Factors Associated with Contralateral Deep Venous Thrombosis after Iliocaval Venous Stenting.

BACKGROUND: The majority of iliac venous obstructions occur on the left side, and endovascular therapy has become the first line treatment for this condition. A left common iliac venous stent will protrude into the inferior vena cava (IVC) to some extent, thereby covering the contralateral common iliac vein (CIV) outflow. This may increase the risk of thrombosis of the contralateral iliac vein. The aim of this paper was to determine the rate of, and factors associated with, contralateral lower limb venous thrombosis after stenting, and to evaluate the results of salvage revascularisation. METHODS: A total of 376 patients (102 from UCH, Galway, Ireland, 2008-16, and 274 from, CHU Nord, Marseille, France, 2000-15) with symptomatic acute or chronic left iliocaval venous obstruction were retrospectively evaluated. Either duplex ultrasound scanning (DUS) or computed tomographic venography (CTV) was used for pre- and post-operative imaging. Data were collected from the PACS system (IMPAX, Agfa, BE) of the Radiology Department, UCH, Galway, and from the electronic medical records of Vascular Surgery department, CHU Nord, Marseille. RESULTS: The median age of stented patients was 46 (range 15-86 years), 80% were female (301/376). Following left CIV stent placement, 10 patients later presented with a right (contralateral) iliac deep venous thrombosis (DVT) resulting in a cumulative incidence of contralateral DVT of 4% according to Kaplan-Meier analysis. Acute DVT (p=.001), non-compliance with the prescribed 6 months anticoagulation (p = 0.05), pre-operative contralateral internal iliac vein (IIV) thrombosis (p = 0.001), and pre-existing IVC filter placement (p = 0.003) were all statistically significantly associated with contralateral DVT. All patients with symptomatic contralateral iliac DVT underwent clot removal in the acute phase. The primary patency of these limbs was 100% at 3 years. CONCLUSION: Stent placement across the iliocaval confluence from the left CIV is associated with a low but definite rate of contralateral iliac vein thrombosis. Acute DVT, pre-operative contralateral IIV thrombosis, pre-existing IVC filters, and anticoagulation non-compliance are significant risk factors.

Iliofemoral venous stenting extending into the femoral region: initial clinical experience with the purpose-designed Zilver Vena stent.

AIM: The aim of the study was to assess the early clinical experience with the Zilver Vena stent in treating patients with iliofemoral venous obstruction at a tertiary referral hospital. METHODS: Demographic, procedural, and follow-up data of 20 patients (12 women; mean age of 59 ± 17 years) treated for iliofemoral vein obstruction between January 2011 and December 2012 were retrospectively reviewed. Most patients presented with acute obstruction (N.=14; 70%), and 10 patients (50%) had an active malignancy. Patency was established venographically at procedure end, and was evaluated with Duplex ultrasound in follow-up. RESULTS: Venous obstructions were attributed primarily to extrinsic compression from a malignant or other mass in the pelvis (N.=9) and May-Thurner (N.=5). Flow was re-established through the obstructed venous segment in all patients at procedure end. In follow-up, three patients experienced early stent thrombosis (<30 days); the clinical patency rate was 85% (17/20 patients). Clinical improvement was demonstrated by decreased leg swelling in the remaining 17 patients. CONCLUSION: The Zilver Vena stent performed favorably in this challenging patient population; these results need to be confirmed in multicenter studies.

Induced pluripotent stem cells: epigenetic memories and practical implications.

Induced pluripotent stem cells (iPSCs) may be obtained by direct reprogramming of different somatic cells to a pluripotent state by forced expression of a handful of transcription factors. It was generally assumed that iPSCs are functionally equivalent to their embryonic stem cell (ESC) counterparts. Recently, a number of research groups have demonstrated that this is not the case, showing that iPSCs retain 'epigenetic memory' of the donor tissue from which they were derived and display skewed differentiation potential. This raises the question whether such cells are fit for experimental, diagnostic or therapeutic purpose. A brief survey of the literature illustrates that differences at both epigenetic and transcriptome level are observed between various pluripotent stem cell populations. Interestingly, iPSC populations with perceived 'anomalies' can be coaxed to a more ESC-like cellular state either by continuous passaging--which attenuates these epigenetic differences--or treatment with small molecules that target the machinery responsible for remodelling the genome. This suggests that the establishment of an epigenetic status approximating an ESC counterpart is largely a passive process. The mechanisms responsible remain to be established. Meanwhile, other areas of reprogramming are rapidly evolving such as, trans-differentiation of one somatic cell type to another by the forced expression of key transcription factors. When it comes to assessing their practical usefulness, the same question will also apply.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Dynamic micro-Hall detection of superparamagnetic beads in a microfluidic channel.

We report integration of an InAs quantum well micro-Hall magnetic sensor with microfluidics and real-time detection of moving superparamagnetic beads. Beads moving within and around the Hall cross area result in positive and negative Hall voltage signals respectively. Relative magnitudes and polarities of the signals measured for a random distribution of immobilized beads over the sensor are in good agreement with calculated values and explain consistently the shape of the dynamic signal.

Near-surface nanoscale InAs Hall cross sensitivity to localized magnetic and electric fields.

We have measured the room temperature response of nanoscale semiconductor Hall crosses to local applied magnetic fields under various local electric gate conditions using scanning probe microscopy. Near-surface quantum wells of AlSb/InAs/AlSb, located just 5 nm from the heterostructure surface, allow very high sensitivity to localized electric and magnetic fields applied near the device surfaces. The Hall crosses have critical dimensions of 400 and 100 nm, while the mean free path of the carriers is about 160 nm; hence the devices nominally span the transition from diffusive to quasi-ballistic transport. With certain small gate voltages (V(g)) the devices of both sizes are strongly responsive to the local magnetic field at the center of the cross, and the results are well described using finite element modeling. At high V(g), the response to local magnetic fields is greatly distorted by strong electric fields applied near the cross corners. However we observe no change in behavior with the size of the device.

Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase.

Catechol-O-methyltransferase is an important enzyme in the metabolism of dopamine and an important regulator of aspects of dopamine-dependent working memory in prefrontal cortex that are disturbed in schizophrenia. This study investigated the phenotype of mice with heterozygous deletion vs. homozygous knockout of the catechol-O-methyltransferase gene across paradigms that access processes relevant for psychotic illness. Homozygotes evidenced improved performance in spontaneous alternation, an index of immediate spatial working memory; this effect appeared more substantive in males and was reflected in performance in aspects of the Barnes maze, an index of spatial learning/memory. Heterozygotes evidenced impaired performance in object recognition, an index of recognition memory; this effect was evident for both sexes at a retention interval of 5 min but appeared more enduring in males. There were no material effects for either genotype in relation to sociability or social novelty preference. While homozygous catechol-O-methyltransferase deletion results in improvement in spatial learning/working memory with little effect on social behavior, heterozygous deletion results in impairment of recognition memory. We have reported recently, using similar methods, that mice with deletion of the schizophrenia risk gene neuregulin-1 evidence disruption to social behavior, with little effect on spatial learning/working memory. The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome.

Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1.

Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.

Human acrocentric chromosomes with transcriptionally silent nucleolar organizer regions associate with nucleoli.

Human ribosomal gene repeats are distributed among five nucleolar organizer regions (NORs) on the p arms of acrocentric chromosomes. On exit from mitosis, nucleoli form around individual active NORs. As cells progress through the cycle, these mini-nucleoli fuse to form large nucleoli incorporating multiple NORs. It is generally assumed that nucleolar incorporation of individual NORs is dependent on ribosomal gene transcription. To test this assumption, we determined the nuclear location of individual human acrocentric chromosomes, and their associated NORs, in mouse> human cell hybrids. Human ribosomal genes are transcriptionally silent in this context. Combined immunofluorescence and in situ hybridization (immuno-FISH) on three-dimensional preserved nuclei showed that human acrocentric chromosomes associate with hybrid cell nucleoli. Analysis of purified nucleoli demonstrated that human and mouse NORs are equally likely to be within a hybrid cell nucleolus. This is supported further by the observation that murine upstream binding factor can associate with human NORs. Incorporation of silent NORs into mature nucleoli raises interesting issues concerning the maintenance of the activity status of individual NORs.

Endovascular management of iliac vein compression (May-Thurner) syndrome.

PURPOSE: To evaluate the feasibility of endovascular techniques in treating venous outflow obstruction resulting from compression of the iliac vein by the iliac artery of the left lower extremity (May-Thurner syndrome). MATERIALS AND METHODS: A retrospective analysis of 39 patients (29 women, 10 men; median age, 46 years) with iliac vein compression syndrome (IVCS) was performed. Nineteen patients presented with acute deep vein thrombosis (DVT) and 20 patients presented with chronic symptoms. All patients presented with leg edema or pain. In the acute group, patients were treated with catheter-directed thrombolysis (120,000-180,000 IU urokinase/h) and angioplasty followed by stent placement. In the chronic group, patients were treated with use of angioplasty and stent placement alone (n = 8), or in combination with thrombolysis (n = 12). Patients were then followed-up with duplex ultrasound and a quality-of-life assessment. RESULTS: Initial technical success was achieved in 34 of 39 patients (87%). The overall patency rate at 1 year was 79%. Symptomatically, 85% of patients were completely or partially improved compared with findings before treatment. Thirty-five of 39 patients received stents. The 1-year patency rate for patients with acute symptoms who received stents was 91.6%; for patients with chronic symptoms who received stents, the 1-year patency rate was 93.9%. Five technical failures occurred. Major complications included acute iliac vein rethrombosis (< 24 hours) requiring reintervention (n = 2). Minor complications included perisheath hematomas (n = 4) and minor bleeding (n = 1). There were no deaths, pulmonary embolus, cerebral hemorrhage, or major bleeding complications. CONCLUSION: Endovascular reconstruction of occluded iliac veins secondary to IVCS (May-Thurner) appears to be safe and effective.

1999 Gary J. Becker Young Investigator Award. MR-guided transjugular portosystemic shunt placement in a swine model.

PURPOSE: To evaluate the performance of portal venous puncture with use of magnetic resonance (MR) guidance, and to place a transjugular intrahepatic portosystemic shunt (TIPS) in a swine model. MATERIALS AND METHODS: A study of 12 swine was performed to evaluate the ability of interventional MR imaging to guide portal vein puncture and TIPS placement. Six swine had catheters placed in the right hepatic vein under C-arm fluoroscopy. A nitinol guide wire was left in the vein and the animals were then moved into an open configuration MR imaging unit. A TIPS needle set was used to puncture the portal vein using MR fluoroscopy. The animals were transferred to the C-arm, and venography confirmed portal vein puncture. A follow-up study was performed in six additional swine to place a TIPS using only MR imaging guidance. MR tracking was used to advance a catheter from the right atrium into the inferior vena cava. Puncture of the portal vein was performed and a nitinol stent was placed, bridging the hepatic parenchyma. MR venogram confirmed placement. RESULTS: Successful portal vein puncture was achieved in all animals. The number of punctures required decreased from 12 in the first animal to a single puncture in the last eight swine. A stent was successfully placed across the hepatic tract in all six swine. CONCLUSIONS: Real-time MR imaging proved to be a feasible method to guide portal vein puncture and TIPS placement in pigs.

Palliation of malignant dysphagia with expanding metallic stents.

PURPOSE: The authors describe their experience with expanding metallic stents for the palliation of malignant dysphagia. MATERIALS AND METHODS: During a 52-month period, 138 stents were inserted in 121 patients with malignant esophageal obstruction. The average age was 74 years; there were 78 men and 43 women. Data regarding the degree of initial dysphagia, presence of an esophago-respiratory fistula, effect of stent placement on swallowing ability, complications at the time of stent placement, and long-term survival were obtained. RESULTS: An improvement in dysphagia symptoms was recorded in more than 95% of patients. The average survival after stent placement was 24 weeks. Complications necessitating further intervention occurred in 26 patients. CONCLUSION: Insertion of self-expanding metallic endoprostheses for the palliation of malignant esophageal obstruction is an effective therapy that can be carried out with relative ease. Successful palliation of symptoms can be expected in more than 95% of cases.

The use of the angio-seal haemostatic puncture closure device in high risk patients.

The use of the Angio-Seal haemostatic puncture closure device in 45 patients considered to be at increased risk of puncture site complications is described. Successful device deployment occurred in 44 of 50 arteries (88%). Two major complications were associated with, but not necessarily caused by, the Angio-Seal device. Four minor complications were observed. In a subset of 23 patients well enough to mobilize early after their procedure, 17 did so at an average of 2.6 h as opposed to the routine 12-18 h for patients after a procedure involving a 6-8F sheath. Once the initial learning curve has been overcome, the Angio-Seal device is a simple and successful method of achieving arterial haemostasis following catheterization and is associated with a low risk of complications. At present we would recommend its use for high risk patients only, as manual compression is effective in the majority of routine cases.

A review of alternative approaches in the management of iatrogenic femoral pseudoaneurysms.

The management of iatrogenic pseudoaneurysms (IPAs) demands close co-operation between radiologist, vascular surgeon and plastic surgeon. Ideally, each patient should be reviewed employing a team approach. Many IPAs require only observation; those with a volume greater than 6 cm3 will require treatment as spontaneous thrombosis is uncommon. Radiological treatment options include ultrasound guided compression repair (UGCR), embolisation, and covered stenting. Occasionally, these are unsuccessful or contra-indicated, and the vascular surgical approach is discussed in detail. Finally, the role of the plastic surgeon in dealing with skin ischaemia is detailed.

Mycotic aneurysm of the external carotid artery.

Mycotic aneurysms of the extracranial carotid arteries are extremely rare. A case is reported of a false aneurysm of the left external carotid artery. This developed secondary to cervical lymphadenitis which did not settle with high dose antibiotic therapy. The diagnosis was made on investigation with carotid doppler ultrasound and confirmed with computerized tomography. Digital subtraction angiography was performed to highlight the vascular anatomy. In addition percutaneous balloon catheter control of blood flow in the external carotid artery was used as an adjunct to surgical management.