Low-RF-loss and large-rejection reconfigurable Brillouin-based RF photonic bandpass filter.

We present a high-performance radio frequency (RF) photonic bandpass filter enabled by combining on-chip Brillouin scattering with a suppressed carrier phase modulation scheme. We achieve a low RF loss of 5 dB and a large stopband rejection of more than 40 dB, which represents a significant improvement of 20 dB to the RF passband gain and 31 dB to the RF rejection ratio over traditional modulation schemes under the same optical power consumption. We further demonstrate filter reconfigurability including multiple passbands, wide frequency (1-20 GHz), and bandwidth tunability (30-350 MHz) without compromising the RF performance.

Ex Vivo CD34+-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease and High Treatment Response.

Ex vivo CD34+-selected T cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic (allo) hematopoietic stem cell transplantation (HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (aGVHD) and chronic GVHD (cGVHD) after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age, 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34+-selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grades II-IV and III-IV aGVHD at 180 days were 16% (95% confidence interval [CI], 12 to 21) and 5% (95% CI, 3 to 9), respectively. The skin was the most frequent organ involved, followed by the gastrointestinal tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. The cumulative incidence of any cGVHD at 3 years was 5% (95% CI, 3 to 9), with a median time of onset of 256 days (range, 95 to 1645). The 3-year transplant-related mortality, relapse, overall survival, and disease-free survival were 24% (95% CI, 18 to 30), 22% (95% CI, 17 to 27), 57% (95% CI, 50 to 64), and 54% (95% CI, 47 to 61), respectively. The 1-year and 3-year probabilities of cGVHD-free/relapse-free survival were 65% (95% CI, 59 to 71) and 52% (95% CI, 45 to 59), respectively. Our findings support the use of ex vivo CD34+-selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS.

Phenomenological Model of the Growth of Ultrasmooth Silver Thin Films Deposited with a Germanium Nucleation Layer.

The structural properties of optically thin (15 nm) silver (Ag) films deposited on SiO2/Si(100) substrates with a germanium (Ge) nucleation layer were studied. The morphological and crystallographical characteristics of Ag thin films with different Ge nucleation layer thicknesses were assessed by cross-sectional transmission electron microscopy (XTEM), reflection high-energy electron diffraction (RHEED), X-ray diffractometry (XRD), grazing incidence X-ray diffractometry (GIXRD), X-ray reflection (XRR), and Fourier transform infrared spectroscopy (FTIR). The surface roughness of Ag thin films was found to decrease significantly by inserting a Ge nucleation layer with a thickness in the range of 1 to 2 nm (i.e., smoothing mode). However, as the Ge nucleation layer thickness increased beyond 2 nm, the surface roughness increased concomitantly (i.e., roughing mode). For the smoothing mode, the role of the Ge nucleation layer in the Ag film deposition is discussed by invoking the surface energy of Ge, the bond dissociation energy of Ag-Ge, and the deposition mechanisms of Ag thin films on a given characteristic Ge nucleation layer. Additionally, Ge island formation, the precipitation of Ge from Ag-Ge alloys, and the penetration of Ge into SiO2 are suggested for the roughing mode. This demonstration of ultrasmooth Ag thin films would offer an advantageous material platform with scalability for applications such as optics, plasmonics, and photonics.

Adaptive Radiation Therapy: A Review of CT-based Techniques.

Adaptive radiation therapy is a feedback process by which imaging information acquired over the course of treatment, such as changes in patient anatomy, can be used to reoptimize the treatment plan, with the end goal of improving target coverage and reducing treatment toxicity. This review describes different types of adaptive radiation therapy and their clinical implementation with a focus on CT-guided online adaptive radiation therapy. Depending on local anatomic changes and clinical context, different anatomic sites and/or disease stages and presentations benefit from different adaptation strategies. Online adaptive radiation therapy, where images acquired in-room before each fraction are used to adjust the treatment plan while the patient remains on the treatment table, has emerged to address unpredictable anatomic changes between treatment fractions. Online treatment adaptation places unique pressures on the radiation therapy workflow, requiring high-quality daily imaging and rapid recontouring, replanning, plan review, and quality assurance. Generating a new plan with every fraction is resource intensive and time sensitive, emphasizing the need for workflow efficiency and clinical resource allocation. Cone-beam CT is widely used for image-guided radiation therapy, so implementing cone-beam CT-guided online adaptive radiation therapy can be easily integrated into the radiation therapy workflow and potentially allow for rapid imaging and replanning. The major challenge of this approach is the reduced image quality due to poor resolution, scatter, and artifacts. Keywords: Adaptive Radiation Therapy, Cone-Beam CT, Organs at Risk, Oncology © RSNA, 2023.

Impact of Adapted Radiotherapy Schedules on Bowel Sparing in Node-Positive Cervical Cancer.

PURPOSE: Definitive radiation therapy (RT) for locally advanced node-positive cervical cancer confers significant toxicity to pelvic organs including the small bowel. Gross nodal disease exhibits significant shrinkage during RT, and yet conventional RT does not account for this change. We evaluated the reduction in absorbed bowel dose using various adaptive RT schedules. METHODS AND MATERIALS: We obtained 130 evaluable scans (computed tomography simulation and 25 cone beam computed tomography scans per patient) of 5 patients who had received definitive external beam RT for lymph node positive cervical cancer daily over 5 weeks. Using a single universal volumetric modulated arc therapy plan with predefined optimization priorities, we created adapted RT plans in 4 schedules: Daily, Weekly, Twice, and NoAdapt (mimicking conventional nonadapted RT). The in silico (computer modeled) patients were treated to 45 Gy to primary cervical disease with a simultaneous integrated boost to 55 Gy to involved lymph nodes. We evaluated dose metrics including D2cc, D15cc, and V45 to determine the impact of adapted RT schedules on bowel sparing. Statistical tests included the Student t test, analysis of variance, and the Spearman rank correlation. RESULTS: The quantity of reduced bowel dose was significantly associated with the chosen planning schedule in all evaluated metrics and was proportional to the frequency of adaptive RT with significant moderate-to-strong monotonicity. Both D2cc and D15cc were reduced an average of 2.7 Gy using daily replanning compared with a nonadapted approach. A minimally adapted strategy of only 2 replans also confers a significant dosimetric benefit over a nonadapted approach. Reduced standard deviations of D2cc and V45 bowel doses over the treatment courses were significantly associated with the choice of planning schedule with strong monotonicity. CONCLUSIONS: All adaptive RT schedules evaluated confer significant dosimetric advantages in bowel sparing over a conventional nonadapted technique, with greater sparing seen with more frequent replanning schedules. These findings warrant future trials of adaptive RT for pelvic malignancies.

Integrated microwave photonic notch filter using a heterogeneously integrated Brillouin and active-silicon photonic circuit.

Microwave photonics (MWP) has unlocked a new paradigm for Radio Frequency (RF) signal processing by harnessing the inherent broadband and tunable nature of photonic components. Despite numerous efforts made to implement integrated MWP filters, a key RF processing functionality, it remains a long-standing challenge to achieve a fully integrated photonic circuit that can merge the megahertz-level spectral resolution required for RF applications with key electro-optic components. Here, we overcome this challenge by introducing a compact 5 mm × 5 mm chip-scale MWP filter with active E-O components, demonstrating 37 MHz spectral resolution. We achieved this device by heterogeneously integrating chalcogenide waveguides, which provide Brillouin gain, in a complementary metal-oxide-semiconductor (CMOS) foundry-manufactured silicon photonic chip containing integrated modulators and photodetectors. This work paves the way towards a new generation of compact, high-resolution RF photonic filters with wideband frequency tunability demanded by future applications, such as air and spaceborne RF communication payloads.

HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.

Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.

Faculty clinical articles: a regular update for the oral healthcare team.

The Faculty of Dental Surgery of the Royal College of Surgeons of England and British Dental Journal have teamed up to provide a regular series of short articles on different aspects of clinical and academic dentistry. This series will provide concise insight into a diverse range of topics with the aim of providing regular ongoing professional development for all members of the oral healthcare team. We begin here, with a short update on the Faculty and overview of the series' aims.

Chromatin structure predicts survival in glioma patients.

The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. The authors use a large set of paired atac-seq and RNA-seq data from surgically resected glioma specimens to infer gene regulatory relationships in glioma. Thirty-eight glioma patient samples underwent atac-seq sequencing and 16 samples underwent additional RNA-seq analysis. Using an atac-seq/RNA-seq correlation matrix, atac-seq peaks were paired with genes based on high correlation values (|r2| > 0.6). Samples clustered by IDH1 status but not by grade. Surprisingly there was a trend for IDH1 mutant samples to have more peaks. The majority of peaks are positively correlated with survival and positively correlated with gene expression. Constructing a model of the top six atac-seq peaks created a highly accurate survival prediction model (r2 = 0.68). Four of these peaks were still significant after controlling for age, grade, pathology, IDH1 status and gender. Grade II, III, and IV (primary) samples have similar transcription factors and gene modules. However, grade IV (recurrent) samples have strikingly few peaks. Patient-derived glioma cultures showed decreased peak counts following radiation indicating that this may be radiation-induced. This study supports the notion that IDH1 mutant and IDH1 wildtype gliomas have different epigenetic landscapes and that accessible chromatin sites mapped by atac-seq peaks tend to be positively correlated with expression. The data in this study leads to a new model of treatment response wherein glioma cells respond to radiation therapy by closing open regions of DNA.

OLIG2 maintenance is not essential for diffuse intrinsic pontine glioma cell line growth but regulates tumor phenotypes.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a pediatric lethal high-grade brainstem glioma with no effective therapies. OLIG2 (oligodendrocyte transcription factor 2) was reported to be critical for the growth of a DIPG cell line CCHMC-DIPG-1. Surprisingly, we found that the CCHMC-DIPG-1 cells express little OLIG2 and exhibit a mesenchymal phenotype, which raised a question regarding the role of OLIG2 in the growth of DIPG cells. METHODS: We evaluated the function of OLIG2 in different DIPG cell lines through molecular and genetic approaches and performed transcriptomic and genomic landscape profiling including whole-genome bisulfite sequencing, RNA-seq, ATAC-seq, and ChIP-seq. shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout approaches were utilized to assess OLIG2 functions in DIPG cell growth. RESULTS: We found that DIPG cells are phenotypically heterogeneous and exhibit the characteristics of distinct malignant gliomas including proneural, classical, and mesenchymal subtypes. OLIG2 knockdown did not impact the growth of CCHMC-DIPG-1 cells, wherein OLIG2 is epigenetically silenced. Moreover, OLIG2 deletion did not substantially impair OLIG2-expressing proneural-like DIPG growth but led to an upregulation of HIPPO-YAP1 and epidermal growth factor receptor (EGFR) signaling and a tumor phenotype shift. Targeting HIPPO-YAP1 and EGFR signaling in OLIG2-deficient DIPG cells inhibited tumor cell growth. CONCLUSIONS: Our data indicate that OLIG2 is dispensable for DIPG growth but regulates the phenotypic switch of DIPG tumor cells. OLIG2 downregulation leads to deregulation of adaptive YAP1 and EGFR signaling. Targeting YAP1 and EGFR pathways inhibits the growth of OLIG2-deficient DIPG cells, pointing to a therapeutic potential by targeting adaptive signaling to treat DIPG tumors with nominal OLIG2 expression.

Development, implementation and feedback for an online speciality membership examination in orthodontics during the COVID-19 pandemic.

Introduction The Royal College of Surgeons of England (RCSEng) and the Royal College of Physicians and Surgeons of Glasgow (RCPSG) offer the bi-collegiate Membership in Orthodontics (MOrth) examination, a summative assessment of specialist knowledge, skill and behaviour in orthodontics. The COVID-19 pandemic has had a profound global effect on almost every facet of normal life, including the conduct of face-to-face examinations. We highlight development, implementation and feedback for the bi-collegiate MOrth Part 2 examination delivered remotely to a cohort of candidates in September 2020 by RCSEng/RCPSG.Methods Two anonymised online surveys (Google Forms) were distributed via electronic mail following completion of the examination diet. Forty-two candidates were sent a survey covering four domains and comprising a total of 31 questions. The 20 examiners were sent a survey containing eight questions. In both surveys, free-text responses were also collected. A rating system was used to categorise responses. All survey responses were summarised in an online data collection sheet.Results The response rate was 78.5% (33/42) and 75% (15/20) for candidates and examiners, respectively. Overall, favourable responses in relation to all sections of the assessment were elicited from candidates with the majority (mean 79.8%; 75.8-81.9%) reporting that the online examination format worked well. Equally, favourable responses were reported by examiners. Notably, 80% of examiners felt that the online exam style did not affect the mark a candidate would receive, and 100% were confident that the marks the candidates received were a reflection of their ability and were not affected by the online delivery of the assessment.Conclusions The feedback from both candidates and examiners relating to an online remote assessment of the bi-collegiate MOrth Part 2 was generally positive. Based on the survey responses, this format of a high-stakes examination was acceptable to all stakeholders, and demonstrated a high level of perceived validity and reliability in terms of content.

High-resolution Spatiotemporal Dynamics of Harmful Algae in the Indian River Lagoon (Florida)-A Case Study of Aureoumbra lagunensis, Pyrodinium bahamense, and Pseudo-nitzschia.

The Indian River Lagoon (IRL), located on the east coast of Florida, is a complex estuarine ecosystem that is negatively affected by recurring harmful algal blooms (HABs) from distinct taxonomic/functional groups. Enhanced monitoring was established to facilitate rapid quantification of three recurrent bloom taxa, Aureoumbra lagunensis, Pyrodinium bahamense, and Pseudo-nitzschia spp., and included corroborating techniques to improve the identification of small-celled nanoplankton (<10 µm in diameter). Identification and enumeration of these target taxa were conducted during 2015-2020 using a combination of light microscopy and species-specific approaches, specifically immunofluorescence flow cytometry as well as a newly developed qPCR assay for A. lagunensis presented here for the first time. An annual bloom index (ABI) was established for each taxon based on occurrence and abundance data. Blooms of A. lagunensis (>2×108 cells L-1) were observed in all six years sampled and across multiple seasons. In contrast, abundance of P. bahamense, largely driven by the annual temperature cycle that moderates life cycle transitions and growth, displayed a strong seasonal pattern with blooms (105-107 cells L-1) generally developing in early summer and subsiding in autumn. However, P. bahamense bloom development was delayed and abundance was significantly lower in years and locations with sustained A. lagunensis blooms. Pseudo-nitzschia spp. were broadly distributed with sporadic bloom concentrations (reaching 107 cells L-1), but with minimal concentrations of the toxin domoic acid detected (<0.02 µg L-1). In summer 2020, multiple monitoring tools characterized a novel nano-cyanobacterium bloom (reaching 109 cells L-1) that coincided with a decline in A. lagunensis and persisted into autumn. Statistical and time-series analyses of this spatiotemporally intensive dataset highlight prominent patterns in variability for some taxa, but also identifies challenges of characterizing mechanisms underlying more episodic yet persistent events. Nevertheless, the intersect of temperature and salinity as environmental proxies proved to be informative in delineating niche partitioning, not only in the case of taxa with long-standing data sets but also for seemingly unprecedented blooms of novel nanoplanktonic taxa.

Elevated troponin levels are predictive of mortality in surgical intracerebral hemorrhage patients.

OBJECTIVE: Elevated troponin levels are a common occurrence after ischemic stroke and subarachnoid hemorrhage (SAH), and have been described as a neurogenic form of myocardial injury. The prognostic significance of this event is controversial with numerous studies citing conflicting results. The importance of cardiac stress is of particular relevance in the operative management of intracerebral hemorrhage (ICH). To this end, we investigated whether troponin levels were an independent predictor of in-hospital mortality from all causes in surgically treated ICH patients. METHODS: We performed a retrospective analysis of 110 patients admitted to Columbia Presbyterian hospital between 1999 and 2007 for ICH and subsequent clot evacuation. Those with angina or recent myocardial infarction were excluded. CT scans were reviewed to determine hematoma size, location, presence of intraventricular hemorrhage (IVH) or SAH, hydrocephalus, and midline shift. Hospital records were examined for known demographic and clinical predictors of mortality. Univariate analysis was used to screen for predictive factors (P

Subcutaneous sumatriptan: association with decreases in postoperative pain and opioid use after elective cranial surgery.

OBJECTIVE: Sumatriptan, a serotonin receptor agonist, has been used in the management of primary headache disorders and has been shown to affect trigeminal dural afferents. There is limited literature on the safety and efficacy of sumatriptan for postcraniotomy pain management. This study aimed to identify whether subcutaneous sumatriptan is a safe and efficacious pain management strategy after elective craniotomy. METHODS: The authors retrospectively reviewed patients who underwent supratentorial or suboccipital craniotomy between 2016 and 2019 that was performed by a single provider at a single institution to identify patients given subcutaneous sumatriptan in the postoperative period. Pain scores and intravenous and oral opioid use were compared in patients with (n = 15) and without (n = 45) sumatriptan administration. RESULTS: Patients with and without sumatriptan administration had no significant differences in baseline characteristics or surgery type. There were no sumatriptan-related complications. The average pain score decreased from 3.9 to 1.3 within 1 hour after sumatriptan administration (p = 0.014). In both adult and pediatric patients there was decreased postoperative pain (adults: pain score of 1.1 vs 7.1, p < 0.001; pediatric: 1.1 vs 3.9, p = 0.007) within the first 48 hours. There were decreases in intravenous opioid use, length of intravenous opioid use, maximum dose of intravenous opioid used, oral opioid use, length of oral opioid use, and maximum dose of oral opioid used in both adult and pediatric patients. CONCLUSIONS: The authors identified subcutaneous sumatriptan as a safe and efficacious tool for postoperative pain management after craniotomy. Large multicenter randomized controlled studies are needed to further evaluate the specific role of sumatriptan in postoperative pain management after craniotomy.

Injectable diblock copolypeptide hydrogel provides platform to deliver effective concentrations of paclitaxel to an intracranial xenograft model of glioblastoma.

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

Frameless Stereotactic Radiosurgery on the Gamma Knife Icon: Early Experience From 100 Patients.

BACKGROUND: The Gamma Knife (GK) Icon (Elekta AB) uses a cone-beam computed tomography (CBCT) scanner and an infrared camera system to support the delivery of frameless stereotactic radiosurgery (SRS). There are limited data on patients treated with frameless GK radiosurgery (GKRS). OBJECTIVE: To describe the early experience, process, technical details, and short-term outcomes with frameless GKRS at our institution. METHODS: We reviewed our patient selection and described the workflow in detail, including image acquisition, treatment planning, mask-based immobilization, stereotactic CBCT localization, registration, treatment, and intrafraction monitoring. Because of the short interval of follow-up, we provide crude rates of local control. RESULTS: Data from 100 patients are reported. Median age is 67 yr old. 56 patients were treated definitively, 21 postoperatively, and 23 had salvage GKRS for recurrence after surgery. Forty-two patients had brain metastases, 26 meningiomas, 16 vestibular schwannomas, 9 high-grade gliomas, and 7 other histologies. Median doses to metastases were 20 Gy in 1 fraction (range: 14-21), 24 Gy in 3 fractions (range: 19.5-27), and 25 Gy in 5 fractions (range: 25-30 Gy). Thirteen patients underwent repeat SRS to the same area. Median treatment time was 17.7 min (range: 5.8-61.7). We found an improvement in our workflow and a greater number of patients eligible for GKRS because of the ability to fractionate treatments. CONCLUSION: We report a large cohort of consecutive patients treated with frameless GKRS. We look forward to studies with longer follow-up to provide valuable data on clinical outcomes and to further our understanding of the radiobiology of hypofractionation in the brain.

Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the frequency, severity, and predictors of neurological deficits after adjuvant embolization for cerebral arteriovenous malformations. METHODS: From 1997 to 2006, 202 of 275 patients with arteriovenous malformation received embolization before microsurgery (n=176) or radiosurgery (n=26). Patients were examined before and after endovascular embolization and at clinical follow-up (mean, 43.4+/-34.6 months). Outcome was classified according to the modified Rankin Scale. New neurological deficits after embolization were defined as minimal (no change in overall modified Rankin Scale), moderate (modified Rankin Scale < or =2), or significant (modified Rankin Scale >2). RESULTS: Two hundred two patients were treated in 377 embolization procedures. There were a total of 29 new clinical deficits after embolization (8% of procedures; 14% of patients), of which 19 were moderate or significant. Postembolization deficits resolved in a significant number of patients over time (P<0.0001). Five patients had persistent neurological deficits due to embolization (1.3% of procedures; 2.5% of patients). In multivariate analysis, the following variables significantly predicted new neurological deficit after embolization: complex arteriovenous malformation with treatment plan specifying more than one embolization procedure (OR, 2.7; 95% CI, 1.4 to 8.6), diameter <3 cm (OR, 3.2; 95% CI, 1.2 to 9.1), diameter >6 cm (OR, 6.2; 95% CI, 1.0 to 57.0), deep venous drainage (OR, 2.7; 95% CI, 1.1 to 6.9), or eloquent location (OR, 2.4; 95% CI, 1.0 to 5.7). These variables were weighted and used to compute an arteriovenous malformation Embolization Prognostic Risk Score for each patient. A score of 0 predicted no new deficits, a score of 1 predicted a new deficit rate of 6%, a score of 2 predicted a new deficit rate of 15%, a score of 3 predicted a new deficit rate of 21%, and a score of 4 predicted a new deficit rate of 50% (P<0.0001). CONCLUSIONS: Small and large size, eloquent location, deep venous drainage, and complex vascular anatomy requiring multiple embolization procedures are risk factors for the development of immediate postembolization neurological deficits. Nevertheless, a significant number of patients with treatment-related neurological deficits improve over time. The low incidence of permanent neurological deficits underscores the usefulness of this technique in carefully selected patients.

Identification and analysis of serpin-family genes by homology and synteny across the 12 sequenced Drosophilid genomes.

BACKGROUND: The Drosophila melanogaster genome contains 29 serpin genes, 12 as single transcripts and 17 within 6 gene clusters. Many of these serpins have a conserved "hinge" motif characteristic of active proteinase inhibitors. However, a substantial proportion (42%) lacks this motif and represents non-inhibitory serpin-fold proteins of unknown function. Currently, it is not known whether orthologous, inhibitory serpin genes retain the same target proteinase specificity within the Drosophilid lineage, nor whether they give rise to non-inhibitory serpin-fold proteins or other, more diverged, proteins. RESULTS: We collated 188 orthologues to the D. melanogaster serpins from the other 11 Drosophilid genomes and used synteny to find further family members, raising the total to 226, or 71% of the number of orthologues expected assuming complete conservation across all 12 Drosophilid species. In general the sequence constraints on the serpin-fold itself are loose. The critical Reactive Centre Loop (RCL) sequence, including the target proteinase cleavage site, is strongly conserved in inhibitory serpins, although there are 3 exceptional sets of orthologues in which the evolutionary constraints are looser. Conversely, the RCL of non-inhibitory serpin orthologues is less conserved, with 3 exceptions that presumably bind to conserved partner molecules. We derive a consensus hinge motif, for Drosophilid inhibitory serpins, which differs somewhat from that of the vertebrate consensus. Three gene clusters appear to have originated in the melanogaster subgroup, Spn28D, Spn77B and Spn88E, each containing one inhibitory serpin orthologue that is present in all Drosophilids. In addition, the Spn100A transcript appears to represent a novel serpin-derived fold. CONCLUSION: In general, inhibitory serpins rarely change their range of proteinase targets, except by a duplication/divergence mechanism. Non-inhibitory serpins appear to derive from inhibitory serpins, but not the reverse. The conservation of different family members varied widely across the 12 sequenced Drosophilid genomes. An approach considering synteny as well as homology was important to find the largest set of orthologues.

The complement cascade: new avenues in stroke therapy.

Recent evidence has shown that after the initial occlusion, a large portion of stroke patients achieve some degree of reperfusion either through collateral circulation or clot dissolution. However, it appears that this reperfusion may lead to increased inflammation-induced damage. Even though the exact mechanism of this secondary injury is unclear, several experimental studies have indicated an intimate connection between complement and this secondary form of damage. We review the available literature and attempt to identify promising clinical therapeutic targets.