Management of a recurrent spinal arachnoid cyst presenting as arachnoiditis in the setting of spontaneous spinal subarachnoid hemorrhage: illustrative case.

BACKGROUND: Spontaneous spinal subarachnoid hemorrhage is a rare pathological entity with a variety of presentations depending on the underlying etiology, which often remains cryptogenic. The literature is sparse regarding the most efficacious treatment or management option, and there is no consensus on follow-up time or modalities. Additionally, there are very few reports that include operative videos, which is provided herein. OBSERVATIONS: The authors present a case of spontaneous spinal subarachnoid hemorrhage without an underlying etiology in a patient with progressive myelopathy, back pain, and lower-extremity paresthesias. She presented to our institution, and because of progressive worsening of her symptoms and the development of compressive arachnoid cysts, she underwent thoracic laminectomies for evacuation of subdural fluid, fenestration of the arachnoid cysts, and lysis of significant arachnoid adhesions. Her clinical course was further complicated by the recurrence of worsening myelopathy and the development of a large compressive arachnoid cyst with further arachnoiditis. The patient underwent repeat surgical intervention for cyst decompression with an improvement in symptoms. LESSONS: This case highlights the importance of long-term follow-up for these complicated cases with an emphasis on repeat magnetic resonance imaging. Unfortunately, surgical intervention is associated with short-term relief of the symptoms and no significant nonoperative management is available for these patients.

Characterizing the Next Generation of Neurosurgeons: A Descriptive Analysis and Publicly Available Web Application of Neurosurgery Residency Programs' Website Data.

OBJECTIVE: Neurosurgery program websites serve as a valuable resource for applicants. However, each website exists in isolation, and it can be difficult to understand the general trends in U.S. neurosurgery resident demographics. In the present study, we collected data from program websites and analyzed the trends in the demographics of the current U.S. neurosurgery residents. METHODS: We used a program list obtained from the American Association of Medical Colleges Electronic Residency Application System to extract data from the current resident complement listed in each program's website, including program, year in program, medical school, sex (male vs. female), graduate and/or PhD degrees, and assessed the trends during 7 years of resident data using linear regression. RESULTS: We identified 116 neurosurgery residency programs in the United States, with 111 providing information on their current resident complement, yielding a dataset of 1599 residents. Of these 1599 residents, 348 (22%) were female, 301 (19%) had a graduate degree in addition to an MD or DO degree, 151 (9.4%) had a PhD degree, 300 (19%) had matched at the program affiliated with their medical school, and 121 (7.6%) had graduated from a foreign medical school. The proportion of matriculating female residents had increased an average of 2.1% annually (95% confidence interval, 0.6%-3.7%) from 2015 to 2021. The other demographic data had not changed significantly during the same period. CONCLUSIONS: In addition to summarizing the current resident demographics, our analysis identified a significant increase in the proportion of female residents between 2015 (15.1%) and 2021 (25.6%). This publicly available dataset should enable additional analyses of the evolution of neurosurgery resident demographics.

Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) After Stroke: Rationale, Design and Protocol for a Prospective Randomized Controlled Trial.

Background: Despite intravenous thrombolysis and endovascular therapy for acute ischemic stroke (AIS), many survivors still have varying degrees of disability. Glyceryl trinitrate (GTN), a nitric oxide (NO) donor, has been previously reported to induce neuroprotection after AIS. The use of GTN to reduce brain damage after stroke remains yet to be elucidated. This study was designed to explore the safety, feasibility, and preliminary efficacy of intravenous administration of GTN after AIS. Methods: A prospective randomized controlled trial is proposed with AIS patients. Participants will be randomly allocated to GTN group and control group with a 1:1 ratio (n = 40). Both groups will be treated with standard therapies according to the current stroke guidelines. Participants allocated to the GTN group will receive intravenous administration of GTN (5 mg GTN in 50 ml saline at a rate of 0.4 mg/h that is continued for 12.5 h/day for 2 days) within 24 h of symptom onset. Participants allocated to the control group will receive intravenous administration at equal capacity of 0.9% normal saline (NS) (total 50 ml/day at 4 ml/h that is continued for 12.5 h/day for 2 days). The primary outcome is safety [systolic blood pressure (SBP) <110 mmHg, headache], while the secondary outcomes include changes in functional outcome and infarction volume. Discussion: Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) is a prospective randomized controlled trial that aims to ascertain the safety, feasibility, and preliminary efficacy of intravenous GTN as a neuroprotection strategy after AIS. These results will provide parameters for future studies as well as provide insights into treatment effects. Any possible neuroprotective qualities of GTN in AIS will also be elucidated. Trial Registration:www.chictr.org.cn, identifier: ChiCTR2100046271.

Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo using Layer-by-Layer Nanoparticles.

Using siRNA therapeutics to treat hematologic malignancies has been unsuccessful because blood cancer cells exhibit remarkable resistance to standard transfection methods. Herein we report the successful delivery of siRNA therapeutics with a dual-targeted, layer-by-layer nanoparticle (LbL-NP). The LbL-NP protects siRNA from nucleases in the bloodstream by embedding it within polyelectrolyte layers that coat a polymeric core. The outermost layer consists of hyaluronic acid (a CD44-ligand) covalently conjugated to CD20 antibodies. The CD20/CD44 dual-targeting outer layer provides precise binding to blood cancer cells, followed by receptor-mediated endocytosis of the LbL-NP. We use this siRNA delivery platform to silence B-cell lymphoma 2 (BCL-2), a pro-survival protein, in vitro and in vivo. The dual-targeting approach significantly enhanced internalization of BCL-2 siRNA in lymphoma and leukemia cells, which led to significant downregulation of BCL-2 expression. Systemic administration of the dual-targeted, siRNA-loaded nanoparticle induced apoptosis and hampered proliferation of blood cancer cells both in cell culture and in orthotopic non-Hodgkin's lymphoma animal models. These results provide the basis for approaches to targeting blood-borne cancers and other diseases, and suggest that LbL nanoassemblies are a promising approach for delivering therapeutic siRNA to hematopoetic cell types that are known to evade transfection by other means.

Biofilm facilitates metal accumulation onto microplastics in estuarine waters.

In aquatic environments, plastic debris accumulates chemical pollutants from the surrounding water, potentially altering the fate of xenobiotics in these ecosystems. The effects of biofouling on the potential for plastic to sorb environmental pollutants remain poorly understood. In this study, we test the hypothesis that concentrations of metals are directly related to biofilm accumulation on microplastics submerged in natural estuarine waters. Two types of pre-production plastic pellets (polylactic acid (PLA) and low-density polyethylene (LDPE)) and glass pellets, were suspended for up to 28 days in an urbanized estuary (San Francisco Bay, California) to investigate how biofilm affects the accumulation of metals on these materials. During the initial weeks of the experiment, biofilm growth differed between locations, but after 28 days, PLA and LDPE had similar amounts of biofilm at the two field sites. Biofilm was the only significant predictor variable for Ba, Cs, Fe, Ga, Ni and Rb, and simple regressions of these metals after one month of submersion predicted much of the variability in the data (respective adjusted R2 values: 0.46, 0.90, 0.86, 0.81, 0.87, 0.90; p < 0.001). For other metals influenced by location or substrate material, multivariate analysis showed that increases in metal concentrations were predicted by increases in biofilm for Cu, Pb, Al, K, U, Co, Mg (p < 0.001) and Mn (p < 0.01). This work highlights the role of biofilm in facilitating metal accumulation on plastic debris and contributes to current understanding of the underlying processes that influence the behavior of microplastics as aquatic contaminants.

Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration.

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb+, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.

Use of field-portable XRF analyzers for rapid screening of toxic elements in FDA-regulated products.

Analytical instrumentation continues its amazing evolution, especially in regard to generating ever more sensitive, faster, and reliable measurements. Perhaps the most difficult challenges are making these instruments small enough to use in the field, equipping them with well-designed software that facilitates and simplifies their use by nonexperts while preserving enough of their analytical capabilities to render them useful for a wide variety of applications. Perhaps the most impressive and underappreciated example of instruments that meet these criteria are field-portable X-ray fluorescence (XRF) analyzers. In the past, these analyzers have been routinely used for environmental applications (lead in paint and soil, metal particulates in air samples collected onto filters), geology studies (ore and soil analysis, precious metal identification), and recycling industries (alloy identification). However, their use in the analysis of toxic elements in food, food ingredients, dietary supplements, and medicinal and herbal products, especially within the FDA and regulatory environments, has been surprisingly limited to date. Although XRF will not replace atomic spectrometry techniques such as ICP-MS for sub-parts per million level analyses, it offers a number of significant advantages including minimal sample preparation, high sample throughputs, rapid and definitive identification of many toxic elements, and accurate quantitative results. As should be obvious from many recent news reports on elevated levels of toxic elements in children's lunchboxes, toys, and supplements, field-portable XRF analyzers can fill a very important niche and are becoming increasingly popular for a wide variety of elemental analysis applications. This perspective begins with a brief review of the theory of XRF to highlight the underlying principle, instrumentation, and spectra. It includes a discussion of various analytical figures of merit of XRF to illustrate its strengths and limitations compared to existing methods such as ICP-MS. It concludes with a discussion of a number of different FDA applications and case studies in which XRF has been used to screen, identify, and in some cases quantify toxic elements in various products. This work clearly demonstrates that XRF analyzers are an exceedingly valuable tool for routine and nonroutine elemental analysis investigations, both in the laboratory and in the field. In the future, it is hoped that both field-portable and laboratory-grade XRF analyzers will see more widespread use for investigational and forensic-type applications of food and other regulated consumer products.

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

AIMS: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. PATIENTS & METHODS: Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. RESULTS: The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. CONCLUSION: This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.

A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma.

BACKGROUND: R115777 is a potent farnesyl transferase inhibitor and has significant antitumor effects in vitro and in vivo. METHODS: The objective of the current study was to determine the objective response proportion in patients with metastatic transitional cell carcinoma (TCC) of the urothelial tract who received treatment with R115777 at a dose of 300 mg orally given twice daily for 21 days followed by 7 days of rest for every 4-week cycle. Thirty-four patients with TCC were enrolled in this Phase II study. Patients were allowed to have received a maximum of one prior systemic chemotherapy regimen, not including chemoradiation or neoadjuvant chemotherapy. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and adequate bone marrow, hepatic, and kidney function. RESULTS: Twice daily administration of oral R115777 was tolerated well. R115777 was absorbed rapidly after oral administration. Grade 3-4 neutropenia (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 5 patients (15%). Grade 3-4 nonhematologic toxicity was rare, consisting of rash and diarrhea in 1 patient each. Two patients (6%) without prior chemotherapy demonstrated partial responses. Thirteen patients (38%) achieved disease stabilization according to World Health Organization criteria that lasted a median of 4 months. No complete responses were observed. CONCLUSIONS: The objective response rate of R115777 was not sufficient to warrant future investigation in TCC as a single agent. Preliminary evidence of the activity of R115777 in 2 chemotherapy-naive patients may warrant further investigation in combination with first-line chemotherapy.

Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer.

PURPOSE: R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken. PATIENTS AND METHODS: Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48-72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m(2) as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily. RESULTS: Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m(2) weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro. CONCLUSIONS: Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.

A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer.

PURPOSE: This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty patients with solid tumors received a median of 2.5 cycles (range 1-30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777. RESULTS: Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients. CONCLUSION: The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.

Proton transfer reaction ion trap mass spectrometer.

Proton transfer reaction mass spectrometry is a relatively new field that has attracted a great deal of interest in the last few years. This technique uses H(3)O(+) as a chemical ionization (CI) reagent to measure volatile organic compounds (VOCs) in the parts per billion by volume (ppbv) to parts per trillion by volume (pptv) range. Mass spectra acquired with a proton transfer reaction mass spectrometer (PTR-MS) are simple because proton transfer chemical ionization is "soft" and results in little or no fragmentation. Unfortunately, peak identification can still be difficult due to isobaric interferences. A possible solution to this problem is to couple the PTR drift tube to an ion trap mass spectrometer (ITMS). The use of an ITMS is appealing because of its ability to perform MS/MS and possibly distinguish between isomers and other isobars. Additionally, the ITMS duty cycle is much higher than that of a linear quadrupole so faster data acquisition rates are possible that will allow for detection of multiple compounds. Here we present the first results from a proton transfer reaction ion trap mass spectrometer (PTR-ITMS). The aim of this study was to investigate ion injection and storage efficiency of a simple prototype instrument in order to estimate possible detection limits of a second-generation instrument. Using this prototype a detection limit of 100 ppbv was demonstrated. Modifications are suggested that will enable further reduction in detection limits to the low-ppbv to high-pptv range. Furthermore, the applicability of MS/MS in differentiating between isobaric species was determined. MS/MS spectra of the isobaric compounds methyl vinyl ketone (MVK) and methacrolein (MACR) are presented and show fragments of different mass making differentiation possible, even when a mixture of both species is present in the same sample. However, MS/MS spectra of acetone and propanal produce fragments with the same molecular masses but with different intensity ratios. This allows quantitative distinction only if one species is predominant. Fragmentation mechanisms are proposed to explain the results.

Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer.

PURPOSE: R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer. PATIENTS AND METHODS: Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]). RESULTS: In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004). CONCLUSION: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

Analysis of pesticide residues on museum objects repatriated to the Hupa tribe of California.

In the past, it was common practice for museum professionals and private collectors to apply a variety of pesticide agents to objects in their collections to preserve them from depredations by microorganisms, fungi, and other pests. The Native American Graves Repatriation and Protection Act allows federally recognized tribes to request that museums return objects taken from their ancestors. Given that poor records were kept on the treatment of individual objects, it is unknown whether specific objects are contaminated with these pesticide agents. Although chemical analysis represents the only reliable means to determine the types and levels of pesticides on these objects, surprisingly few publications document the extent of this contamination in museum collections. This paper reports on the determination of arsenic, mercury, and several organic pesticides on 17 objects that were recently repatriated to the Hupa tribe in northern California. Four samples were taken from each object: two for arsenic and mercury analysis via flame atomic absorption spectrophotometry and two for organic pesticide analysis via gas chromatography/mass spectrometry. Percent levels (wt/wt) of mercury were detected on many samples, and 0.001 to 0.183% (wt/wt) levels of p-dichlorobenzene, naphthalene, thymol, lindane, and/or DDT were detected on many of the samples. These results indicate that Hupa tribal members should not wear these objects in religious ceremonies, proper precautions should be followed when dealing with potentially contaminated objects, and that more serious consideration should be given to this issue at a national level.

Controls over monoterpene emissions from boreal forest conifers.

We investigated controls over the emission of monoterpenes from two species of boreal forest conifers, black spruce (Picea mariana Miller (B.S.P.)) and jack pine (Pinus banksiana Lamb). Monoterpenes are important in plants as carbon-based defensive compounds and in the atmosphere as photochemically reactive compounds that affect ozone and carbon monoxide concentrations. We examined ecological theories of plant allocation to defensive compounds in relation to emission rates of monoterpenes from the foliage of these two species. Monoterpene emission from plants is controlled by the vapor pressure of the monoterpenes within plant tissues, and vapor pressure is controlled by two parameters, air temperature and terpene concentration within the tissues. We measured the concentration of terpenes and nitrogen within foliage and the emission rate from foliage, and demonstrated that emission rate was linearly related to nitrogen concentration and exponentially related to air temperature. Current theories of plant allocation to carbon-based defenses predict an inverse relationship between foliar nitrogen and carbon-based defenses. We found that, under certain circumstances, these theories were sufficient to predict concentrations and emissions, but under other circumstances, the theories did not predict monoterpene concentrations or emissions. These results are discussed in the context of landscape/regional modeling of hydrocarbon emission from vegetation.