Rose Du

HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion

Development of hypoxic regions is an indicator of poor prognosis in many tumors. Here, we demonstrate that HIF1alpha, the direct effector of hypoxia, partly through increases in SDF1alpha, induces recruitment of bone marrow-derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+, and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP-9 activity of bone marrow-derived CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1alpha, SDF1alpha levels decrease, and fewer BM-derived cells are recruited to the tumors, decreasing MMP-9 and mobilization of VEGF. VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment.

On the transition coordinate for protein folding

To understand the kinetics of protein folding, we introduce the concept of a “transition coordinate” which is defined to be the coordinate along which the system progresses most slowly. As a practical implementation of this concept, we define the transmission coefficient for any conformation to be the probability for a chain with the given conformation to fold before it unfolds. Since the transmission coefficient can serve as the best possible measure of kinetic distance for a system, we present two methods by which we can determine how closely any parameter of the system approximates the transmission coefficient. As we determine that the transmission coefficient for a short-chain heteropolymer system is dominated by entropic factors, we have chosen to illustrate the methods mentioned by applying them to geometrical properties of the system such as the number of native contacts and the looplength distribution. We find that these coordinates are not good approximations of the transmission coefficient and therefore, cannot adequately describe the kinetics of protein folding.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Effect of Presenting Hemorrhage on Outcome after Microsurgical Resection of Brain Arteriovenous Malformations

OBJECTIVE:We hypothesized that patients with unruptured arteriovenous malformations (AVMs) at presentation have an increased risk of deterioration compared with patients with ruptured AVMs. METHODS:A consecutive series of 224 patients treated microsurgically by a single neurosurgeon during a period of 6.4 years was analyzed. Initial hemorrhagic presentation was the primary predictor variable. Neurological outcomes were assessed by use of the Modified Rankin Scale (MRS) and Glasgow Outcome Scale (GOS), and logistic regression identified predictors of deterioration at follow-up (mean duration, 1.3 yr) relative to baseline before any intervention. RESULTS:Overall, 120 patients (54%) presented with hemorrhage, and all 224 patients underwent microsurgical resection. Complete resection was achieved in 220 patients (98%). According to GOS score, 13 patients (5.8%) deteriorated; according to MRS score, 45 patients (20.1%) deteriorated. Fifteen patients (6.7%) died. Hemorrhagic presentation was associated with improved outcomes, with a mean change in MRS score of +0.89 in patients with ruptured AVMs and −0.38 in patients with unruptured AVMs (P < 0.001). The final mean MRS scores in patients with unruptured AVMs were better than those in patients with ruptured AVMs (1.44 versus 1.90; P = 0.048). Presentation with an unruptured AVM was a predictor of worsening MRS score (odds ratio, 2.33; 95% confidence interval, 1.3–4.3; P = 0.006) but not of worsening GOS score. CONCLUSION:Presentation with AVM hemorrhage is an underappreciated predictor of outcome after therapy that includes microsurgical resection. Patients with ruptured AVMs tended to have deficits at presentation and generally improved after surgery, whereas patients with unruptured AVMs tended to have normal or nearly normal neurological function at presentation and were susceptible to worsening, albeit slight, as measured by MRS scores. Sensitive outcome measures such as MRS detect subtle symptoms and impairments missed by coarser measures such as GOS. Patients should be counseled that the risks associated with elective resection of unruptured AVMs may be higher than recognized previously. Hemorrhagic brain injury and its secondary effects may mask this surgical morbidity.

The natural history of intracranial cavernous malformations

Literature reports on the natural history of cerebral cavernous malformations (CMs) are numerous, with considerable variability in lesion epidemiology, hemorrhage rates, and risk factors for hemorrhage. In this review, the authors performed a meta-analysis of 11 natural history studies. The overall male-to-female ratio was 1:1, and the mean age at presentation was 30.6 years. Overall, 37% of patients presented with seizures, 36% with hemorrhage, 23% with headaches, 22% with focal neurological deficits, and 10% were asymptomatic. Some patients had more than one symptom. Seizure presentation was most prevalent among supratentorial CMs, while focal neurological deficits were common in patients with infratentorial CMs. By location, CMs were in the cerebral hemispheres (66%), brainstem (18%), basal ganglia or thalamus (8%), cerebellum (6%), and other (2.5% [combined supra- and infratentorial, callosal or insular]). Overall, 19% of patients harbored multiple intracranial CMs, and 9% had radiographically apparent associated developmental venous anomalies. An overall annual hemorrhage rate of 2.4% per patient-year (range 1.6%-3.1%) was identified across 3 studies. Prior hemorrhage and female sex were risk factors for bleeding, while CM size and multiplicity did not affect hemorrhage rates. Although not impacting the hemorrhage rate itself, deep location was a risk factor for increased clinical aggressiveness.

Angiopoietin-2 Facilitates Vascular Endothelial Growth Factor-Induced Angiogenesis in the Mature Mouse Brain

Background and Purpose— A better understanding of angiogenic factors and their effects on cerebral angiogenesis is necessary for the development of effective therapeutic strategies for ischemic brain injury. Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis in the adult mouse brain. However, the function of angiopoietin-2 (Ang-2) in cerebral angiogenesis has not been clarified. The goal of this study was to identify the combined effects of VEGF and Ang-2 on cerebral angiogenesis and the blood–brain barrier (BBB). Methods— Six groups of 6 adult male CD-1 mice underwent AdlacZ (viral vector control), AdVEGF, AdAng2, VEGF protein, VEGF protein plus AdAng2, or saline (negative control) injection. Microvessels were counted using lectin staining on tissue sections after 2 weeks of treatment. Matrix metalloproteinase-9 (MMP-9) activity was determined by zymography. The presence of zonula occludens-1 (ZO-1) protein was determined by Western blot and immunohistochemistry. Results— Mice treated with VEGF protein infusion plus AdAng-2 significantly increased microvessel counts relative to all other groups (P<0.05). The changes in MMP-9 activity paralleled the reduced ZO-1 expression in the VEGF plus Ang-2–treated group compared with the other 5 groups (P<0.05). Double-labeled immunostaining demonstrated that ZO-1–positive staining was significantly decreased on the microvessel wall in the VEGF plus Ang-2–treated group. Conclusions— Our study demonstrates that the combination of VEGF and Ang-2 promotes more angiogenesis compared with VEGF alone. Furthermore, the combination of VEGF and Ang-2 may lead to BBB disruption because it increases MMP-9 activity and inhibits ZO-1 expression.

Effect of the neurosurgeon's surgical experience on outcomes from intraoperative aneurysmal rupture.

OBJECTIVE:The neurosurgeon’s surgical experience is one of the most important and least studied factors affecting a patient’s outcome after an intraoperative rupture of an aneurysm. Therefore, this analysis was undertaken to evaluate the effect of the neurosurgeon’s experience on the management of this catastrophe in a consecutive series of patients treated microsurgically. METHODS:The neurosurgeon’s surgical experience was analyzed in terms of annual aneurysm case volume and duration. Management of intraoperative aneurysmal rupture was analyzed in terms of timing of rupture, duration of temporary clipping, and neurological outcomes using the Glasgow Outcome Scale. During a 7-year period in which 1038 aneurysms were treated microsurgically in 838 patients, 68 (6.6%) ruptured intraoperatively. RESULTS:The neurosurgeon’s annual aneurysm case volume increased by 35% over this period, and mean case duration decreased by 31%. The annual frequency of intraoperative ruptures fluctuated, with most (88%) occurring with previously ruptured aneurysms in patients with subarachnoid hemorrhage. With increasing surgical experience, the number of ruptures during predissection and clip application, the mean duration of temporary clipping, and the surgical mortality rate all declined, whereas the number of patients experiencing a good outcome (Glasgow Outcome Scale score of 5 or 4) increased. CONCLUSION:Intraoperative rupture is an unavoidable danger in aneurysm surgery that does not diminish with increasing surgical experience of the neurosurgeon performing the operation. However, experience did improve the neurosurgeon’s response to aneurysm rupture and the patients’ outcomes. Mental anticipation and technical repetition over time transform into efficiency, confidence, and insight in the management of this distressing intraoperative event.

The effects of diffuseness and deep perforating artery supply on outcomes after microsurgical resection of brain arteriovenous malformations.

OBJECTIVEDiffuse arteriovenous malformations (AVM) have non-compact niduses, irregular margins, and intervening brain parenchyma. Deep perforating arteries often contribute to the ragged border of these diffuse AVMs. We hypothesized that diffuseness and deep perforator supply increase the difficulties and risks associated with microsurgical AVM resection. METHODSDiffuseness was quantified using computer-generated outlines of AVMs on angiograms, contour plots with varying image intensities, and calculations of nidus area-intensity profiles. Diffuse AVMs had nonlinear area-intensity profiles with high transition intensities ([I*] greater than 0.5). A consecutive series of 304 patients who were treated with microsurgical AVM resection over a period of 7.8 years was analyzed, along with quantification of diffuseness in a subset of 103 consecutive patients. Neurological outcomes were assessed by using the Modified Rankin Scale, and logistic regression analysis was used to identify predictors of deterioration and poor outcome at late follow-up evaluation. RESULTSDiffuse niduses were observed in 25% of patients, and 18% of patients had deep perforating artery supply. Patients with compact AVMs were more likely to have good outcomes or overall improvement (88 and 87%, respectively) than patients with diffuse AVMs (65 and 54%, respectively) (P = 0.008 and P < 0.001, respectively). Similarly, absence of deep perforator supply was associated with good outcomes or improvement in 85 and 78% of patients, respectively, compared with 63 and 64% of patients, respectively, in patients with deep perforator supply (P < 0.001 and P = 0.028, respectively). By logistic regression analysis, diffuseness and deep perforator supply were both associated with significant increases in surgical risk. CONCLUSIONDiffuseness and deep perforating artery supply are subtle features of an AVM that predict worse outcomes after microsurgical resection. Diffuseness makes surgical planes more difficult to determine and follow, whereas deep perforators are friable, poorly visualized, and located in eloquent white matter tracts. The Spetzler-Martin grading scale does not directly account for these two features; however, they should be considered carefully when making treatment recommendations to patients with AVMs.

Magnetic resonance neurography for the evaluation of peripheral nerve, brachial plexus, and nerve root disorders.

OBJECT Treatment of spinal and peripheral nerve lesions relies on localization of the pathology by the use of neurological examination, spinal MR imaging and electromyography (EMG)/nerve conduction studies (NCSs). Magnetic resonance neurography (MRN) is a novel imaging technique recently developed for direct imaging of spinal and peripheral nerves. In this study, the authors analyzed the role of MRN in the evaluation of spinal and peripheral nerve lesions. METHODS Imaging studies, medical records, and EMG/NCS results were analyzed retrospectively in a consecutive series of 191 patients who underwent MRN for spinal and peripheral nerve disorders at the University of California, San Francisco between March 1999 and February 2005. Ninety-one (47.6%) of these patients also underwent EMG/NCS studies. RESULTS In those who underwent both MRN and EMG/NCS, MRN provided the same or additional diagnostic information 32 and 45% of patients, respectively. Magnetic resonance neurograms were obtained at a median of 12 months after the onset of symptoms. The utility of MRN correlated with the interval between the onset of symptoms to MRN. Twelve patients underwent repeated MRN for serial evaluation. The decrease in abnormal signal detected on subsequent MRN correlated with time from onset of symptoms and the time interval between MRN, but not with resolution of symptoms. Twenty-one patients underwent MRN postoperatively to assess persistent, recurrent, or new symptoms; of these 3 (14.3%) required a subsequent surgery. CONCLUSIONS Magnetic resonance neurography is a valuable adjunct to conventional MR imaging and EMG/NCS in the evaluation and localization of nerve root, brachial plexus, and peripheral nerve lesions. The authors found that MRN is indicated in patients: 1) in whom EMG and traditional MR imaging are inconclusive; 2) who present with brachial plexopathy who have previously received radiation therapy to the brachial plexus region; 3) who present with brachial plexopathy and have systemic tumors; and 4) in patients under consideration for surgery for peripheral nerve lesions or after trauma. Magnetic resonance neurography is limited by the size of the nerve trunk imaged and the timing of the study.

The natural history of cerebral dural arteriovenous fistulae.

BACKGROUND Hemorrhage from cerebral dural arteriovenous fistulae (dAVF) is a considerable source of neurological morbidity and even mortality. OBJECTIVE To evaluate the natural history of cerebral dAVF. METHODS We reviewed our own cohort of 70 dAVF and incorporated results from the literature, synthesizing pooled hemorrhage rates and evaluating risk factors for 395 dAVF in 6 studies. RESULTS No hemorrhages occurred during 409 lesion-years of follow-up of Borden type I dAVF; however, cortical venous drainage developed in 1.4%. Like type I dAVF, type II dAVF demonstrated a female predilection and were most commonly transverse-sigmoid or cavernous. Eighteen percent of type II dAVF presented with hemorrhage (95% confidence interval [CI]: 8%-36%), and the annual hemorrhage rate was 6% (95% CI: 0.1%-19%). Borden type III dAVF demonstrated a male predilection and were most commonly tentorial or petrosal. Thirty-four percent presented with hemorrhage (95% CI: 0.4%-49%), with an annual hemorrhage rate of 10% (95% CI: 4%-20%), increasing to 21% for those with venous ectasia (95% CI: 4%-66%). The hemorrhage rate decreased to 2% for asymptomatic or minimally symptomatic type II or III dAVF (95% CI: 0.2%-8%), and increased to 10% for those presenting with nonhemorrhagic neurological deficits (95% CI: 0.9%-41%) and to 46% for those presenting with hemorrhage (95% CI: 11%-130%). CONCLUSION Venous ectasia is a significant risk factor for hemorrhage among dAVF with cortical venous drainage. In addition, those with hemorrhagic presentation, even compared with nonhemorrhagic neurological deficit presentation, as well as Borden type III dAVF compared with type II dAVF demonstrated a trend toward greater hemorrhage rates.