Association between CYP2C19 Polymorphisms and Outcomes in Cerebral Endovascular Therapy.

BACKGROUND AND PURPOSE: Differing responses to clopidogrel following endovascular treatment of cerebrovascular diseases may increase the risk of vascular complications. CYP2C19 gene polymorphisms influence clopidogrel activity. We aimed to study the clinical impact of CYP2C19 gene polymorphisms in patients undergoing endovascular treatment. MATERIALS AND METHODS: This was a prospective, longitudinal, observational study. Information on demographics and cerebrovascular status was collected as baseline. Clopidogrel response was tested by the VerifyNow P2Y12 assay. CYP2C19 genotyping was undertaken by polymerase chain reaction-restriction fragment length polymorphism. Three-month follow-up data included vascular complications, mortality, and modified Rankin Scale score. Associations were investigated among CYP2C19 genotypes, clopidogrel responsiveness, and clinical outcomes. RESULTS: One hundred and eight participants were included. Median age was 56 years (interquartile range, 48.8-65.0 years), and 35 (32.4%) were male. Forty-four participants were classified into group 1 (homozygous CYP2C19*1/*1); 31, into group 2 (25 with CYP2C19*1/*2, two with CYP2C19*1/*3, three with CYP2C19*3/*3, one with CYP2C19*2/*3); 28, into group 3 (24 with CYP2C19*1/*17, four with CYP2C19*17/*17); and 5, into group 4 (CYP2C19*2/*17). A significantly higher proportion of participants in group 3 experienced ischemic events (9 of 28, 32.1%) compared with group 1 (5 of 44, 11.4%; P = .04; odds ratio, 3.7; 95% confidence interval, 1.1-12.6). There was no significant difference in clopidogrel response among the 4 genotype groups. CONCLUSIONS: Individuals with CYP2C19*17 may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. Larger studies are required to confirm the influence of CYP2C19*17 on clinical outcomes and to understand the mechanisms for increased ischemic events.

Picture-to-puncture time in acute stroke endovascular intervention: are we getting faster?

BACKGROUND: In acute stroke management, time efficiency in the continuum of patient management is critical. We aimed to determine if implementation of system improvements at our institution translated to reduced picture-to-puncture (P2P) times over a 6-year period. METHODS: We conducted a single-center retrospective analysis using a prospective acute stroke database of patients treated with intra-arterial therapy from October 2007 to October 2013. Patient demographics, stroke severity, neuroimaging and treatment time points were collected. Annual P2P times, defined as the interval between pretreatment neuroimaging (picture) and commencement of intra-arterial therapy (puncture), were assessed and compared. RESULTS: From 2007 to 2013 a total of 189 patients were identified, of which 181 met the study criteria. At initial presentation, median baseline NIH Stroke Severity score was 17.00 (IQR 11.00-22.00). Annual median P2P times decreased from 171 to 123.5 min, showing a median decrease of 11.5 min per annum (95% CI -23.9 to 0.9) and trending towards statistical significance (p=0.069). Plotted data revealed longer P2P times in instances where stroke onset or CT acquisition times were out-of-hours. Using median regression modeling, the annual decrease in P2P median time reached statistical significance when independently adjusting for CT acquisition time (13.5 min P2P median time reduction, 95% CI -27.0 to -0.1, p=0.048) and for stroke onset time (14.5 min annual P2P median time reduction, 95% CI -26.1 to -2.8, p=0.015). CONCLUSIONS: As a consequence of systems improvement at our institution, we were able to demonstrate improved annual median P2P times from 2007 to 2013.

Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.

Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.

A single centre study of coil embolization of intracranial aneurysms comparing bare platinum and PGLA-coated coils.

There is no robust consensus on the efficacy of polyglycolic/polylactic acid (PGLA)-coated coils used in the endovascular embolization of intracranial aneurysms. We present a comparative study of bare platinum coils and PGLA-coated Gugliemi Detachable Coils (GDC) in the treatment of intracranial aneurysms at a single centre, using target aneurysm recurrence and angiographic recanalization as the primary endpoints. We included all patients treated between 1998 and 2009 who had undergone at least one angiographic post-procedural follow-up. Patient demographics, clinical presentation, operative notes, and all relevant imaging were collected. Of the 441 aneurysms with follow-up, 290 were treated with at least one PGLA coil and 151 aneurysms were treated exclusively with bare platinum coils. At follow-up, 26.5% of platinum controls demonstrated angiographic recanalization, compared to 31.4% of PGLA-treated aneurysms (p=0.002). PGLA-treated aneurysms were more likely to have an angiographic remnant at follow-up (odds ratio [OR]=1.96, 95% confidence interval [CI]=1.26-3.04, p=0.003). The post-operative Raymond score was the only predictor of retreatment (OR=1.6, 95% CI=1.08-2.24, p=0.020), and was the second strongest predictor of a complete angiographic result at follow-up (OR=1.67, 95% CI=1.22-2.27, p=0.001). We concluded that PGLA-coated coils demonstrated poorer post-operative and long-term angiographic occlusion in the treatment of intracranial aneurysms, compared to bare platinum coils.

Glasgow coma scale does not predict outcome post-intra-arterial treatment for basilar artery thrombosis.

BACKGROUND AND PURPOSE: Evidence to guide patient selection for IA therapy in acute basilar artery thrombosis is lacking. The GCS is frequently used as a selection criterion, based on the view that higher GCS correlates with better neurologic outcome. This view has not been systematically studied. We hypothesize that low GCS does not correlate with poor outcome and that it should not preclude IA therapy. MATERIALS AND METHODS: We included 40 consecutive patients with basilar artery thrombosis treated with IA therapy. Clinical characteristics, GCS, time to intervention, and postprocedural TIMI scores were collected. Recanalization was defined as TIMI grade 2 or 3; clinical outcome was measured by 90-day mRS. RESULTS: Median patient age was 63.5 years. Most presented with gaze palsies (67.5%) or hemiparesis (45%). Median GCS was 9, the median time to intervention was 7.2 hours, and recanalization rate was 82.5%. Good neurologic outcome (mRS ≤ 1) occurred in 30%. There was no correlation between GCS and 90-day mRS (Spearman ρ - 0.174, P = .283). Equal numbers of patients with good neurologic outcome of mRS ≤ 1 (n = 12) had a GCS of ≤6 or >6. In those with GCS ≤ 6 for >3 hours, 33.3% had good neurologic outcome-a similar rate to that of the overall cohort. Statistical significance was demonstrated between time to IA therapy within 6 hours and mRS ≤ 2. CONCLUSIONS: Low GCS score did not correlate with poor neurologic outcome in patients with acute basilar artery thrombosis managed with IA therapy. It is not appropriate to exclude patients from IA therapy on the basis of low GCS.

Bone subtraction CT angiography for the detection of intracranial aneurysms.

INTRODUCTION: The aim of the study was to retrospectively analyse the accuracy of CT angiography (CTA) of the Circle of Willis and a prototype bone subtraction CT angiogram (BSCTA) compared with digital subtraction angiography (DSA) in the detection of intracranial aneurysms. METHODS: A total of 36 patients with suspected subarachnoid haemorrhage who had CTA scans that had matching DSA studies between November 2005 and December 2006 were retrospectively reviewed by two experienced neurointerventionalist. Three-dimensional volume-rendered (3D VR) CTA and BSCTA were reviewed, followed by review of the source data in multi-planar reformats (MPRs). The results were then assessed for sensitivity and specificity compared with the gold standard DSA. Time taken to review the studies, visibility of the ophthalmic, posterior communicating arteries, superior cerebella artery, posterior cerebral artery on the 3D VR BSCTA and CTA were analysed. BSCTA was assessed for residual bone and artificial stenosis. Further, the aneurysms were analysed for suitability of endovascular treatment versus surgical treatment based on CTA and BSCTA with MPR and 3D VR. RESULTS: CTA 3D VR sensitivity and specificity was 94 and 80%, respectively. CTA MPR sensitivity and specificity was 100% and 90%, respectively. When both CTA 3D VR and MPR images were combined the sensitivity and specificity was 100 and 90%, respectively. BSCTA 3D VR sensitivity and specificity was 91 and 90%, respectively, and the MPR sensitivity and specificity was 97 and 90%, respectively. When both BSCTA 3D VR and MPR images were combined the sensitivity was 97% with a specificity of 90% Overall, an 84% correlation was found between both CTA and BSCTA when compared with DSA for assessing for suitability of endovascular treatment versus surgical treatment. A statistically significant difference was shown between the time taken to review the CTA and BSCTA (P < 0.001 confidence interval 3.1-3.9 min). CONCLUSION: In this study there was no significant difference between the diagnostic ability of BSCTA compared with CTA. Importantly, both CTA and BSCTA had high sensitivities and specificities compared to DSA.

Targeting mTOR-dependent tumours with specific inhibitors: a model for personalized medicine based on molecular diagnoses.

Cancer cells are characterized by aberrant growth arising from deregulated signalling pathways. The mammalian target of rapamycin (mTOR) pathway integrates multiple growth signals coming from both intracellular and extracellular cues. In this short review, we summarize what is known about the efficacy of targeting the mTOR pathway to treat cancer patients, and we explain the rationale behind promising new inhibitors that could show more potent tumour growth inhibition than did the first generation of these drugs.

Iliocaval arteriovenous fistula presenting with multiple organ failure.

Iliac arteriovenous fistulas are an uncommon condition, which may be spontaneous or traumatic in nature. Such fistulas classically present with a triad of high-output cardiac failure, pulsatile abdominal mass with a bruit and unilateral leg ischaemia or venous congestion. We describe a case of an iliocaval fistula secondary to rupture of a common iliac artery aneurysm, with an unusual presentation of multiple organ failure, masquerading as sepsis. We describe the CT findings of iliocaval fistula, which was the means of diagnosis in this study.

Unusual presentation of perirenal lung metastases.

Lung cancer is not commonly known to metastasize to the perirenal space, with only five such cases previously published. We present an unusual case of perirenal lung metastases manifesting as diffuse perinephric stranding which to our knowledge has not been described before.

Endovascular treatment of arterial mesenteric ischaemia: a retrospective review.

Mesenteric ischaemia is a condition that has traditionally been managed surgically. It poses a challenging diagnostic and therapeutic problem, particularly in the acute setting. We review a small series of eight patients managed with endovascular techniques for either acute or chronic mesenteric ischaemia at The Royal Melbourne Hospital, from 1997 to 2002. We describe our results and relate these to the recent published literature regarding endovascular and surgical management of mesenteric ischaemia. Our experience confirms the valuable contribution of angioplasty and stenting in chronic mesenteric ischaemia, which compares favourably with surgery with regards to complication rates and mortality. We suggest the need for further studies to compare the long-term efficacy of endovascular techniques compared with surgery in the management of chronic mesenteric ischaemia. Furthermore, we demonstrate a role for endovascular management in acute mesenteric ischaemia, in the appropriate clinical setting.

Gene-expression changes induced by Feline immunodeficiency virus infection differ in epithelial cells and lymphocytes.

Infection of cats with Feline immunodeficiency virus (FIV) is an important model for understanding comparative lentivirus biology. In vivo, FIV infects lymphocytes and monocyte/macrophages, but in vitro infection is commonly investigated in epithelial Crandell-Reese Feline Kidney (CRFK) cells. In this study, the transcriptional responses of CRFK cells and primary lymphocytes to infection with FIV 34TF, a cloned subtype A virus, and FIV USgaB01, a biological subtype B isolate, were determined. Reverse-transcribed mRNA from both cell types was hybridized to microarrays containing 1700 human expressed sequence tags in duplicate and data were analysed with Significance Analysis of Microarrays (sam) software. Results from six experiments assessing homeostatic cross-species hybridization excluded 3.48 % inconsistently detected transcripts. Analysis of data from five time points over 48 h after infection identified 132 and 24 differentially expressed genes in epithelial cells and lymphocytes, respectively. Genes involved in protein synthesis, the cell cycle, structure and metabolism were affected. The magnitude of gene-expression changes ranged from 0.62 to 1.62 and early gene induction was followed by downregulation after 4 h. Transcriptional changes in CRFK cells were distinct from those in lymphocytes, except for heat-shock cognate protein 71, which was induced at multiple time points in both cell types. These findings indicate that FIV infection induces transcriptional changes of a modest magnitude in a wide range of genes, which is probably reflective of the relatively non-cytopathic nature of virus infection.

Acute presentations of renal artery stenosis in three patients with a solitary functioning kidney.

Renal artery stenosis can present uncommonly in the acute state as flash pulmonary oedema and hypertensive encephalopathy. We present three such cases in patients with a solitary functioning kidney, with successful management via renal artery angioplasty and stent insertion.

Angioplasty and stenting of the superior mesenteric artery in acute mesenteric ischaemia.

Acute mesenteric ischaemia is a challenging diagnostic problem with a very high mortality. Traditionally, laparotomy is required for definitive management. We describe a successful case of angioplasty and stenting of the superior mesenteric artery in a surgically unfit patient. We recommend that stenting be considered only in situations where the diagnosis has been made prior to bowel infarction, and if the patient poses a poor operative risk.

Doppler ultrasound (pre- and post-contrast enhancement) for detection of recurrent stenosis in stented renal arteries: preliminary results.

The purpose of the present paper was to assess whether conventional renal Doppler ultrasound and the commonly used parameters of peak systolic velocity and renal aortic ratio may be an appropriate modality for the follow-up of renal artery stents. A total of 19 arteries in 15 patients was examined with both renal Doppler ultrasound and angiography for the presence or absence of recurrent renal artery stenosis. Disease was considered present on angiography if the arterial diameter was more than 60% stenotic. Doppler criteria for stenosis were either a peak systolic velocity of > 180 cm/s or a renal aortic ratio of > 3.0. Echo enhancement with Levovist (Schering, Berlin, Germany) was used if studies were technically unsuccessful or to improve diagnostic confidence. Renal Doppler ultrasound detected 100% of renal artery stenoses. The specificity was 75%, the positive predictive value was 67% and the negative predictive value was 100%. Echo enhancement improved the technical success rate from 89 to 95% and also increased diagnostic confidence in six examinations. The present limited study suggests that similar renal Doppler parameters as used for the study of unstented renal arteries may be applied to the examination of renal arteries with renal stents in situ. It therefore suggests that Doppler ultrasound may provide an adequate non-invasive means of renal artery stent follow-up, particularly when combined with echo-enhancing agents. Further study is warranted to confirm these initial conclusions.

Using Doppler sonography to reveal renal artery stenosis: an evaluation of optimal imaging parameters.

OBJECTIVE: The aim of this study was to determine the accuracy of direct and indirect parameters for the diagnosis of renal artery stenosis and to determine the most useful thresholds for these parameters. SUBJECTS AND METHODS: One hundred twenty-five arteries in 63 patients were examined with renal Doppler sonography and angiography for the presence or absence of renal artery stenosis. Arteries were considered stenosed on angiography if there was a diameter reduction of greater than 60%. Renal Doppler sonographic measures of peak systolic velocity, renal aortic ratio, acceleration time, and acceleration were recorded and compared with the angiographically determined presence or absence of disease. RESULTS: Doppler examination was technically successful in 87% of kidneys and 76% of patients. Receiver operating characteristic analysis showed the optimal peak systolic velocity threshold to be 180 cm/sec and the optimal renal aortic ratio threshold to be 3.0. An acceleration time greater than 70 msec and an acceleration less than 300 cm/sec2 yielded sensitivities of 41% and 56%, respectively, and specificities of 85% and 62%, respectively. Combining a renal aortic ratio of greater than 3.0 or peak systolic velocity greater than 180 cm/sec provided the best combination of parameters with a sensitivity and sensitivity at 85% and 76%, respectively. CONCLUSION: The most accurate use of parameters was found to be a combination of either peak systolic velocity greater than 180 cm/sec or renal aortic ratio greater than 3.0. Indirect parameters were not found to be useful in predicting the presence or absence of renal artery stenosis.

Imaging and stenting for renal artery stenosis.

Renal artery stenosis is a potentially correctable cause of hypertension and renal failure, using endoluminal or, less commonly, surgical techniques. A number of imaging techniques can be used to diagnose renal artery stenosis, all with similar accuracy.

Contrast-enhanced Doppler ultrasound for renal artery stenosis.

The use of renal artery Doppler ultrasound for the diagnosis of renal artery stenosis is a well-established technique in selected populations, but the technical failure rate of the examination leading to incomplete studies is a major drawback. The results of ultrasound contrast-enhanced renal artery Doppler for renal artery stenosis, using the echo-enhancing agent, Levovist, are reported here. Sixteen patients (22 arteries) were examined with Levovist. The technical success rate of these examinations was 91%, and all four renal artery stenoses were correctly identified. It is concluded that the use of ultrasound contrast (Levovist) increases the technical success rate of renal artery Doppler ultrasound in this setting, with similar accuracy to unenhanced Doppler examinations.

Patellar tendinosis (jumper's knee): findings at histopathologic examination, US, and MR imaging. Victorian Institute of Sport Tendon Study Group.

PURPOSE: To determine the histopathologic findings of patellar tendinosis ("jumper's knee") demonstrated with ultrasonography (US) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: Twenty-four athletes (28 knees) with jumper's knee (23 men, one women; mean age, 30.9 years) scheduled to undergo open tenotomy underwent US patellar tendon examination. Seventeen patients (19 knees) also underwent MR imaging. Tissue was obtained for histopathologic examination in all 28 cases. Eleven age-, height-, and weight-matched athletes (22 knees) without previous knee symptoms served as control subjects for the US examination. Control material for histopathologic examination was obtained in 20 cadavers (39 knees). Data were analyzed with standard statistical methods. RESULTS: MR imaging and US both revealed an abnormal zone at the proximal patellar tendon attachment. Histopathologic examination revealed mucoid degeneration in all tendons in patients and in 8% (three of 39) of tendons in cadavers (P < .01). CONCLUSION: Jumper's knee is characterized by consistent changes at MR imaging, US, and histopathologic examination and is appropriately described as patellar tendinosis.

Efficient optical elements to generate intensity weighted spot arrays: design and fabrication.

We report on the design and fabrication of fully 2-D surface relief diffraction elements that can split a single collimated beam into many beams in an arbitrary intensity distribution. These splitters were designed by computer using simulated annealing, and made into phase gratings by electron-beam lithography followed by plasma etching into quartz glass. Both two and four phase level gratings have been fabricated, allowing a wide range of uniform and weighted spot patterns to be generated. These grating elements have a measured diffraction efficiency of over 74%, with the beam intensity ratios accurate to within 1% of their target values.