Coil embolization of ruptured intrahepatic pseudoaneurysm through percutaneous transhepatic biliary drainage.

A 75-year-old man with chronic cholangitis and a common bile duct stone that was not previously identified was admitted for right upper quadrant pain. Acute cholecystitis with cholangitis was suspected on abdominal computed tomography (CT); therefore, endoscopic retrograde cholangiopancreatography with endonasal biliary drainage was performed. On admission day 5, hemobilia with rupture of two intrahepatic artery pseudoaneurysms was observed on follow-up abdominal CT. Coil embolization of the pseudoaneurysms was conducted using percutaneous transhepatic biliary drainage. After several days, intrahepatic artery pseudoaneurysm rupture recurred and coil embolization through a percutaneous transhepatic biliary drainage tract was conducted after failure of embolization via the hepatic artery due to previous coiling. After the second coil embolization, a common bile duct stone was removed, and the patient presented no complications during 4 months of follow-up. We report a case of intrahepatic artery pseudoaneurysm rupture without prior history of intervention involving the hepatobiliary system that was successfully managed using coil embolization through percutaneous transhepatic biliary drainage.

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Microcatheter Looping to Facilitate Aneurysm Selection in Coil Embolization of Paraclinoid Aneurysms.

OBJECTIVE: Described herein is a microcatheter looping technique to facilitate aneurysm selection in paraclinoid aneurysms, which remains to be technically challenging due to the inherent complexity of regional anatomy. MATERIALS AND METHODS: This retrospective study was approved by our Institutional Review Board, and informed consent was waived. Microcatheter looping method was employed in 59 patients with paraclinoid aneurysms between January 2012 and December 2013. In the described technique, construction of a microcatheter loop, which is steam-shaped or pre-shaped, based on the direction of aneurysms, is mandatory. The looped tip of microcatheter was advanced into distal internal carotid artery and positioned atop the target aneurysm. By steering the loop (via inner microguidewire) into the dome of aneurysm and easing tension on the microcatheter, the aneurysm was selected. Clinical and morphologic outcomes were assessed with emphasis on technical aspects of the treatment. RESULTS: Through this looping technique, a total of 59 paraclinoid aneurysms were successfully treated. After aneurysm selection as described, single microcatheter technique (n = 25) was most commonly used to facilitate coiling, followed by balloon protection (n = 21), stent protection (n = 7), multiple microcatheters (n = 3), and stent/balloon combination (n = 3). Satisfactory aneurysmal occlusion was achieved through coil embolization in 44 lesions (74.6%). During follow-up of 53 patients (mean interval, 10.9 ± 5.9 months), only one instance (1.9%) of major recanalization was observed. There were no complications related to microcatheter looping. CONCLUSION: This microcatheter looping method facilitates safe and effective positioning of microcatheter into domes of paraclinoid aneurysms during coil embolization when other traditional microcatheter selection methods otherwise fail.

Microcatheter Looping to Facilitate Aneurysm Selection in Coil Embolization of Paraclinoid Aneurysms

OBJECTIVE: Described herein is a microcatheter looping technique to facilitate aneurysm selection in paraclinoid aneurysms, which remains to be technically challenging due to the inherent complexity of regional anatomy. MATERIALS AND METHODS: This retrospective study was approved by our Institutional Review Board, and informed consent was waived. Microcatheter looping method was employed in 59 patients with paraclinoid aneurysms between January 2012 and December 2013. In the described technique, construction of a microcatheter loop, which is steam-shaped or pre-shaped, based on the direction of aneurysms, is mandatory. The looped tip of microcatheter was advanced into distal internal carotid artery and positioned atop the target aneurysm. By steering the loop (via inner microguidewire) into the dome of aneurysm and easing tension on the microcatheter, the aneurysm was selected. Clinical and morphologic outcomes were assessed with emphasis on technical aspects of the treatment. RESULTS: Through this looping technique, a total of 59 paraclinoid aneurysms were successfully treated. After aneurysm selection as described, single microcatheter technique (n = 25) was most commonly used to facilitate coiling, followed by balloon protection (n = 21), stent protection (n = 7), multiple microcatheters (n = 3), and stent/balloon combination (n = 3). Satisfactory aneurysmal occlusion was achieved through coil embolization in 44 lesions (74.6%). During follow-up of 53 patients (mean interval, 10.9 +/- 5.9 months), only one instance (1.9%) of major recanalization was observed. There were no complications related to microcatheter looping. CONCLUSION: This microcatheter looping method facilitates safe and effective positioning of microcatheter into domes of paraclinoid aneurysms during coil embolization when other traditional microcatheter selection methods otherwise fail.

Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.

A risk factor analysis of prospective symptomatic haemorrhage in adult patients with cerebral cavernous malformation.

OBJECTIVE: The purpose of this study was to assess the risk factors of prospective symptomatic haemorrhage in a large series of adult patients with cerebral cavernous malformation (CM). METHODS: Three hundred twenty-six patients >18 years of age with 410 CMs were evaluated retrospectively. Symptomatic haemorrhage was defined as new clinical symptoms with radiographic features of haemorrhage. Clinical data and the characteristics of CM were analysed. MR appearance was divided into three groups according to Zabramski's classification. RESULTS: The overall haemorrhage rate of CM was 4.46% per lesion-year. The overall annual haemorrhage rate according to MR appearance was as follows: type I, 9.47%; type II, 4.74%; and type III, 1.43%. A multivariate analysis revealed that prior symptomatic haemorrhage (p<0.001) and MR appearance (p<0.001) were statistically significant. After multiple comparisons, type I (p<0.001) and type II (p=0.016) showed higher haemorrhage risk than type III. However, no significant difference in haemorrhage rate was observed between type I and type II (p=0.105). Other variables including female gender, age, location, multiplicity, hypertension, size and associated venous angioma were not significant. The haemorrhage rates based on risk factors were estimated at 3 years as follows: 33.77% in patients with prior haemorrhage versus 7.54% in patients without prior haemorrhage (p<0.001); type I, 27.62% vs type II, 15.44% vs type III, 5.38% (p<0.001). CONCLUSIONS: Prior symptomatic haemorrhage and MR appearance could be related to prospective symptomatic CM haemorrhage in adults. A prospective multicentre observational study is necessary to confirm our results.

An update on the diagnosis and treatment of adult Moyamoya disease taking into consideration controversial issues.

Moyamoya disease (MMD) is characterized by a chronic progressive steno-occlusive disease at the distal portion of the internal carotid artery (ICA) with abnormal Moyamoya vessel (MMV) development without associated diseases. Recent advances in radiologic tests have increased the number of MMD patients. Beyond detection improvement by magnetic resonance angiography (MRA) or cerebral angiography, predicting factors for disease severity, future hemorrhage, clinical outcome, post-op complications, and technical advances in assessing cerebral hemodynamics have been increasingly reported. Although treatment of pediatric MMD is well established, controversy remains over the treatment in adult patients. In particular, there are debates over the disease entity of adult MMD, contralateral progression in adult unilateral MMD, treatment strategy for asymptomatic adult MMD, and the association of MMD with thyroid disease. The purpose of this review is to provide an update on the diagnosis and treatment of adult MMD while addressing controversial issues.

X-ray structure of prephenate dehydratase from Streptococcus mutans.

Prephenate dehydratase is a key enzyme of the biosynthesis of L-phenylalanine in the organisms that utilize shikimate pathway. Since this enzymatic pathway does not exist in mammals, prephenate dehydratase can provide a new drug targets for antibiotics or herbicide. Prephenate dehydratase is an allosteric enzyme regulated by its end product. The enzyme composed of two domains, catalytic PDT domain located near the N-terminal and regulatory ACT domain located near the C-terminal. The allosteric enzyme is suggested to have two different conformations. When the regulatory molecule, phenylalanine, is not bound to its ACT domain, the catalytic site of PDT domain maintain open (active) state conformation as Sa-PDT structure. And the open state of its catalytic site become closed (allosterically inhibited) state if the regulatory molecule is bound to its ACT domain as Ct-PDT structure. However, the X-ray structure of prephenate dehydratase from Streptococcus mutans (Sm-PDT) shows that the catalytic site of Sm-PDT has closed state conformation without phenylalanine molecule bound to its regulatory site. The structure suggests a possibility that the binding of phenylalanine in its regulatory site may not be the only prerequisite for the closed state conformation of Sm-PDT.

Contralateral progression and its risk factor in surgically treated unilateral adult moyamoya disease with a review of pertinent literature.

BACKGROUND: The fate of the contralateral unaffected side of the surgically treated unilateral moyamoya disease (MMD) in adults has not been well described due to the limited number of cases and the heterogeneous ages and treatment methods. The aim of this study was to evaluate the contralateral angiographic progression rate and its risk factors in homogeneous adult MMD patients who underwent surgical revascularization, with a review of pertinent literature. METHODS: Forty-one surgically treated unilateral MMD patients were retrospectively evaluated. We reviewed medical and radiological records including data on gender, age, hypertension (HTN), smoking, familial MMD, presenting symptom, surgical method, Suzuki stage, and contralateral progression. Then, we conducted univariate and multivariate analyses to determine risk factors. RESULTS: Six of the 41 cases (14.6%) exhibited contralateral progression during the mean follow-up of 34 months. Four of those six patients (66.7%) were asymptomatic. Additional revascularization surgery was performed in the two symptomatic patients. The presence of a contralateral angiographic abnormality on initial angiography was a statistically significant risk factor for progression (OR, 49.00; p = 0.04). Younger age at diagnosis (32.7 ± 7.8 years in progression group vs. 42.5 ± 10.3 years in non-progression group, p = 0.046) was statistically significant in the univariate analysis, but age was not a significant factor in the multivariate analysis (p = 0.82). Other variables, such as gender (p = 0.13), HTN (p = 0.24), smoking (p = 0.47), and familial MMD (p = 0.20), did not show statistical significance. CONCLUSIONS: The presence of a contralateral angiographic abnormality on initial angiography was a significant risk factor for progression in surgically treated unilateral adult MMD. Consequently, patients with contralateral abnormalities should be monitored closely.

Expression of cellular retinoic acid-binding protein-I (CRABP-I) in the cerebrospinal fluid of adult onset moyamoya disease and its association with clinical presentation and postoperative haemodynamic change.

OBJECTIVE: The elevation of cellular retinoic acid-binding protein-I (CRABP-I) has been suggested as a candidate in the pathogenesis of paediatric moyamoya disease (MMD). However, few studies have addressed CRABP-I in adult onset MMD. The aim of this study was to examine the expression of CRABP-I in the cerebrospinal fluid (CSF) of adult onset MMD, and to evaluate its association with clinical presentation and postoperative haemodynamic change. METHODS: This study examined the CSF from 103 patients: bilateral MMD, n=58 (56.3%); unilateral MMD, n=19 (18.4%); atherosclerotic cerebrovascular disease (ACVD), n=21 (20.4%); and control group, n=5 (4.9%). The intensity of CRABP-I was confirmed by western blotting and expressed as the median (25th-75th percentile). The differences in CRABP-I expression according to disease entity (unilateral MMD vs bilateral MMD vs ACVD), initial presenting symptoms (haemorrhage vs ischaemia) and postoperative haemodynamic change (vascular reserve in single photon emission CT and basal collateral vessels in digital subtraction angiography) were analysed. RESULTS: CRABP-I intensities in bilateral MMD (1.45(0.86-2.52)) were significantly higher than in unilateral MMD (0.91(0.78-1.20)) (p=0.044) or ACVD (0.85(0.66-1.11)) (p=0.004). No significant differences were noted based on the initial presenting symptoms (p=0.687). CRABP-I was not associated with improvement in vascular reserve (p=0.327), but with decrease in basal collateral vessels (p=0.023) postoperatively. CONCLUSIONS: Higher CRABP-I in the CSF can be associated with typical bilateral MMD pathogenesis in adults. Additionally, postoperative basal collateral change may be related to the degree of CRABP-I expression.

A retrospective analysis on the natural history of incidental small paraclinoid unruptured aneurysm.

OBJECTIVE: The optimal consensus concerning treatment of incidental small paraclinoid unruptured intracranial aneurysms (UIAs) remains controversial. The aim of this retrospective study was to reveal the natural history of small paraclinoid UIAs with the goal of informing the treatment plan. METHODS: 524 patients harbouring 568 paraclinoid UIAs (≤5 mm) were retrospectively evaluated during the mean follow-up of 35.4 months. The aneurysms were divided into two groups with respect to arterial branch: related (ophthalmic and superior hypophyseal artery), and non-related. Medical records were reviewed concerning multiple variables, such as sex, age, hypertension (HTN), diabetes mellitus, smoking and aneurysmal factors (size, arterial relationship, multiplicity and the occurrence of rupture and growth). The cumulative risk and the risk factors of aneurysmal rupture and growth were analysed. RESULTS: Two aneurysmal (0.35%) ruptures and 17 growths (3.0%) were observed during the follow-up of 1675.5 aneurysm-years with an annual rupture of 0.12% and an annual growth of 1.01%. The cumulative survival without aneurysmal growth reached a significant difference in aneurysms ≥4 mm (p=0.001), HTN (p=0.002), and arterial branch-related location (p=0.001). Multivariate analysis disclosed that aneurysm ≥4 mm (HR, 4.41; p=0.003), HTN (HR, 5.74; p=0.003), arterial branch-related location (HR, 6.04; p=0.002), and multiplicity (HR, 0.27; p=0.042) were significant predictive factors for aneurysm growth. CONCLUSIONS: Although incidental small paraclinoid UIAs have a relatively lower rupture and growth risk, patients with high-risk factors, including aneurysm ≥4 mm, HTN, arterial branch-related aneurysms, and multiple aneurysms must be monitored closely. The limitation of the retrospective nature of this study should be taken into consideration.

Re-endovascular recanalization for acute middle cerebral artery reocclusion after surgical embolectomy.

A 62-year-old woman with atrial fibrillation underwent burr hole trephination for a chronic subdural hematoma. Two days later the patient suddenly presented with motor dysphasia and slightly decreased motor power. Time of flight MR angiography revealed distal M1 occlusion without diffusion restriction. Stent-assisted mechanical thrombectomy was attempted but failed. Post-procedure MRI illustrated a small area of diffusion restriction within the peri-insular and parietal areas. Immediate surgical embolectomy was performed but reocclusion of M1 was documented in the postoperative angiography. Stent-assisted revascularization with a Solitaire stent was conducted and immediate restoration of blood flow was observed. The patient's motor weakness and motor dysphasia recovered fully. Re-endovascular intervention can be beneficial in selected patients for acute middle cerebral artery reocclusion after surgical embolectomy when endovascular thrombectomy fails.

Dissecting aneurysm of vertebral artery manifestating as contralateral abducens nerve palsy.

Isolated abducens nerve paresis related to ruptured vertebral artery (VA) aneurysm is rare. It usually occurs bilaterally or ipsilaterally to the pathologic lesions. We report the case of a contralateral sixth nerve palsy following ruptured dissecting VA aneurysm. A 38-year-old man was admitted for the evaluation of a 6-day history of headache. Abnormalities were not seen on initial computed tomography (CT). On admission, the patient was alert and no signs reflecting neurologic deficits were noted. Time of flight magnetic resonance angiography revealed a fusiform dilatation of the right VA involving origin of the posterior inferior cerebellar artery. The patient suddenly suffered from severe headache with diplopia the day before the scheduled cerebral angiography. Neurologic examination disclosed nuchal rigidity and isolated left abducens nerve palsy. Emergent CT scan showed high density in the basal and prepontine cistern compatible with ruptured aneurismal hemorrhage. Right vertebral angiography illustrated a right VA dissecting aneurysm with prominent displaced vertebrobasilar artery to inferiorly on left side. Double-stent placement was conducted for the treatment of ruptured dissecting VA aneurysm. No diffusion restriction signals were observed in follow-up magnetic resonance imaging of the brain stem. Eleven weeks later, full recovery of left sixth nerve palsy was documented photographically. In conclusion, isolated contralateral abducens nerve palsy associated with ruptured VA aneurysm may develop due to direct nerve compression by displaced verterobasilar artery triggered by primary thick clot in the prepontine cistern.

Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.

Re-endovascular recanalization for acute middle cerebral artery reocclusion after surgical embolectomy.

A 62-year-old woman with atrial fibrillation underwent burr hole trephination for a chronic subdural hematoma. Two days later the patient suddenly presented with motor dysphasia and slightly decreased motor power. Time of flight MR angiography revealed distal M1 occlusion without diffusion restriction. Stent-assisted mechanical thrombectomy was attempted but failed. Post-procedure MRI illustrated a small area of diffusion restriction within the peri-insular and parietal areas. Immediate surgical embolectomy was performed but reocclusion of M1 was documented in the postoperative angiography. Stent-assisted revascularization with a Solitaire stent was conducted and immediate restoration of blood flow was observed. The patient's motor weakness and motor dysphasia recovered fully. Re-endovascular intervention can be beneficial in selected patients for acute middle cerebral artery reocclusion after surgical embolectomy when endovascular thrombectomy fails.

Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.

Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

Slowly recovering isolated bilateral abducens nerve palsy after embolization of ruptured anterior communicating artery aneurysm.

Bilateral abducens nerve palsy related to ruptured aneurysm of the anterior communicating artery (ACoA) has only been reported in four patients. Three cases were treated by surgical clipping. No report has described the clinical course of the isolated bilateral abducens nerve palsy following ruptured ACoA aneurysm obliterated with coil. A 32-year-old man was transferred to our institution after three days of diplopia, dizziness and headache after the onset of a 5-minute generalized tonic-clonic seizure. Computed tomographic angiography revealed an aneurysm of the ACoA. Magnetic resonance imaging showed focal intraventricular hemorrhage without brain stem abnormalities including infarction or space-occupying lesion. Endovascular coil embolization was conducted to obliterate an aneurysmal sac followed by lumbar cerebrospinal fluid (CSF) drainage. Bilateral paresis of abducens nerve completely recovered 9 weeks after ictus. In conclusion, isolated bilateral abducens nerve palsy associated with ruptured ACoA aneurysm may be resolved successfully by coil embolization and lumbar CSF drainage without directly relieving cerebrospinal fluid pressure by opening Lillequist's membrane and prepontine cistern.

Intravenous flat-detector computed tomography angiography for high-grade carotid stenosis.

AIM: The significant feature of intravenous flat-detector computed tomography (IV FDCT) angiography is its role in neurointerventional setting without patient transfer. However, few studies have addressed the accuracy of IV FDCT in estimating carotid stenosis and length. This study examined the reliability of IV FDCT in the diagnosis of high-grade carotid stenosis and stenosis length with digital subtraction angiography (DSA) as the reference. METHODS: Intravenous flat-detector CT and DSA were conducted simultaneously for 33 patients with 42 stenosed carotid arteries who were suspected of having symptomatic high-grade stenosis by carotid duplex ultrasound, magnetic resonance angiography, or CT angiography. The degree of stenosis and length discrepancy between 2 tests were recorded by 2 readers. RESULTS: The intraobserver and interobserver agreements were excellent for measuring high-grade carotid stenosis (κ = 0.87 and 0.82). Intravenous flat-detector CT had a sensitivity of 96.3%, specificity of 93.3%, and negative predictive value of 93.3% for detecting high-grade stenosis (≥70%) compared with DSA. Bland-Altman plots demonstrated excellent correlation of the degree of stenosis IV FDCT with DSA. Length discrepancy (IV FDCT - DSA, in millimeters) did not differ significantly according to degree of stenosis (Spearman rank test; r = 0.18, P = 0.26). CONCLUSIONS: Intravenous flat-detector CT can be a feasible and time-saving test for evaluating high-grade carotid stenosis and stenosis length.