Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.

Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-(13)C]acetate and can do so while simultaneously oxidizing [1,6-(13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.

Arrive and wait: Inactive bacterial taxa contribute to perceived soil microbiome resilience after a multidecadal press disturbance.

Long-term (press) disturbances like the climate crisis and other anthropogenic pressures are fundamentally altering ecosystems and their functions. Many critical ecosystem functions, such as biogeochemical cycling, are facilitated by microbial communities. Understanding the functional consequences of microbiome responses to press disturbances requires ongoing observations of the active populations that contribute to functions. This study leverages a 7-year time series of a 60-year-old coal seam fire (Centralia, Pennsylvania, USA) to examine the resilience of soil bacterial microbiomes to a press disturbance. Using 16S rRNA and 16S rRNA gene amplicon sequencing, we assessed the interannual dynamics of the active subset and the 'whole' bacterial community. Contrary to our hypothesis, the whole communities demonstrated greater resilience than active subsets, suggesting that inactive members contributed to overall structural resilience. Thus, in addition to selection mechanisms of active populations, perceived microbiome resilience is also supported by mechanisms of dispersal, persistence, and revival from the local dormant pool.

Mechanically operated signalling scaffolds.

Cellular signalling is a complex process and involves cascades of enzymes that, in response to a specific signal, give rise to exact cellular responses. Signalling scaffold proteins organise components of these signalling pathways in space and time to co-ordinate signalling outputs. In this review we introduce a new class of mechanically operated signalling scaffolds that are built into the cytoskeletal architecture of the cell. These proteins contain force-dependent binary switch domains that integrate chemical and mechanical signals to introduce quantised positional changes to ligands and persistent alterations in cytoskeletal architecture providing mechanomemory capabilities. We focus on the concept of spatial organisation, and how the cell organises signalling molecules at the plasma membrane in response to specific signals to create order and distinct signalling outputs. The dynamic positioning of molecules using binary switches adds an additional layer of complexity to the idea of scaffolding. The switches can spatiotemporally organise enzymes and substrates dynamically, with the introduction of ∼50 nm quantised steps in distance between them as the switch patterns change. Together these different types of signalling scaffolds and the proteins engaging them, provide a way for an ordering of molecules that extends beyond current views of the cell.

Multisubstrate DNA stable isotope probing reveals guild structure of bacteria that mediate soil carbon cycling.

Soil microorganisms determine the fate of soil organic matter (SOM), and their activities compose a major component of the global carbon (C) cycle. We employed a multisubstrate, DNA-stable isotope probing experiment to track bacterial assimilation of C derived from distinct sources that varied in bioavailability. This approach allowed us to measure microbial contributions to SOM processing by measuring the C assimilation dynamics of diverse microorganisms as they interacted within soil. We identified and tracked 1,286 bacterial taxa that assimilated 13C in an agricultural soil over a period of 48 d. Overall 13C-assimilation dynamics of bacterial taxa, defined by the source and timing of the 13C they assimilated, exhibited low phylogenetic conservation. We identified bacterial guilds composed of taxa that had similar 13C assimilation dynamics. We show that C-source bioavailability explained significant variation in both C mineralization dynamics and guild structure, and that the growth dynamics of bacterial guilds differed significantly in response to C addition. We also demonstrate that the guild structure explains significant variation in the biogeographical distribution of bacteria at continental and global scales. These results suggest that an understanding of in situ growth dynamics is essential for understanding microbial contributions to soil C cycling. We interpret these findings in the context of bacterial life history strategies and their relationship to terrestrial C cycling.

Is Immobilization Technique Associated With Postoperative Pubic Rami Diastasis Following Bladder Exstrophy Closure?

OBJECTIVE: Pelvic osteotomies relieve tension of the bladder and fascial closures during bladder exstrophy repair. Multiple techniques for postoperative immobilization of the pelvis and lower extremities have been described. The primary aim of this study was to assess differences in short and long-term changes in pubic rami diastasis when comparing Bryant traction to spica cast immobilization. Secondary aims included a comparison of length of stay, skin-related complications, and urologic outcomes. METHODS: We performed a single-institutional retrospective review of bladder exstrophy patients younger than 18 months of age who underwent posterior pelvic osteotomy and bladder exstrophy closure from April 2005 to April 2020. Short-term and long-term pubic rami diastasis were defined as postoperative measurements ≤6 months and ≥12 months, respectively. Secondary outcomes included length of stay, pressure ulcer, skin rash/abrasion, urethrocutaneous fistula, and bladder or fascial dehiscence rates. Multivariable logistic regression assessed for an association between immobilization type and degree of diastasis while controlling for age at the time of diastasis measurement and sex. RESULTS: Fifteen patients underwent Bryant traction and 36 patients underwent spica cast immobilization. In both the short-term and long-term, there was a greater reduction in pubic diastasis in the spica cast group ( P = 0.002 and P = 0.05, respectively). After adjustments, there were higher odds of having a greater reduction in pubic rami diastasis in both the short-term (odds ratio: 2.71, 95% CI: 1.52-4.86, P = 0.001) and long-term (odds ratio: 2.41, 95% CI: 1.00-5.80, P = 0.05). Length of stay was significantly higher in Bryant's traction group (26 vs 19 d, P < 0.001). Rates of pressure ulcers were higher in the Bryant traction group (26.7% vs 0%, P = 0.005). Rates of skin rash/abrasions, urethrocutaneous fistula, and bladder/fascial dehiscence did not differ. CONCLUSIONS: Spica cast immobilization is a safe and effective immobilization method. Compared with Bryant traction, spica cast immobilization was associated with a greater reduction in postoperative pubic diastasis both short and long-term, along with a shorter length of hospitalization and reduced rate of pressure ulcers. LEVEL OF EVIDENCE: Level III-therapeutic study.

Metagenomic stable isotope probing reveals bacteriophage participation in soil carbon cycling.

Soil viruses are important components of the carbon (C) cycle, yet we still know little about viral ecology in soils. We added diverse 13 C-labelled carbon sources to soil and we used metagenomic-SIP to detect 13 C assimilation by viruses and their putative bacterial hosts. These data allowed us to link a 13 C-labelled bacteriophage to its 13 C-labelled Streptomyces putative host, and we used qPCR to track the dynamics of the putative host and phage in response to C inputs. Following C addition, putative host numbers increased rapidly for 3 days, and then more gradually, reaching maximal abundance on Day 6. Viral abundance and virus:host ratio increased dramatically over 6 days, and remained high thereafter (8.42 ± 2.94). From Days 6 to 30, virus:host ratio remained high, while putative host numbers declined more than 50%. Putative host populations were 13 C-labelled on Days 3-30, while 13 C-labelling of phage was detected on Days 14 and 30. This dynamic suggests rapid growth and 13 C-labelling of the host fueled by new C inputs, followed by extensive host mortality driven by phage lysis. These findings indicate that the viral shunt promotes microbial turnover in soil following new C inputs, thereby altering microbial community dynamics, and facilitating soil organic matter production.

Bacterial community dynamics explain carbon mineralization and assimilation in soils of different land-use history.

Soil dwelling microorganisms are key players in the terrestrial carbon cycle, driving both the degradation and stabilization of soil organic matter. Bacterial community structure and function vary with respect to land use; yet the ecological drivers of this variation remain poorly described and difficult to predict. We conducted a multi-substrate DNA-stable isotope probing experiment across cropland, old-field, and forest habitats to link carbon mineralization dynamics with the dynamics of bacterial growth and carbon assimilation. We tracked the movement of 13 C derived from five distinct carbon sources as it was assimilated into bacterial DNA over time. We show that carbon mineralization, community composition, and carbon assimilation dynamics all differed with respect to land use. We also show that microbial community dynamics affect carbon assimilation dynamics and are associated with soil DNA content. Soil DNA yield is easy to measure and may be useful in predicting microbial community dynamics linked to soil carbon cycling. Soil dwelling microorganisms are key players in the terrestrial carbon cycle, driving both the degradation and stabilization of soil organic matter. Microbial communities vary with respect to land use, but we still have an incomplete understanding of how variation in community structure links to variation in community function. DNA stable isotope probing (DNA-SIP) is a high-resolution method that can identify specific microbial taxa that assimilate carbon in situ. We conducted a large-scale multi-substrate DNA-SIP experiment to explore differences in bacterial activity across land-use regimes. We show that microbial community dynamics vary with land use, that these dynamics are linked to soil carbon cycling, and that they are associated with easily measured soil properties.

Tracing Carbon Metabolism with Stable Isotope Metabolomics Reveals the Legacy of Diverse Carbon Sources in Soil.

Tracking the metabolic activity of whole soil communities can improve our understanding of the transformation and fate of carbon in soils. We used stable isotope metabolomics to trace 13C from nine labeled carbon sources into the water-soluble metabolite pool of an agricultural soil over time. Soil was amended with a mixture of all nine sources, with one source isotopically labeled in each treatment. We compared changes in the 13C enrichment of metabolites with respect to carbon source and time over a 48-day incubation and contrasted differences between soluble sources (glucose, xylose, amino acids, etc.) and insoluble sources (cellulose and palmitic acid). Whole soil metabolite profiles varied singularly by time, while the composition of 13C-labeled metabolites differed primarily by carbon source (R2 = 0.68) rather than time (R2 = 0.07), with source-specific differences persisting throughout incubations. The 13C labeling of metabolites from insoluble carbon sources occurred slower than that from soluble sources but yielded a higher average atom percent (atom%) 13C in metabolite markers of biomass (amino acids and nucleic acids). The 13C enrichment of metabolite markers of biomass stabilized between 5 and 15 atom% 13C by the end of incubations. Temporal patterns in the 13C enrichment of tricarboxylic acid cycle intermediates, nucleobases (uracil and thymine), and by-products of DNA salvage (allantoin) closely tracked microbial activity. Our results demonstrate that metabolite production in soils is driven by the carbon source supplied to the community and that the fate of carbon in metabolites do not generally converge over time as a result of ongoing microbial processing and recycling. IMPORTANCE Carbon metabolism in soil remains poorly described due to the inherent difficulty of obtaining information on the microbial metabolites produced by complex soil communities. Our study demonstrates the use of stable isotope probing (SIP) to study carbon metabolism in soil by tracking 13C from supplied carbon sources into metabolite pools and biomass. We show that differences in the metabolism of sources influence the fate of carbon in soils. Heterogeneity in 13C-labeled metabolite profiles corresponded with compositional differences in the metabolically active populations, providing a basis for how microbial community composition correlates with the quality of soil carbon. Our study demonstrates the application of SIP-metabolomics in studying soils and identifies several metabolite markers of growth, activity, and other aspects of microbial function.

Community Organization and Metagenomics of Bacterial Assemblages Across Local Scale pH Gradients in Northern Forest Soils.

Soil pH has shown to predict bacterial diversity, but mechanisms are still poorly understood. To investigate how bacteria distribute themselves as a function of soil pH, we assessed community composition, diversity, assembly, and gene abundance across local (ca. 1 km) scale gradients in soil pH from ~ 3.8 to 6.5 created by differences in soil parent material in three northern forests. Plant species were the same on all sites, with no evidence of agriculture in the past. Concentrations of extractable calcium, iron, and phosphorus also varied significantly across the pH gradients. Among taxa, Alphaproteobacteria and Acidobacteria were more common in soils with acidic pH values. Overall richness and diversity of OTUs peaked at intermediate pH values. Variations in OTU richness and diversity also had a quadratic fit with concentrations of extractable calcium and phosphorus. Community assembly was via homogeneous deterministic processes in soils with acidic pH values, whereas stochastic processes dominated in soils with near-neutral pH values. Although we expected selection via genes for acid tolerance response in acidic soils, genes for genetic information processing were more selective. Taxa in higher pH soils had differential abundance of transporter genes, suggesting adaptation to acquire metabolic substrates from soils. Soil bacterial communities in northern forest soils are incredibly diverse, and we still have much to learn about how soil pH and co-varying soil parameters directly drive gene selection in this critical component of ecosystem structure.

Surgical Site Infection After Autologous Cranioplasty for Decompressive Craniectomy in Traumatic Brain Injury: A Retrospective Review of Two Level 1 Trauma Centers.

OBJECT: Surgical site infection (SSI) after cranioplasty can result in unnecessary morbidity. This analysis was designed to determine the risk factors of SSI after cranioplasty in patients who received a decompressive craniectomy with the autologous bone for traumatic brain injury (TBI). METHODS: A retrospective review was performed at two level 1 academic trauma centers for adult patients who underwent autologous cranioplasty after prior decompressive craniectomy for TBI. Demographic and procedural variables were collected and analyzed for associations with an increased incidence of surgical site infection with two-sample independent t tests and Mann Whitney U tests, and with a Bonferroni correction applied in cases of multiple comparisons. Statistical significance was reported with a P value of < 0.05. RESULTS: A total of 71 patients were identified. The mean interval from craniectomy to cranioplasty was 99 days (7-283), and 3 patients developed SSIs after cranioplasty (4.2%). Postoperative drain placement (P > 0.08) and administration of intrawound vancomycin powder (P = 0.99) were not predictive of infection risk. However, a trend was observed suggesting that administration of prophylactic preoperative IV vancomycin is associated with a reduced infection rate. CONCLUSIONS: The SSI rate after autologous cranioplasty in TBI patients is lower than previously reported for heterogeneous groups and indications, and the infection risk is comparable to other elective neurosurgical procedures. As such, the authors recommend attempting to preserve native skull and perform autologous cranioplasty in this population whenever possible.

Simulating metagenomic stable isotope probing datasets with MetaSIPSim.

BACKGROUND: DNA-stable isotope probing (DNA-SIP) links microorganisms to their in-situ function in diverse environmental samples. Combining DNA-SIP and metagenomics (metagenomic-SIP) allows us to link genomes from complex communities to their specific functions and improves the assembly and binning of these targeted genomes. However, empirical development of metagenomic-SIP methods is hindered by the complexity and cost of these studies. We developed a toolkit, 'MetaSIPSim,' to simulate sequencing read libraries for metagenomic-SIP experiments. MetaSIPSim is intended to generate datasets for method development and testing. To this end, we used MetaSIPSim generated data to demonstrate the advantages of metagenomic-SIP over a conventional shotgun metagenomic sequencing experiment. RESULTS: Through simulation we show that metagenomic-SIP improves the assembly and binning of isotopically labeled genomes relative to a conventional metagenomic approach. Improvements were dependent on experimental parameters and on sequencing depth. Community level G + C content impacted the assembly of labeled genomes and subsequent binning, where high community G + C generally reduced the benefits of metagenomic-SIP. Furthermore, when a high proportion of the community is isotopically labeled, the benefits of metagenomic-SIP decline. Finally, the choice of gradient fractions to sequence greatly influences method performance. CONCLUSIONS: Metagenomic-SIP is a valuable method for recovering isotopically labeled genomes from complex communities. We show that metagenomic-SIP performance depends on optimization of experimental parameters. MetaSIPSim allows for simulation of metagenomic-SIP datasets which facilitates the optimization and development of metagenomic-SIP experiments and analytical approaches for dealing with these data.

Lateral Segregation of Photosystem I in Cyanobacterial Thylakoids.

Photosystem I (PSI) is the dominant photosystem in cyanobacteria and it plays a pivotal role in cyanobacterial metabolism. Despite its biological importance, the native organization of PSI in cyanobacterial thylakoid membranes is poorly understood. Here, we use atomic force microscopy (AFM) to show that ordered, extensive macromolecular arrays of PSI complexes are present in thylakoids from Thermosynechococcus elongatus, Synechococcus sp PCC 7002, and Synechocystis sp PCC 6803. Hyperspectral confocal fluorescence microscopy and three-dimensional structured illumination microscopy of Synechocystis sp PCC 6803 cells visualize PSI domains within the context of the complete thylakoid system. Crystallographic and AFM data were used to build a structural model of a membrane landscape comprising 96 PSI trimers and 27,648 chlorophyll a molecules. Rather than facilitating intertrimer energy transfer, the close associations between PSI primarily maximize packing efficiency; short-range interactions with Complex I and cytochrome b6f are excluded from these regions of the membrane, so PSI turnover is sustained by long-distance diffusion of the electron donors at the membrane surface. Elsewhere, PSI-photosystem II contact zones provide sites for docking phycobilisomes and the formation of megacomplexes. PSI-enriched domains in cyanobacteria might foreshadow the partitioning of PSI into stromal lamellae in plants, similarly sustained by long-distance diffusion of electron carriers.

Label-free Single-Molecule Quantification of Rapamycin-induced FKBP-FRB Dimerization for Direct Control of Cellular Mechanotransduction.

Chemically induced dimerization (CID) has been applied to study numerous biological processes and has important pharmacological applications. However, the complex multistep interactions under various physical constraints involved in CID impose a great challenge for the quantification of the interactions. Furthermore, the mechanical stability of the ternary complexes has not been characterized; hence, their potential application in mechanotransduction studies remains unclear. Here, we report a single-molecule detector that can accurately quantify almost all key interactions involved in CID and the mechanical stability of the ternary complex, in a label-free manner. Its application is demonstrated using rapamycin-induced heterodimerization of FRB and FKBP as an example. We revealed the sufficient mechanical stability of the FKBP/rapamycin/FRB ternary complex and demonstrated its utility in the precise switching of talin-mediated force transmission in integrin-based cell adhesions.

Diverse genotypes of the amphibian-killing fungus produce distinct phenotypes through plastic responses to temperature.

Phenotypes are the target of selection and affect the ability of organisms to persist in variable environments. Phenotypes can be influenced directly by genes and/or by phenotypic plasticity. The amphibian-killing fungus Batrachochytrium dendrobatidis (Bd) has a global distribution, unusually broad host range, and high genetic diversity. Phenotypic plasticity may be an important process that allows this pathogen to infect hundreds of species in diverse environments. We quantified phenotypic variation of nine Bd genotypes from two Bd lineages (Global Pandemic Lineage [GPL] and Brazil) and a hybrid (GPL-Brazil) grown at three temperatures (12, 18 and 24°C). We measured five functional traits including two morphological traits (zoospore and zoosporangium sizes) and three life history traits (carrying capacity, time to fastest growth and exponential growth rate) in a phylogenetic framework. Temperature caused highly plastic responses within each genotype, with all Bd genotypes showing phenotypic plasticity in at least three traits. Among genotypes, Bd generally showed the same direction of plastic response to temperature: larger zoosporangia, higher carrying capacity, longer time to fastest growth and slower exponential growth at lower temperatures. The exception was zoospore size, which was highly variable. Our findings indicate that Bd genotypes have evolved novel phenotypes through plastic responses to temperature over very short timescales. High phenotypic variability likely extends to other traits and may facilitate the large host range and rapid spread of Bd.

Detection of 2-hydroxyglutarate in brain tumors by triple-refocusing MR spectroscopy at 3T in vivo.

PURPOSE: To test the efficacy of triple-refocusing MR spectroscopy (MRS) for improved detection of 2-hydroxyglutarate (2HG) in brain tumors at 3T in vivo. METHODS: The triple-refocusing sequence parameters were tailored at 3T, with density-matrix simulations and phantom validation, for enhancing the 2HG 2.25-ppm signal selectivity with respect to the adjacent resonances of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA). In vivo MRS data were acquired from 15 glioma patients and analyzed with LCModel using calculated basis spectra. Metabolites were quantified with reference to water. RESULTS: A triple-refocusing sequence (echo time = 137 ms) was obtained for 2HG detection. The 2HG 2.25-ppm signal was large and narrow while the Glu and Gln signals between 2.2 and 2.3 ppm were minimal. The optimized triple refocusing offered improved separation of 2HG from Glu, Gln and GABA when compared with published MRS methods. 2HG was detected in all 15 patients, the estimated 2HG concentrations ranging from 2.4 to 15.0 mM, with Cramer-Rao lower bounds of 2%-11%. The 2HG estimates did not show significant correlation with total choline. CONCLUSION: The optimized triple refocusing provides excellent 2HG signal discrimination from adjacent resonances and may confer reliable in vivo measurement of 2HG at relatively low concentrations. Magn Reson Med 78:40-48, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis.

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Unusual skull tumors with psammomatoid bodies: a diagnostic challenge.

AIM: We describe a series of three diagnostically challenging, histologically similar fibro-osseous skull masses. METHODS: The cases were identified in our archives among 50,000 neuropathology specimens. A comprehensive review of the histological, immunohistochemical, ultrastructural, and imaging features as well as the clinical outcome was performed. RESULTS: The routine histology was similar in all 3 cases and showed spindle cell proliferations with frequent calcospheres or psammomatoid bodies. There was no evidence of an underlying subdural component. Immunohistochemistry for the meningioma markers EMA and SSTR2A raised the possibility of intraosseous meningioma, as all 3 lesions were convincingly positive for epithelial membrane antigen (EMA) and 1 lesion was convincingly positive for the somatostatin receptor subtype 2A (SSTR2A); weak, questionable positivity for SSTR2 was present in the remaining 2 cases. In addition, electron microscopy was available in 1 case and showed features consistent with meningioma. CONCLUSIONS: Overall, the findings were most consistent with intraosseous meningioma. Primary intraosseous meningiomas are rare lesions that may present a diagnostic challenge. It is important to consider meningiomas in the differential diagnosis, as extradural meningiomas are associated with an increased risk of recurrence and may occasionally undergo malignant transformation.
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Pre-treatment factors associated with detecting additional brain metastases at stereotactic radiosurgery.

The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS-planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1 mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34 % of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into <2, 2-3, or ≥3 cm, additional metastases were identified in 37, 29, and 18 %, respectively. While this increase in the number of metastases is largely due to the difference in imaging technique, the number and size of the metastases were also associated with finding additional lesions. These clinical factors may be considered when determining treatment options for brain metastases.

Management of intracranial aneurysms associated with arteriovenous malformations.

Intracranial or brain arteriovenous malformations (BAVMs) are some of the most interesting and challenging lesions treated by the cerebrovascular neurosurgeon. It is generally believed that the combination of BAVMs and intracranial aneurysms (IAs) is associated with higher hemorrhage rates at presentation and higher rehemorrhage rates and thus with a more aggressive course and natural history. There is wide variation in the literature on the prevalence of BAVM-associated aneurysms (range 2.7%-58%), with 10%-20% being most often cited in the largest case series. The risk of intracranial hemorrhage in patients with unruptured BAVMs and coexisting IAs has been reported to be 7% annually, compared with 2%-4% annually for those with BAVM alone. Several different classification systems have been applied in an attempt to better understand the natural history of this combination of lesions and implications for treatment. Independent of the classification used, it is clear that a few subtypes of aneurysms have a direct hemodynamic correlation with the BAVM itself. This is exemplified by the fact that the presence of a distal flow-related or an intranidal aneurysm appears to be associated with an increased hemorrhage risk, when compared with an aneurysm located on a vessel with no direct supply to the BAVM nidus. Debate still exists regarding the etiology of the association between those two vascular lesions, the subsequent implications for patients' risk of hemorrhagic stroke, and finally the determination of which patients warrant treatment and when. The ultimate goals of the treatment of a BAVM associated with an IA are to prevent hemorrhage, avoid stepwise neurological deterioration, and eliminate the mortality risk associated with recurrent hemorrhagic events. The treatment is only justifiable if the risks associated with an intervention are lower than or equivalent to the long-term risks of disability or mortality caused by the lesion itself. When faced with this difficult decision, a few questions need to be answered by the treating neu-rosurgeon: What is the mode of presentation? What is the symptomatic lesion? Which one of the lesions bled? What is the relationship between the BAVM and IA? Is it possible to safely treat both BAVM and IA? The objective of this review is to discuss the demographics, natural history, classification, and strategies for management of BAVMs associated with IAs.