The rotation of the earth on its axis results in alternating light and temperature conditions that have guided the evolution of nearly all forms of life. The resultant biological timekeepers are known as circadian clocks. This internal 24-hour oscillator orchestrates critical aspects of growth, development, and metabolism to synchronize with the appropriate time of day and impart adaptive advantages. In the plant model organism Arabidopsis thaliana, a number of the molecular components of the circadian clock have been identified. However, critical nodes of this complex transcriptional network remain undiscovered. To address this deficiency, we created a collection of nearly every transcription factor encoded in the Arabidopsis genome. This transcription factor library platform allows us to conduct unbiased genome-wide screens for new genes functioning within the circadian clock. Using heterologous expression systems such as yeast one-hybrid and yeast two-hybrid, we have detected many protein-DNA and protein-protein interactions that indicate heretofore unrecognized regulatory connections. Initial investigations using an abridged transcription factor collection led to the discovery of CCA1 HIKING EXPEDITION (CHE) as a component of the Arabidopsis circadian clock. Further experiments with this platform are enabling the identification of a number of new circadian clock components, thereby greatly expanding our understanding of this genetic network and informing in -silico models of the clock. In addition, we have used the transcription factor library collection to conduct a systematic in-planta overexpression screen for novel regulators of the circadian clock. This approach has helped overcome many of the barriers to gene discovery associated with forward genetic screens. Proving the effectiveness of this method, we were able to identify members of the B-Box Zinc Finger protein family that display previously undiscovered robust circadian phenotypes when overexpressed. Functional genomic toolsets such as this transcription factor library are becoming essential to gaining a systems level understanding of complex biological processes

Object

Management of unruptured arteriovenous malformations (AVMs) is controversial. In the first randomized trial of unruptured AVMs (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [ARUBA]), medically managed patients had a significantly lower risk of death or stroke and had better outcomes. The University of California, San Francisco (UCSF) was one of the participating ARUBA sites. While 473 patients were screened for eligibility, only 4 patients were enrolled in ARUBA. The purpose of this study is to report the treatment and outcomes of all ARUBA-eligible patients at UCSF.

Methods

The authors compared the treatment and outcomes of ARUBA-eligible patients using prospectively collected data from the UCSF brain AVM registry. Similar to ARUBA, they compared the rate of stroke or death in observed and treated patients and used the modified Rankin Scale to grade outcomes.

Results

Of 74 patients, 61 received an intervention and 13 were observed. Most treated patients had resection with or without preoperative embolization (43 [70.5%] of 61 patients). One of the 13 observed patients died after AVM hemorrhage. Nine of the 61 treated patients had a stroke or died. There was no significant difference in the rate of stroke or death (HR 1.34, 95% CI 0.12-14.53, p = 0.81) or clinical impairment (Fisher's exact test, p > 0.99) between observed and treated patients.

Conclusions

The risk of stroke or death and degree of clinical impairment among treated patients was lower than reported in ARUBA. The authors found no significant difference in outcomes between observed and treated ARUBA-eligible patients at UCSF. Results in ARUBA-eligible patients managed outside that trial led to an entirely different conclusion about AVM intervention, due to the primary role of surgery, judicious surgical selection with established outcome predictors, and technical expertise developed at high-volume AVM centers.

Background

Arteriovenous malformation (AVM) patients present in 4 ways relative to hemorrhage: (1) unruptured, without a history or radiographic evidence of old hemorrhage (EOOH); (2) silent hemorrhage, without a bleeding history but with EOOH; (3) ruptured, with acute bleeding but without EOOH; and (4) reruptured, with acute bleeding and EOOH.

Objective

We hypothesized that characteristics and outcomes in the unrecognized group of silent hemorrhage patients may differ from those of unruptured patients.

Methods

Two hundred forty-two patients operated-on since 1997 were categorized by hemorrhage status and hemosiderin positivity in this cohort study: unruptured (group 1), silent hemorrhage (group 2), and ruptured/reruptured (group 3/4). Group 3/4 was combined because hemosiderin cannot distinguish acute hemorrhage from older silent hemorrhage.

Results

Hemosiderin was found in 45% of specimens. Seventy-five patients (31.0%) had unruptured AVMs, 30 (12.4%) had silent hemorrhage, and 137 (56.6%) had ruptured/reruptured AVMs. Deep drainage, posterior fossa location, preoperative modified Rankin Scale (mRS) score, outcome, and macrophage score were different across groups. Only the macrophage score was different between the groups without clinical hemorrhage. Outcomes were better in silent hemorrhage patients than in those with frank rupture (mean mRS scores of 1.2 and 1.7, respectively).

Conclusion

One-third of patients present with silent AVM hemorrhage. No clinical or anatomic features differentiate these patients from unruptured patients, except the presence of hemosiderin and macrophages. Silent hemorrhage can be diagnosed using magnetic resonance imaging with iron-sensitive imaging. Silent hemorrhage portends an aggressive natural history, and surgery halts progression to rerupture. Good final mRS outcomes and better outcomes than in those with frank rupture support surgery for silent hemorrhage patients, despite the findings of ARUBA.

Object

Patients with posterior fossa arteriovenous malformations (AVMs) are more likely to present with hemorrhage than those with supratentorial AVMs. Observed patients subject to the AVM natural history should be informed of the individualized effects of AVM characteristics on the clinical course following a new, first-time hemorrhage. The authors hypothesize that the debilitating effects of first-time bleeding from an AVM in a previously intact patient with an unruptured AVM are more pronounced when AVMs are located in the posterior fossa.

Methods

The University of California, San Francisco prospective registry of brain AVMs was searched for patients with a ruptured AVM who had a pre-hemorrhage modified Rankin Scale (mRS) score of 0 and a post-hemorrhage mRS score obtained within 2 days of the hemorrhagic event. A total of 154 patients met the inclusion criteria for this study. Immediate post-hemorrhage presentation mRS scores were dichotomized into nonsevere outcome (mRS ≤ 3) and severe outcome (mRS > 3). There were 77 patients in each group. Univariate and multivariate logistic regression analyses using severe outcome as the binary response were run. The authors also performed a logistic regression analysis to measure the effects of hematoma volume and AVM location on severe outcome.

Results

Posterior fossa location was a significant predictor of severe outcome (OR 2.60, 95% CI 1.20-5.67, p = 0.016) and the results were strengthened in a multivariate model (OR 4.96, 95% CI 1.73-14.17, p = 0.003). Eloquent location (OR 3.47, 95% CI 1.37-8.80, p = 0.009) and associated arterial aneurysms (OR 2.58, 95% CI 1.09, 6.10; p = 0.031) were also significant predictors of poor outcome. Hematoma volume for patients with a posterior fossa AVM was 10.1 ± 10.1 cm(3) compared with 25.6 ±28.0 cm(3) in supratentorial locations (p = 0.003). A logistic analysis (based on imputed hemorrhage volume values) found that posterior fossa location was a significant predictor of severe outcome (OR 8.03, 95% CI 1.20-53.77, p = 0.033) and logarithmic hematoma volume showed a positive, but not statistically significant, association in the model (p = 0.079).

Conclusions

Patients with posterior fossa AVMs are more likely to have severe outcomes than those with supratentorial AVMs based on this natural history study. Age, sex, and ethnicity were not associated with an increased risk of severe outcome after AVM rupture, but posterior fossa location, associated aneurysms, and eloquent location were associated with poor post-hemorrhage mRS scores. Posterior fossa hematomas are poorly tolerated, with severe outcomes observed even with smaller hematoma volumes. These findings support an aggressive surgical posture with respect to posterior fossa AVMs, both before and after rupture.

Purpose To determine if adrenal calcifications seen at computed tomography (CT) are associated with familial cerebral cavernous malformations (fCCMs) in carriers of the CCM1 Common Hispanic Mutation. Materials and Methods This study was approved by the institutional review board. The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease. ^© RSNA, 2017.

Brain arteriovenous malformations (bAVMs) are vascular lesions that can cause significant morbidity and mortality, particularly when they bleed, i.e., rupture. Determining the risk of rupture for bAVMs is a crucial task to determine the most appropriate approach to patients with bAVM. Furthermore, patients who present with a hemorrhagic event also have a higher risk of subsequent hemorrhage. Determination of the hemorrhage risk and management strategy for incidentally discovered bAVMs still remains a controversial subject. In recent years, we have identified silent intralesional microhemorrhages (SIMs) as a possible risk factor for subsequent hemorrhage in patients with bAVMs. The principal aim of this study was to determine critical histological features that can be correlated with preoperative radioimaging findings, and allow better identification of patients with greater risk of adverse outcome. Here we provide a detailed descriptive analysis of the morphometric assessment of bAVMs in order to provide reproducible methodology that will aid in correlating preoperative radioimaging findings with histological features that may be significantly associated with increased risk of hemorrhage/rupture.

Objective

The pathogenesis of dural arteriovenous fistulas (DAVFs) remains poorly defined. Prior studies on thrombophilia as a risk factor for DAVF development are limited by small sample sizes and poor generalizability.

Methods

In this longitudinal observational study, all patients with intracranial DAVFs evaluated at the University of California, San Francisco from December 1994 through April 2014 were identified. After obtaining patient consent, 3 thrombophilic mutations, factor V Leiden (rs6025), MTHFR (rs1801133), and prothrombin G20210A, were genotyped. The authors evaluated the association of thrombophilia status (presence of any thrombophilic mutation) and clinical and angiographic characteristics using either a 2-sample t-test or Fisher's exact test.

Results

A total of 116 patients with diagnosed intracranial DAVFs were included in the study. Twenty-five (22%) patients met criteria for thrombophilia. Focal neurological deficits tended to occur more frequently in the thrombophilia group (78% vs 57%, p = 0.09). Angiographic characteristics of DAVFs, including high-risk venous flow pattern, multiplicity of DAVF, and the presence of venous sinus thrombosis, did not differ significantly between the 2 groups but tended to be more common in the thrombophilic than in the nonthrombophilic group.

Conclusions

This study is one of the largest of thrombophilia and DAVF to date. The frequency of mutations associated with thrombophilia in this study was higher than that in the general population.

Myeloid immune cells are abundant in both ruptured and unruptured brain arteriovenous malformations (bAVMs). The role of central nervous system (CNS) resident and circulating monocyte-derived macrophages in bAVM pathogenesis has not been fully understood. We hypothesize that CNS resident macrophages enhance bAVM development and hemorrhage. RNA sequencing using cultured endothelial cells (ECs) and mouse bAVM samples revealed that downregulation of two bAVM causative genes, activin-like kinase 1 (ALK1) or endoglin, increased inflammation and innate immune signaling. To understand the role of CNS resident macrophages in bAVM development and hemorrhage, we administrated a colony-stimulating factor 1 receptor inhibitor to bAVM mice with brain focal Alk1 deletion. Transient depletion of CNS resident macrophages at an early stage of bAVM development mitigated the phenotype severity of bAVM, including a prolonged inhibition of angiogenesis, dysplastic vasculature formation, and infiltration of CNS resident and circulating monocyte-derived macrophages during bAVM development. Transient depletion of CNS resident macrophages increased EC tight junction protein expression, reduced the number of dysplasia vessels and severe hemorrhage in established bAVMs. Thus, EC AVM causative gene mutation can activate CNS resident macrophages promoting bAVM progression. CNS resident macrophage could be a therapeutic target to mitigate the development and severity of bAVMs.

Stroke is an important risk factor for bone fracture. We showed previously that bone fracture at the acute stage of ischemic stroke worsens, and activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) improves, stroke recovery by attenuating inflammation. We hypothesized that activation of α-7 nAchR also improves the blood-brain barrier (BBB) integrity. Permanent distal middle cerebral artery occlusion (pMCAO) was performed on C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA 568487 (PHA, α-7 nAchR-specific agonist), 6 mg/kg methyllycaconitine (MLA, α-7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Brain water content, the expression of monoamine oxidase B (MAO-B), and tight junction protein (claudin-5) were assessed. We found that tibia fracture increased water content in the ischemic stroke brain (p = 0.006) and MAO-B-positive astrocytes (p < 0.001). PHA treatment reduced water content and MAO-B-positive astrocytes and increased claudin-5 expression in stroke and stroke + tibia fracture mice (p < 0.05), while MLA had the opposite effect. Our findings suggest that in addition to inhibiting inflammation, activation of α-7 nAchR also reduces brain edema, possibly through diminished astrocyte oxidative stress and improved BBB integrity. Thus, the α-7 nAchR-specific agonist could be developed into a new therapy for improving recovery of patients with stroke or stroke + bone fracture.