outcome observed in 30 (79%) and poor outcome in 8 (21%) patients. Angiographic improvement based on TIMI scoring was seen in 24 (63%) patients, and no improvement was seen in 14 (37%). In 4 patients (11%), good outcome was obtained at 6 months despite no angiographic improvement on TIMI. No cases of intracranial rebleed or additional neurologic deficit following administration of abciximab were encountered. CONCLUSION: In this small retrospective series, abciximab was safe and effective when used as a rescue agent for thromboembolic complications encountered during coiling of intracerebral aneurysms.

Development of improved SNAP25 endopeptidase immuno-assays for botulinum type A and E toxins.

Botulinum neurotoxins contain proteases that cleave specific intra-neural proteins essential for neurotransmitter release. Toxin types A, E and C1 intra-cellularly cleave SNAP25 resulting in a flaccid paralysis. As a consequence, various different endopeptidase assays have been developed to specifically detect the toxins enzymatic activity, however, many of these suffer from variability, low sensitivity or unwanted interference exerted by product specific excipients. The current studies utilised solid phase synthesized SNAP25(137-206) peptide substrate, and specific antibody to either the SNAP25(190-197) or (173-180) octapeptide epitopes that become exposed following cleavage by toxin types A or E respectively. Assay sensitivity was increased 50 fold by the use of an optimal 0.5% Tween 20 concentration in tandem to 0.1% albumin together with an improved, simplified assay design without a pre-activation / reduction step. Sensitivities capable of detecting 0.01 LD50/ml (40fg/ml or 0.3fM) of type A toxin was achieved with a linear dose response between 0.1 and 1 LD50/ml. This provides sufficient sensitivity and precision (inter assay GCV of < 2%) for monitoring activity within any current or newly marketed therapeutic products containing less units per vial and may also make it applicable for other applications. Both purified haemagglutinin free and complexed toxins could be detected equally. Unlike type A, type E activity could unexpectedly be detected in the complete absence of reducing conditions and the optimal assay had a limit of detection of 0.2LD50/ml (4.8pg/ml) with a linear dose response between 1 and 10LD50/ml. The principle of using a detecting antibody to a substrate sequence buried within the native substrates alpha-helix may be further expanded to other specific enzyme cleavage reactions in the future.

Person-centred dementia services are feasible, but can they be sustained?

BACKGROUND: we evaluated a specialist community-based dementia service to establish whether high quality care was being delivered and the conditions for doing so. The service was in an urban part of Rushcliffe Primary Care Trust, Nottinghamshire, United Kingdom. The service comprised an assessment team of an occupational therapist, a community psychiatric nurse and a community care officer, supported by 235 h per week of care delivered by a team of specially trained community care workers. METHODS: a qualitative study was performed using non-participant observation, semi-structured interviews and focus groups, and analysed using a thematic framework approach. There were 2 focus groups involving staff, 11 interviews of staff and stakeholders, and interviews of 15 carers of people with dementia. RESULTS: the care provided was appreciated by carers, and the service was approved by staff and stakeholders. Care was delivered using a rehabilitative style that aimed to maintain personhood, rather than to promote independence. Clients were usually referred with the object of preventing unwanted admission to institutional care but, over time, moving into an institution ceased to be a uniformly undesirable outcome. The service's resources were reduced during the evaluation period, in part to meet mental health needs in intermediate care services. CONCLUSIONS: an appropriately resourced and constructed specialist service using an adaptive rehabilitation approach aimed at maintaining personhood can deliver good individualised care to people with dementia, but specific and appropriate commissioning for these services is needed to nurture them.