Philippe Bijlenga

Uncoupling Protein-3 Expression in Rodent Skeletal Muscle Is Modulated by Food Intake but Not by Changes in Environmental Temperature

A new member of the uncoupling protein (UCP) family called UCP3 has recently been cloned and shown to be highly expressed in skeletal muscle of rodents and humans. In the present study, UCP3 was overexpressed in C2C12myoblasts where it acts as an uncoupling protein. Changes in UCP3 mRNA expression were examined in rodent muscles under conditions known to modulate thermogenesis in brown adipose tissue. In skeletal muscle, UCP3 expression did not change in response to 48 h of cold exposure (6 °C), whereas it was decreased by 81% or increased 5.6-fold by 1 week of 50% food restriction or fasting, respectively. It was also decreased by 36% in soleus muscle of obese (fa/fa) as compared with lean Zucker rats. The unexpected rise of UCP3 mRNA level induced by fasting did not change in vitro muscle basal heat production rate but decreased by 31% the capacity to produce heat in response to the uncoupler carbonylcyanidep-trifluoromethoxyphenylhydrazone. This decrease may reflect underlying uncoupling by UCP3. Up-regulation of UCP3 mRNA after a 24-h fast was still observed in mice exposed at thermoneutrality. These results show that the increase in UCP3 expression induced by fasting is associated with the maintenance of thermogenesis measured in muscle in vitro and is not modulated by environmental temperature. The notion that UCP3 expression is modulated by food intake is of importance to better understand the pathophysiology of obesity in humans.

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Transvenous embolization of a ruptured deep cerebral arteriovenous malformation. A technical note.

Ruptured cerebral arteriovenous malformations (AVMs) usually require treatment to avoid re-bleeding. Depending on the angioarchitecture and center strategy, the treatment can be surgical, endovascular, radiosurgical or combined methods. The classic endovascular approach is transarterial, but sometimes it is not always applicable. The transvenous approach has been described as an alternative for the endovascular treatment of small AVMs when arterial access or another therapeutic method is not possible. This approach can be considered when the nidus is small and if there is a single draining vein. We present a technical note on a transvenous approach for the treatment of a ruptured AVM in a young patient.

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk

The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5′ of the endothelin receptor type A with P = 2.2 × 10−8 [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10−7, PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10−7, PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.

Early surgery for brainstem cavernomas

SummaryBackground. The purpose was to review our experience with the surgical management of brainstem cavernomas (BSCs) and especially the impact of the surgical timing on the clinical outcome.Method. We retrospectively reviewed 22 patients harboring a BSC, who underwent 23 procedures.Findings. Surgery was carried out during the early stage after the last haemorrhage, with a mean delay of 21.6 days (range 4–90 days). Sixteen procedures were performed after a first bleeding event while seven after multiple bleedings. Complete resection was achieved in 19 patients (86.4%). Early after surgery, 12 patients (52.2%) improved neurologically, 5 (21.7%) were stable and 6 (26.1%) worsened. New postoperative deficits were noted after 9 procedures (39.1%). Statistically significant factors for postoperative aggravation were: late surgery (P = 0.046) and multiple bleedings (P = 0.043). No patient operated on within the first 19 days after bleeding did worsen (n = 11), as opposed to 6 out of 12 who did when operated on later. After a mean follow-up of 44.9 months, 20 patients (90.9%) were improved, 1 patient (4.6%) was worse and 1 patient was lost to follow-up (4.6%), after reoperation for rebleeding of a previously completely resected cavernoma. Late morbidity was reduced to 8.6%. The mean Glasgow Outcome Scale (GOS) at the end of the follow-up period was 4.24, compared to a mean preoperative GOS of 3.22 (P<0.001). Complete neurological recovery of motor deficits, sensory disturbances, cranial nerves (CNs), internuclear ophtalmoplegia and cerebellar dysfunction were respectively 41.7%, 38.5%, 52.6%, 60.0% and 58.3%. Among the most affected CNs: CN 3, CN 5 and CN 7 were more prone to completely recover, respectively in 60.0%, 70.0% and 69.2%.Conclusions. Surgical removal of BSCs is feasible in experienced hands with acceptable morbidity and good outcome. Early surgery and single bleeding were associated with better surgical results.

Blood blister-like aneurysms: single center experience and systematic literature review.

Blood blister-like aneurysms (BBAs) are a controversial entity. They arise from non-branching sites on the supraclinoid internal carotid artery (ICA) and are suspected to originate from a dissection. Our aim is to describe the BBA cases seen in our center and to present a systematic review of the literature on BBAs. We analyzed the eleven cases of BBA admitted to our center from 2003 to 2012. We assessed the medical history, treatment modality (endovascular and/or surgery), complications and clinical outcome. The cohort included 8 women and 4 men with a mean age of 53.16 years. Treatment of the BBA consisted of stenting and coiling in 5 patients, stenting only in 4 patients, coiling and clipping in 1 patient, clipping only in 1 patient, and conservative treatment in 1 patient. A good outcome was found in 10 patients, as defined by a modified Rankin Scale (mRS) less than or equal to two at three months. A systematic review of the literature was performed, and 314 reported patients were found: 221 patients were treated with a primarily surgical approach, and 87 patients were treated with a primarily endovascular approach. A rescue or second treatment was required in 46 patients (21%). The overall estimated treatment morbidity rate was 17%, and the mortality rate was 15%. BBAs exhibit more aggressive behavior compared to saccular aneurysms, and more intra-operative complications occur with BBAs, independent of the treatment type offered. They are also significantly more likely to relapse and rebleed after treatment. Endovascular treatment offers a lower morbidity-mortality compared with surgical approaches. Multilayer flow-diverting stents appear to be a promising strategy.

A DSA-Based Method Using Contrast-Motion Estimation for the Assessment of the Intra-Aneurysmal Flow Changes Induced by Flow-Diverter Stents

BACKGROUND AND PURPOSE: Flow-diverter stents modify intra-aneurysmal blood flow and induce the progressive thrombosis of intracranial aneurysms followed by stable vascular reconstruction. The aim of this study was to report a new method for the appraisal of intracranial blood flow from DSA performed during endovascular treatment procedures. MATERIALS AND METHODS: A cohort of 24 patients with unruptured IAs who underwent FDS implantation was prospectively recruited. Pre- and post-DSA sequences in combination with 3D rotational angiography were acquired. The quantification of arterial and intra-aneurysmal flow was accomplished by using an optical flow approach. Flow reduction was assessed by using a new metric termed the mean aneurysm flow amplitude ratio. The correlation between the MAFA ratio and the incidence of aneurysm thrombosis was assessed by using receiver operating characteristic analysis and the Fisher exact test when the optimum Youden index was found. RESULTS: The quantification of flow was successfully achieved in 21 of 24 patients (87.5%). On the imaging follow-up, 18 aneurysms developed complete thrombosis (87.5%) and 3 displayed residual circulation (12.5%). The threshold analysis of the MAFA ratio significantly predicted thrombosis at 12 months below a threshold of 1.03 (P = .035). There was no significant correlation between the time for complete occlusion of the aneurysm and contrast stagnation inside the aneurysm after treatment (P > .05). CONCLUSIONS: The MAFA ratio based on DSA flow quantification appears to be a reliable predictor for the assessment of stent treatment outcomes in this small study. These results open the door for perioperative flow quantification and provide indices that may help clinicians make appropriate intraprocedural decisions.

Intracranial aneurysm stenting: Follow‐up with MR angiography

Intracranial stenting is increasingly being used to treat intracranial aneurysms and stenoses. We wanted to assess the utility of magnetic resonance angiography (MRA) in the follow‐up of patients treated with various types of intracranial stents and to assess the utility of performing gadolinium‐enhanced MRA. A total of 19 patients having undergone intracranial stenting for aneurysms were imaged by MRI at 1.5T. A total of 20 stents were placed in 19 patients. In addition to conventional T2‐ and diffusion‐weighted MRI, 3D time‐of‐flight MRA was performed before and after contrast administration. In the case of metallic INX stents (N = 7), there was a signal drop at the level of the vessel. which did not allow to evaluating the parent vessel, whereas this was visible in Nitinol stents (N = 8). Additionally a stent with a wire had a small artifact (N = 3). Contrast administration also improved vessel lumen visualization. In the case of Nitinol stents, MRA can be used to reliably demonstrate the vessel lumen after intracranial stenting. The use of postcontrast 3D time‐of‐flight imaging helps improve the intraluminal definition. J. Magn. Reson. Imaging 2006.

Risk of Rupture of Small Anterior Communicating Artery Aneurysms Is Similar to Posterior Circulation Aneurysms

Background and Purpose— According to the International Study of Unruptured Intracranial Aneurysms (ISUIA), anterior circulation (AC) aneurysms of <7 mm in diameter have a minimal risk of rupture. It is general experience, however, that anterior communicating artery (AcoA) aneurysms are frequent and mostly rupture at <7 mm. The aim of the study was to assess whether AcoA aneurysms behave differently from other AC aneurysms. Methods— Information about 932 patients newly diagnosed with intracranial aneurysms between November 1, 2006, and March 31, 2012, including aneurysm status at diagnosis, its location, size, and risk factors, was collected during the multicenter @neurIST project. For each location or location and size subgroup, the odds ratio (OR) of aneurysms being ruptured at diagnosis was calculated. Results— The OR for aneurysms to be discovered ruptured was significantly higher for AcoA (OR, 3.5 [95% confidence interval, 2.6–4.5]) and posterior circulation (OR, 2.6 [95% confidence interval, 2.1–3.3]) than for AC excluding AcoA (OR, 0.5 [95% confidence interval, 0.4–0.6]). Although a threshold of 7 mm has been suggested by ISUIA as a threshold for aggressive treatment, AcoA aneurysms <7 mm were more frequently found ruptured (OR, 2.0 [95% confidence interval, 1.3–3.0]) than AC aneurysms of 7 to 12 mm diameter as defined in ISUIA. Conclusions— We found that AC aneurysms are not a homogenous group. Aneurysms between 4 and 7 mm located in AcoA or distal anterior cerebral artery present similar rupture odds to posterior circulation aneurysms. Intervention should be recommended for this high-risk lesion group.