Negative feedback for DARS2-Fis complex by ATP-DnaA supports the cell cycle-coordinated regulation for chromosome replication.

In Escherichia coli, the replication initiator DnaA oscillates between an ATP- and an ADP-bound state in a cell cycle-dependent manner, supporting regulation for chromosome replication. ATP-DnaA cooperatively assembles on the replication origin using clusters of low-affinity DnaA-binding sites. After initiation, DnaA-bound ATP is hydrolyzed, producing initiation-inactive ADP-DnaA. For the next round of initiation, ADP-DnaA binds to the chromosomal locus DARS2, which promotes the release of ADP, yielding the apo-DnaA to regain the initiation activity through ATP binding. This DnaA reactivation by DARS2 depends on site-specific binding of IHF (integration host factor) and Fis proteins and IHF binding to DARS2 occurs specifically during pre-initiation. Here, we reveal that Fis binds to an essential region in DARS2 specifically during pre-initiation. Further analyses demonstrate that ATP-DnaA, but not ADP-DnaA, oligomerizes on a cluster of low-affinity DnaA-binding sites overlapping the Fis-binding region, which competitively inhibits Fis binding and hence the DARS2 activity. DiaA (DnaA initiator-associating protein) stimulating ATP-DnaA assembly enhances the dissociation of Fis. These observations lead to a negative feedback model where the activity of DARS2 is repressed around the time of initiation by the elevated ATP-DnaA level and is stimulated following initiation when the ATP-DnaA level is reduced.

[Symptomatic arachnoid cyst in an elderly patient who developed motor aphasia].

The patient was an 83-year-old woman with a history of breast cancer, distal right radial edge bone fracture, and cervical spine symptoms who had been diagnosed with an arachnoid cyst 9 years previously. She was examined by a nearby doctor, because of an approximately 1-year history of reduced verbal output; she also begun experiencing difficulties with walking. However, she was diagnosed with aging, a history of cervical spondylosis, and the effects of past fractures.At the time of this consultation, she was conscious and lucid, with mild right-sided hemiparesis, was unable to write, and had mild motor aphasia. Head magnetic resonance imaging revealed an arachnoid cyst (longer axis: 10 cm) in the left frontal lobe that did not take up contrast media. There was also a midline shift. The cause of the right hemiparesis and motor aphasia was probably compression of the left frontal lobe by the arachnoid cyst.We performed excision of the cyst wall by craniotomy and placed a cyst-peritoneal shunt under general anesthesia. At approximately one week after surgery, the patient was able to write and her motor aphasia improved. She was discharged 20 days after the operation.It is rare for an arachnoid cyst to increase in size after childhood. In the present case, surgical treatment led to a good outcome in an elderly patient with a symptomatic arachnoid cyst. Arachnoid cysts rarely increase in size. These cysts may become symptomatic in elderly people after lying clinically dormant for a long time.

A novel mode of DnaA-DnaA interaction promotes ADP dissociation for reactivation of replication initiation activity.

ATP-DnaA is temporally increased to initiate replication during the cell cycle. Two chromosomal loci, DARS (DnaA-reactivating sequences) 1 and 2, promote ATP-DnaA production by nucleotide exchange of ADP-DnaA for timely initiation. ADP-DnaA complexes are constructed on DARS1 and DARS2, bearing a cluster of three DnaA-binding sequences (DnaA boxes I-III), promoting ADP dissociation. Although DnaA has an AAA+ domain, which ordinarily directs construction of oligomers in a head-to-tail manner, DnaA boxes I and II are oriented oppositely. In this study, we constructed a structural model of a head-to-head dimer of DnaA AAA+ domains, and analyzed residues residing on the interface of the model dimer. Gln208 was specifically required for DARS-dependent ADP dissociation in vitro, and in vivo analysis yielded consistent results. Additionally, ADP release from DnaA protomers bound to DnaA boxes I and II was dependent on Gln208 of the DnaA protomers, and DnaA box III-bound DnaA did not release ADP nor require Gln208 for ADP dissociation by DARS-DnaA complexes. Based on these and other findings, we propose a model for DARS-DnaA complex dynamics during ADP dissociation, and provide novel insight into the regulatory mechanisms of DnaA and the interaction modes of AAA+ domains.

Coil embolization of recurrent ruptured vertebral artery dissection through a marathon microcatheter: A case report.

A 56-year-old healthy woman presented with subarachnoid hemorrhage caused by ruptured vertebral artery dissecting aneurysm and was treated with internal trapping of the affected site including the aneurysm. She suffered rebleeding due to recanalization of the aneurysm 5 days after the first treatment. Because of the close proximity of the coil mass to the posterior inferior cerebellar artery (PICA) origin at first treatment, additional coil embolization by tight packing of the coil mass was planned. However, navigation of the microcatheter into the coil mass was challenging due to the tightly packed coil mass. Thus, a Marathon microcatheter, which has narrower outer diameter and is designed for liquid embolization, was used and successfully placed into the coil mass in an anterograde fashion. Thereafter, the DAC was advanced just proximal to the coil mass to reduce the kickback of the microcatheter during deployment of the coils and avoid the coil mass expansion toward the PICA origin, resulting in complete obliteration of the aneurysm with PICA preservation. Follow-up angiography performed 6 months after the second treatment showed complete obliteration of the aneurysm. The patient's course was uneventful after 1 year following the second treatment, with a modified Rankin Scale score of 1. Therefore, coil embolization through the tightly packed coil mass using a Marathon microcatheter is feasible. A low-profile DAC is also useful for enabling physicians to push the coil deployed through the flexible Marathon microcatheter.

Endovascular treatment for secondary basilar occlusion caused by spontaneous thrombus migration from the vertebral artery: Two case reports.

Thrombus migration is a well-known clinical condition that occurs before mechanical thrombectomy and after intravenous thrombolysis in patients with anterior circulation strokes. Although thrombus migration from the vertebral artery (VA) can result in life-threatening basilar artery (BA) occlusion, its occurrence in the posterior circulation has rarely been discussed. Two patients with secondary BA occlusion caused by spontaneous thrombus migration from the VA are presented. A 60-year-old man with a left cerebellar infarction secondary to ipsilateral VA occlusion was admitted to our hospital 8 hours after onset, with a National Institute of Health Stroke Scale (NIHSS) score of 4. The patient became comatose 3.5 hours after arrival owing to subsequent BA occlusion. He was successfully treated with mechanical thrombectomy. A 74-year-old man with right cerebellar infarction secondary to ipsilateral VA occlusion was admitted to our hospital 26 hours after onset, with an NIHSS score of 3. He became comatose 1 hour after arrival owing to BA occlusion and was treated with thrombectomy, followed by internal and external decompression. Despite the mild symptoms of VA occlusion and consequently delayed admission to the hospital, stroke physicians should be aware that spontaneous thrombus migration from the VA to the BA can result in a life-threatening presentation.

Endovascular intervention for bilateral paramedian thalamic stroke due to occlusion of the unilateral P1 segment of the posterior cerebral artery: illustrative cases.

BACKGROUND: Occlusion of the unilateral P1 segment can result in bilateral paramedian thalamic infarction in patients with anatomical variants of the bilateral paramedian thalamic artery arising from a single P1 segment. Despite the life-threatening presentation of bilateral paramedian thalamic stroke, timely diagnosis is often challenging. OBSERVATIONS: The authors herein describe 3 patients treated with endovascular intervention for occlusion of the unilateral P1 segment wherein the bilateral paramedian thalamic arteries arose. All patients were admitted to the authors' emergency department with sudden-onset coma and respiratory distress; however, initial computed tomography was unremarkable. Despite suspicion of basilar artery occlusion, vertebral and carotid angiography revealed occlusion of the unilateral P1 segment. All patients were successfully treated with endovascular intervention. Overall, 2 patients had favorable outcomes (modified Rankin scale [mRS] scores of 0 and 1), whereas in 1 patient, the mRS score reached a baseline score of 3. LESSONS: In patients with the variant of the bilateral paramedian thalamic artery arising from a single P1 segment, occlusion of the unilateral P1 segment can be life threatening; nevertheless, timely endovascular treatment is effective. Carotid and vertebral angiography, rather than magnetic resonance or computed tomography angiography, is useful for immediate and reliable diagnosis of the relatively small vascular lesions.

Balloon-hooking technique for stabilizing a guiding catheter in tortuous supra-aortic vessel: A case report.

Objective: When performing endovascular interventions for supra-aortic vessels, the tortuous vascular anatomy observed in patients with atherosclerotic lesions often limits the ability to maintain a stable guiding catheter position. Here, we report a case of right vertebral artery (VA) stenosis treated with transfemoral stenting and discuss the utility of balloon-hooking technique using partially inflated balloon for stabilizing the balloon guiding catheter (BCG) in the supra-aortic vessel. Case presentation: A 74-year-old man who underwent right carotid artery stenting, coronary artery bypass grafting, and bilateral iliac artery stenting was admitted to our emergency department because of dizziness related to head movement. Computed tomography angiography revealed right VA origin stenosis and left subclavian artery (SA) occlusion. The patient underwent stenting of the right VA. After several unsuccessful cannulation attempts into the right VA through transradial access, transfemoral access was obtained through the left iliac stent. A 9-Fr BGC was navigated into the right SA. The balloon was partially inflated just distal to the first curve of the right SA and used as hook by pulling back until the proximal edge of the balloon was pushed distally by the lesser curvature of the SA, resulting in stabilization of the BGC and successful angioplasty and stent deployment at the VA stenosis. The patient's symptoms resolved completely, without any neurological deficits. Conclusions: Balloon-hooking technique using a partially inflated BGC is feasible for stabilizing the guiding catheter in tortuous supra-aortic vessel.

Drag-out technique using a large balloon fixed with an aspiration catheter for retrieving residual thrombus on the wall of the superior sagittal sinus: illustrative case.

BACKGROUND: The authors report a patient with sagittal sinus thrombosis that was resistant to reported endovascular treatments but successfully recanalized by dragging out the thrombus using a large balloon fixed with an aspiration catheter. OBSERVATIONS: A 57-year-old man presented with the persistent headache and a simple partial seizure. Diagnostic study with computed tomography and angiography demonstrated the superior sagittal sinus (SSS) thrombosis. Due to the neurological worsening even after systemic heparinization, the patient underwent mechanical thrombectomy. Despite six passes of stent retrievers and a large-bore aspiration catheter, functional recanalization was not achieved. Therefore, the so-called dental floss technique was attempted using a large compliant balloon catheter (Transform 7 × 7 mm). However, the balloon catheter just wobbled along the lesion without recanalization. To restrict the movement of the balloon catheter, the distal shaft of the balloon catheter was fixed with the aspiration catheter, and both the balloon and the aspiration catheter were slowly pulled to drag the thrombus out, resulting in recanalization of cortical veins as well as the SSS. LESSONS: Dragging the thrombus using a large balloon fixed with an aspiration catheter was a useful technique to retrieve sticky thrombus in the patients with the sinus thrombosis.

Predicting the consistency of intracranial meningiomas using apparent diffusion coefficient maps derived from preoperative diffusion-weighted imaging.

OBJECTIVE: The consistency of meningiomas is a critical factor affecting the difficulty of resection, operative complications, and operative time. The apparent diffusion coefficient (ADC) is derived from diffusion-weighted imaging (DWI) and is calculated using two optimized b values. While the results of comparisons between the standard ADC and the consistency of meningiomas vary, the shifted ADC has been reported to be strongly correlated with liver stiffness. The purpose of the present prospective cohort study was to determine whether preoperative standard and shifted ADC maps predict the consistency of intracranial meningiomas. METHODS: Standard (b values 0 and 1000 sec/mm2) and shifted (b values 200 and 1500 sec/mm2) ADC maps were calculated using preoperative DWI in patients undergoing resection of intracranial meningiomas. Regions of interest (ROIs) were placed within the tumor on standard and shifted ADC maps and registered on the navigation system. Tumor tissue located at the registered ROI was resected through craniotomy, and its stiffness was measured using a durometer. The cutoff point lying closest to the upper left corner of a receiver operating characteristic (ROC) curve was determined for the detection of tumor stiffness such that an ultrasonic aspirator or scissors was always required for resection. Each tumor tissue sample with stiffness greater than or equal to or less than this cutoff point was defined as hard or soft tumor, respectively. RESULTS: For 76 ROIs obtained from 25 patients studied, significant negative correlations were observed between stiffness and the standard ADC (ρ = -0.465, p < 0.01) and the shifted ADC (ρ = -0.490, p < 0.01). The area under the ROC curve for detecting hard tumor (stiffness ≥ 20.8 kPa) did not differ between the standard ADC (0.820) and the shifted ADC (0.847) (p = 0.39). The positive predictive value (PPV) for the combination of a low standard ADC and a low shifted ADC for detecting hard tumor was 89%. The PPV for the combination of a high standard ADC and a high shifted ADC for detecting soft tumor (stiffness < 20.8 kPa) was 81%. CONCLUSIONS: A combination of standard and shifted ADC maps derived from preoperative DWI can be used to predict the consistency of intracranial meningiomas.

Improvement in gait function after carotid endarterectomy is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex: a 123I-iomazenil SPECT study.

OBJECTIVE: Carotid endarterectomy (CEA) often restores cerebral perfusion and neurotransmitter receptor function, which is seen on early and late images, respectively, on brain I-iomazenil single-photon emission computed tomography (SPECT). The reliability of gait-related parameters obtained using a triaxial accelerometer, a portable device for gait assessment, has been confirmed with test-retest measurements. The purpose of the present prospective cohort study was to determine whether improvement in gait function after CEA is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex. METHODS: Gait testing using a triaxial accelerometer was performed preoperatively and 6 months postoperatively in 64 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≥70%). I-iomazenil SPECT was also performed with scanning within 30 min (early images) and at 180 min (late images) after tracer administration before and after surgery. SPECT data were analyzed using a three-dimensional stereotactic surface projection, and motor (Brodmann 4) and premotor (Brodmann 6) cortexes in each hemisphere were combined and defined as the motor-related cortex. RESULTS: Based on preoperative and postoperative gait testing, seven patients (11%) showed postoperative improved gait. Logistic regression analysis revealed that postoperative increase in I-iomazenil uptake in the motor-related cortex ipsilateral to surgery on early [95% confidence interval (CI), 4.32-365.21; P = 0.0477) or late (95% CI, 9.45-1572.57; P = 0.0173) images was an independent predictor of postoperative improved gait. CONCLUSIONS: Improvement in gait function after CEA is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex.

Two-Year Clinical, Cerebral Hemodynamic, and Cognitive Outcomes of Adult Patients Undergoing Medication Alone for Symptomatically Ischemic Moyamoya Disease Without Cerebral Misery Perfusion: A Prospective Cohort Study.

BACKGROUND: In nonsurgical adult moyamoya disease (MMD) patients with ischemic onset and stable hemodynamics, the cerebral hemodynamic and cognitive course remains unclear. OBJECTIVE: To clarify, through a prospective cohort study, 2-yr clinical, cerebral hemodynamic, and cognitive outcomes of adult patients receiving medication alone for symptomatically ischemic MMD without cerebral misery perfusion. METHODS: Seventy patients without cerebral misery perfusion on the first 15O gas positron emission tomography (PET) were clinically followed up for 2 yr. The second PET was performed at the end of the 2-yr follow-up. Neuropsychological tests were also performed at the study entry and the end of the 2-yr follow-up. RESULTS: During the 2-yr follow-up period, 2 patients (3%) developed further cerebral ischemic symptoms and showed new cerebral misery perfusion on PET performed at recurrence. None of the 68 patients without further ischemic symptoms showed cerebral misery perfusion on second PET. All 66 patients who underwent the first and second neuropsychological tests displayed unchanged interval cognition at the 2-yr follow-up. CONCLUSION: Among adult patients receiving medication alone for symptomatically ischemic MMD without cerebral misery perfusion, the incidence of recurrent ischemic events was 3% per 2 yr. In patients without recurrent ischemic events, cerebral hemodynamics and cognitive function had not deteriorated by 2 yr after the last event.

Cilostazol may improve cognition better than clopidogrel in non-surgical adult patients with ischemic moyamoya disease: subanalysis of a prospective cohort.

OBJECTIVE: Adult patients with ischemic moyamoya disease (MMD) who receive treatment with antiplatelet drugs reportedly show improvements in neuropsychological test scores after around 2 years. The purpose of the present study subanalyzing the same patient cohort used in a previous study was to determine which antiplatelet drug, clopidogrel or cilostazol, results in better improvement of cognitive function among non-surgical adult patients showing ischemic MMD without severe hemodynamic compromise. METHODS: Sixty-six patients without cerebral misery perfusion on 15O gas positron emission tomography were treated with pharmacotherapy alone. Patients ≥50 years old and <50 years old initially received clopidogrel and cilostazol, respectively. Any patient suffering side effects of the antiplatelet drug switched to the other antiplatelet drug. Neuropsychological tests were performed at study entry and at the end of the 2-year follow-up, and differences in each neuropsychological test score between the two time points (second test score - first test score) were calculated and defined as Δ scores. RESULTS: Among the five neuropsychological tests, Δ scores for two tests were significantly greater in patients treated with cilostazol (n = 36) than in those treated with clopidogrel (n = 30), and Δ scores of the remaining three tests did not differ between patient groups. Based on Δ scores, 15 patients (23%) were defined as showing interval cognitive improvement. On multivariate analysis, cilostazol administration (95% confidence interval, 1.19-193.98; P = 0.0361) represented an independent predictor of interval cognitive improvement. CONCLUSIONS: Cilostazol may improve cognition better than clopidogrel in non-surgical adult patients with ischemic MMD.

Preoperative brain temperature imaging on proton magnetic resonance spectroscopy predicts hemispheric ischemia during carotid endarterectomy for unilateral carotid stenosis with inadequate collateral blood flow.

Objective Preoperative magnetic resonance (MR) angiography sometimes shows the absence of collateral flow via the circle of Willis. This study examined whether brain temperature (BT) imaging on multi-voxel proton MR spectroscopy after this finding increases the accuracy of predicting hemispheric ischemia during internal carotid artery (ICA) clamping during endarterectomy for patients with symptomatic unilateral carotid stenosis. Methods In 52 patients with ICA stenosis (≥70%) and absence of collateral blood flow via the circle of Willis on preoperative MR angiography, BT imaging was displayed using proton multi-voxel MR spectroscopy. The difference between BTs in the affected and contralateral hemispheres (BTaffected hemisphere - BTcontralateral hemisphere) in the deep white matter of the centrum semiovale was calculated and defined as hemispheric ΔBT. Development of cerebral hemispheric ischemia during ICA clamping was determined from intraoperative electroencephalography (EEG). Results Multivariate analysis revealed that high preoperative hemispheric ΔBT was significantly associated with development of EEG-defined hemispheric ischemia (95% confidence intervals [CIs], 5.376-15.452; p = 0.006). The positive-predictive value for development of EEG-defined hemispheric ischemia was significantly greater for preoperative hemispheric ΔBT following preoperative MR angiography (95%CI, 42-87%) than for preoperative MR angiography alone (95%CI, 13-37%). Conclusions For patients without collateral flow via the circle of Willis, BT imaging increases the predictive accuracy for development of hemispheric ischemia during ICA clamping during CEA.

Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease.

The present study examined whether preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. Among 65 adult patients with ischemic moyamoya disease, 19 had misery perfusion in the precentral region on preoperative 15O positron emission tomography and underwent arterial bypass surgery for that region. Brain technetium-99 m-labeled ethyl cysteinate dimer single-photon emission computed tomography (SPECT) was preoperatively performed with and without hyperventilation challenge and relative cerebrovascular contractile reactivity to hypocapnia (RCVCRhypocap) (%/mmHg) was calculated in the precentral region. Development of cerebral hyperperfusion syndrome was determined using perioperative changes of symptoms and brain N-isopropyl-p-[123I]-iodoamphetamine SPECT performed after surgery. RCVCRhypocap was significantly lower in the 6 patients with cerebral hyperperfusion syndrome (-2.85 ± 1.10%/mmHg) than in the 13 patients without cerebral hyperperfusion syndrome (0.18 ± 1.97%/mmHg; p = 0.0050). Multivariate analysis demonstrated low RCVCRhypocap as an independent predictor of cerebral hyperperfusion syndrome (95% confidence interval, 0.04-0.96; p = 0.0433). Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease.