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The opioid crisis is a worldwide phenomenon that has devastating effects on individuals and their families. It has been a growing problem with high costs to society in the US. The physical dependence on opioids results in withdrawal symptoms when the individual stops taking the drugs. The most used opioids are prescription drugs like hydrocodone and oxycodone combinations. Now that the medical community is cutting back on prescription narcotics, the addicted patients are turning more to readily available alternatives such as heroin and fentanyl. The fear of withdrawal symptoms and craving for the drugs keep the patients on a continuous search for more opioids. Options for opioid addiction now exist. Substitution therapy started with methadone. We now have a better alternative in the drug buprenorphine. It is available in several forms. The patient at home can use it daily to prevent cravings and withdrawal symptoms. Any licensed physician can prescribe buprenorphine if they get an X-Waiver. This is a free, easy-to-obtain addition to one’s DEA license. Buprenorphine is the current future of opiate addiction treatment. In concert with other supportive measures such as counseling, buprenorphine can help patients return to an opiate-free, more normal, and productive life.

This article examines what the author argues is Ovid's accidental discovery of gender dysphoria with recourse to an incident in the Metamorphoses. The author argues that Ovid has accidentally discovered gender dysphoria as evidenced through the character of Iphis in Book IX of the Metamorphoses. It is unlikely that Ovid could have imagined the ramifications of such a “discovery”; however, the “symptoms” described in his narrative match exceedingly closely with modern, clinical definitions. These are explored in the article along with how Ovid may have, through personal experience, been able to achieve such a penetrating, albeit accidental, insight. The wider, epistemological context of this topic is considered alongside Ovid's personal circumstances which may have contributed to his unique understanding of a condition that modern science has only recently identified.

OBJECTIVEBiopsies of brainstem lesions are performed to establish a diagnosis in the setting of an atypical clinical or radiological presentation, or to facilitate molecular studies. A better understanding of the safety and diagnostic yield of brainstem biopsies would help guide appropriate patient selection.METHODSAll patients who underwent biopsy of a brainstem lesion during the period from January 2011 to June 2019 were reviewed. Demographic, radiological, surgical, and outcome data were collected.RESULTSA total of 58 patients underwent 65 brainstem biopsies during the study period. Overall, the median age was 7.6 years (IQR 3.9–14.2 years). Twenty-two of the 65 biopsies (34%) were open, 42 (65%) were stereotactic, and 1 was endoscopic. In 3 cases (5%), a ventriculoperitoneal shunt was placed, and in 9 cases (14%), a posterior fossa decompression was performed during the same operative session as the biopsy. An intraoperative MRI (iMRI) was performed in 28 cases (43%). In 3 of these cases (11%), the biopsy was off target and additional samples were obtained during the same procedure. New neurological deficits were noted in 5 cases (8%), including sensory deficits, ophthalmoparesis/nystagmus, facial weakness, and hearing loss; these deficits persisted in 2 cases and were transient in 3 cases. A pseudomeningocele occurred in 1 patient; no patients developed a CSF leak or infection. In 8 cases (13%) an additional procedure was needed to obtain a diagnosis.CONCLUSIONSBrainstem biopsies are safe and effective. Target selection and approach should be a collaborative effort. iMRI can be used to assess biopsy accuracy in real time, thereby allowing any adjustment if necessary.

Background Posterior communicating (Pcom) aneurysms in the modern era have tended toward increased complexity and technical difficulties. The pretemporal approach is a valuable extension to the pterional approach for basilar apex aneurysms, but its advantages for Pcom aneurysms have not been previously elucidated. Objective To quantify characteristics of the pretemporal approach to the Pcom. Methods We dissected 6 cadaveric heads (12 sides) with a pretemporal transclinoidal approach and measured the following variables: (1) exposed length of internal carotid artery (ICA) proximal to the Pcom artery; (2) exposed circumference of ICA at the origin of Pcom; (3) deep working area between the optic nerve and tentorium/oculomotor nerve; (4) superficial working area; (5) exposure depth; and (6) the frontotemporal (superior posterolateral) and (7) orbito-sphenoidal (inferior anterolateral) angles of exposure. Results Compared with pterional craniotomy, the pretemporal transclinoidal approach increased the exposed length of the proximal ICA from 3.3 to 11.7 mm (P = .0001) and its circumference from 5.1 to 7.8 mm (P = .0003), allowing a 210° view of the ICA (vs 137.9°). The deep and superficial working areas also significantly widened from 53.7 to 92.4 mm2 (P = .0048) and 252.8 to 418.2 mm2 (P = .0001), respectively; the depth of the exposure was equivalent. The frontotemporal and spheno-Sylvian angles increased by 17° (P = .0006) and 10° (P = .0037), respectively. Conclusion The pretemporal approach can be useful for complex Pcom aneurysms by providing easier proximal control, wider working space, improved aneurysm visualization, and more versatile clipping angles. Enhanced exposure results in a potentially higher rate of complete aneurysm obliteration and complication avoidance.

Motivated by the extreme black hole near horizon geometry equation and the Ellis–Ehlers equation of mathematical cosmology, we prove a Bakry–Émery generalization of a theorem of Frankel that closed minimal hypersurfaces in a complete manifold with a suitable curvature bound must intersect. We do not assume that the Bakry–Émery vector field is of gradient type. We also present splitting theorems of warped product type for manifolds bounded by hypersurfaces obeying Bakry–Émery curvature bounds.

OBJECTIVEStenoocclusive cerebral vasculopathy is an infrequent delayed complication of ionizing radiation. It has been well described with photon-based radiation therapy but less so following proton-beam radiotherapy. The authors report their recent institutional experience in evaluating and treating children with radiation-induced cerebral vasculopathy.METHODSEligible patients were age 21 years or younger who had a history of cranial radiation and subsequently developed vascular narrowing detected by MR arteriography that was significant enough to warrant cerebral angiography, with or without ischemic symptoms. The study period was January 2011 to March 2019.RESULTSThirty-one patients met the study inclusion criteria. Their median age was 12 years, and 18 (58%) were male. Proton-beam radiation therapy was used in 20 patients (64.5%) and photon-based radiation therapy was used in 11 patients (35.5%). Patients were most commonly referred for workup as a result of incidental findings on surveillance tumor imaging (n = 23; 74.2%). Proton-beam patients had a shorter median time from radiotherapy to catheter angiography (24.1 months [IQR 16.8–35.4 months]) than patients who underwent photon-based radiation therapy (48.2 months [IQR 26.6–61.1 months]; p = 0.04). Eighteen hemispheres were revascularized in 15 patients. One surgical patient suffered a contralateral hemispheric infarct 2 weeks after revascularization; no child treated medically (aspirin) has had a stroke to date. The median follow-up duration was 29.2 months (IQR 21.8–54.0 months) from the date of the first catheter angiogram to last clinic visit.CONCLUSIONSAll children who receive cranial radiation therapy from any source, particularly if the parasellar region was involved and the child was young at the time of treatment, require close surveillance for the development of vasculopathy. A structured and detailed evaluation is necessary to determine optimal treatment.

OBJECTIVE An ischemic stroke following an elective craniotomy in a child is perceived to be a rare event. However, to date there are few papers on this topic. The purpose of this study was to investigate the occurrence of stroke following elective intracranial surgery at a children’s hospital. METHODS The authors performed a retrospective review of all patients who developed a perioperative stroke following an elective craniotomy from 2010 through 2017. Data were collected using an institutional database that contained demographic, medical, radiological, and outcome variables. RESULTS A total of 1591 elective craniotomies were performed at the authors’ institution during the study period. Of these, 28 (1.8%) were followed by a perioperative stroke. Radiographic diagnosis of the infarction occurred at a median of 1.7 days (range 0–9 days) from the time of surgery, and neurological deficits were apparent within 24 hours of surgery in 18 patients (62.5%). Infarcts tended to occur adjacent to tumor resection sites (86% of cases), and in a unilateral (89%), unifocal (93%), and supratentorial (93%) location. Overall, 11 (39.3%) strokes were due to a perforating artery, 10 (35.7%) were due to a large vessel, 4 (14.3%) were venous, and 3 (10.7%) were related to hypoperfusion or embolic causes. Intraoperative MRI (iMRI) was used in 11 of the 28 cases, and 6 (55%) infarcts were not detected, all of which were deep. CONCLUSIONS The incidence of stroke following an elective craniotomy is low, with nearly all cases (86%) occurring after tumor resection. Perforator infarcts were most common but may be missed on iMRI. ABBREVIATIONS ACA = anterior cerebral artery; AChA = anterior choroidal artery; ACS NSQIP-P = American College of Surgeons National Surgical Quality Improvement Program–Pediatric; CVA = cerebrovascular accident; DWI = diffusion weighted imaging; iMRI = intraoperative MRI; MCA = middle cerebral artery; mRS = modified Rankin Scale; PCA = posterior cerebral artery.

The Woven EndoBridge (WEB) device (MicroVention, Aliso Viejo, California) is an intrasaccular flow disruptor used for the treatment of both unruptured and ruptured intracranial aneurysms. WEB has been shown to have 54% complete and 85% adequate aneurysm occlusion rates at 1-yr follow-up.1 Residual and recurrent ruptured aneurysms have been shown to have a higher risk of re-rupture than completely occluded aneurysms.2 With increased utilization of WEB in the United States, optimizing treatment strategies of residual aneurysms previously treated with the WEB device is essential, including surgical clipping.3,4 Here, we present an operative video demonstrating the surgical clip occlusion of previously ruptured middle cerebral artery and anterior communicating artery aneurysms that had been treated with the WEB device and had sizable recurrence on follow-up angiography. Informed consent was obtained from both patients. Lessons learned include the following: (1) the WEB device is highly compressible, unlike coils; (2) proximal WEB marker may interfere with clip closure; (3) no evidence of WEB extrusion into the subarachnoid space; (4) no more scarring than expected in ruptured cases; and (5) clipping is a feasible option for treating WEB recurrent or residual aneurysms.

Wide-necked bifurcation aneurysms are common when evaluating both ruptured and unruptured intracranial aneurysms and can pose unique challenges. The Woven EndoBridge device (recently approved in the US) is specifically designed for the treatment of these aneurysms. This article serves to introduce the device to a wider audience with a thorough review of the literature, device design, indications, pre-operative evaluation, procedural usage and potential pitfalls.Lay abstract The Woven EndoBridge device recently received approval by the US FDA for use in certain types of difficult to treat brain aneurysms. This article is primarily a descriptive and technical article aimed at doctors who use catheter-based techniques to treat problems of the blood vessels. Initial studies show that the device is at least as effective as previously existing methods, though more research needs to be done regarding long-term outcomes.

This chapter explains how an adaptation to the TI method can allow more direct comparisons across institutions through a calculation of absolute productivity. The tutorial builds from the case study used in Chaps. 4 and 5. It shows how a feature scaling technique can open the door for absolute productivity calculation and applies threshold analysis to the transformed data. The chapter concludes by discussing further implications and benefits of interpreting a single set of data through multiple lenses.

This chapter introduces additional productivity concepts and definitions necessary for conducting different types of productivity analyses. It expands upon the school districts case study from the previous chapter and adds nuance to the investigation. The tutorial shows several ways to estimate productivity to address diverse and often conflicting interests among stakeholders. It then shows how to normalize results for easier interpretation. The chapter concludes by stressing that productivity measurement exercises in schools or not-for-profits should always entertain multiple treatments of data to entertain multiple perspectives on performance.

This chapter introduces the concepts and procedures of conducting a productivity threshold analysis. A threshold analysis provides a wider view of the potential productivity portrayals that could be generated from a single set of data. The tutorial expands upon the case study of four universities from the previous chapter. It provides more data and shows how to further optimize the previous chapter’s code. It then demonstrates how to create both education and research indicators for a more comprehensive view of institutional academic productivity. Next it shows how any productivity metric composing more than one output indicator requires some notion of value-weighting for the individual output elements. Finally it presents a way to visualize the range of portrayals that can precipitate from different value-weighting schemes. The chapter concludes by stressing how a threshold analysis can be a valuable strategic exercise, helping to address questions about how use of resources and measured performance line up with institutional objectives.

This chapter introduces the concept of productivity frontier analysis and appropriate applications of the method. It explains how data envelopment analysis (DEA) is one of the most popular techniques for conducting a frontier analysis. It then provides a walk-through for how the DEA algorithm works. The tutorial in this chapter explores a case study of five hypothetical not-for-profit organizations. It demonstrates how to use DEA on data from these organizations and how to interpret results. The chapter stresses how the direct results of DEA cannot be taken at face value, especially when the data elements being examined are non-priced. It explains how risks emerge if data are not interrogated further.

This chapter introduces values analysis for DEA. It steps the reader through how and why values analysis needs to be conducted when using DEA for education institutions and not-for-profits. The tutorial expands up on the case study of five non-for-profit organisations from the previous chapter. It demonstrates how to make best use of all the results a DEA analysis provides, and illustrates how different portrayals of the data may be more or less appropriate depending upon stakeholder values and objectives. The chapter further entertains the possibility that initial results may not produce appropriate findings, and it provides the reader with alternative approaches and several additional considerations for adding depth to the analysis.

This chapter familiarizes the reader with concepts and applications of inputs and outputs as they relate to conducting a productivity assessment. It uses two hypothetical school districts as a case study for measurement and benchmarking. The tutorial in this chapter demonstrates how to clean and prepare institutional data for analysis. It establishes common data structures that will be used for the remainder of the book. It then leads the reader through an indicative example of using institutional inputs and outputs to generate productivity insights and visualize results.

BACKGROUND Bibliometrics is defined as the study of statistical and mathematical methods used to quantitatively analyze scientific literature. The application of bibliometrics in neurosurgery continues to evolve. OBJECTIVE To calculate a number of publication productivity measures for almost all neurosurgical residents and departments within North America. These measures were correlated with survey results on the educational environment within residency programs. METHODS During May to June 2017, data were collected from departmental websites and Scopus to compose a bibliometric database of neurosurgical residents and residency programs. Data related to authorship value and study content were collected on all articles published by residents. A survey of residency program research and educational environment was administered to program directors and coordinators; results were compared with resident academic productivity. RESULTS The median number of publications in residency was 3; median h-index and Resident index were 1 and 0.17 during residency, respectively. There was a statistically significant difference in academic productivity among male neurosurgical residents compared with females. The majority of articles published were tier 1 clinical articles. Residency program research support was significantly associated with increased resident productivity (P < .001). Scholarly activity requirements were not associated with increased resident academic productivity. CONCLUSION This study represents the most comprehensive bibliometric assessment of neurosurgical resident academic productivity during training to date. New benchmarks for individual and department academic productivity are provided. A supportive research environment for neurosurgical residents is associated with increased academic productivity, but a scholarly activity requirement was, surprisingly, not shown to have a positive effect.

This article examines some complex connections between Pythagorean symbolism and related aspects of ancient Greek mythology concerning wolves, lycanthropy, the colour white, music, Mt. Lykaion in Arcadia, the gods Zeus, Apollo, Artemis and Pan as well as ancient mystical rites of initiation and the philosopher Plato. These connections are at times obscure but well attested in the sources. The article goes through each of them in turn and demonstrates their connectivity, along with broader implications in the mythology of the Near East. In the course of researching another article on the Pythagorean symbolism in Plato’s Philebus, I came across a number of interesting themes which did not fit easily into that overall discussion but which I felt were nonetheless significant enough to merit their own inquiry. These initially concerned the symbolic nature of the colour white but further researches also led me down a curious path that included no less than werewolves (or the first lycanthrope, to be precise), cannibalism and human sacrifice which connected with Pythagorean symbolism in the Plato’s works and elsewhere. This article examines this symbolism, in context, and its broader associations in ancient Greek ritual and mystical practices. The etymology of the colour white in ancient Greek is itself significant. Leukos (viz LSJ) "white" can also mean "shining" or "brilliant" and leukos was used to refer to normal sunlight too. Thus the previous assertion in another article that its symbolism related to the Pythagorean "central fire", the Form of Whiteness itself and other aspects of divinity found in both Platonic and Pythagorean sources. 1 Leukos is derived from the base lyk-, meaning "light" or "shining". The Lykabantides, for instance, were the hours that make up the year, that is, "the path of light", referring to the course of the sun throughout its annual cycle. The Greek word for wolf, lykos, also shares the same base lykand it seems that this is no accident. Wolves were thought to appear at the break of dawn (lykē) or at twilight, thus the conceptual association. 2

“Despite great advancements in the management of aneurysmal subarachnoid hemorrhage (SAH), outcomes following SAH rupture have remained relatively unchanged” ( Chowdhury et al., 2014 ). These patients range in age from newborn to elderly and have a wide variety of signs and symptoms associated with their pathology. Despite their diversity, anesthetic management of all patients with cerebrovascular disease revolves around a few basic principles: maintenance of adequate cerebral blood flow and optimal cerebral perfusion, decreasing risk of intracranial hemorrhage, minimizing risk of cerebral ischemia and preventing resultant neurologic injury, and avoidance of cerebral hyperperfusion ( Black, Sulek, & Day, 1998 , p. 265). The development of an anesthesia plan for aneurysmal pathology is dependent upon familiarity with the procedure, close collaboration with the surgeon and additional support physicians with meaningful communication before, during, and immediately after the surgical procedure. Successful anesthetic management of these patients requires a thorough understanding of the natural history, pathophysiology, and surgical requirements of the procedure ( Eng & Lam, 1994 ).

Our new Contrast Optimization technique allows for robust and efficient optimization on the system MTF at a given spatial frequency. The method minimizes the wavefront differences between pairs of rays separated by a pupil shift corresponding to the targeted spatial frequency, which maximizes the MTF. Further computational efficiency is achieved by using Gaussian Quadrature to determine the pattern of rays sampled. Examples are given to demonstrate the advantages of the technique.

Intravascular foreign bodies are a known complication of medical and dental procedures. Dental anesthetic needles may be broken off and retained in the oropharynx. These needles have occasionally been reported to migrate through the oral mucosa in to deeper structures. Here we present the case of a 57-year-old man who had a retained dental needle that had migrated into his internal carotid artery. The needle was removed using endovascular techniques. To our knowledge, this is the first report of a retained dental needle being retrieved using this method. We review the literature on intravascular foreign bodies, retained dental needles, and endovascular techniques for retrieval of such foreign bodies.

Dorsally exophytic brainstem tumors arise from within the brainstem itself. As the tumor grows, it pulls eloquent tissue with it, resulting in a shape that is analogous to the sides of a volcano. Rather than a resection that is flush with the brainstem being performed, this functional tissue on the lateral edges of the tumor must be identified and preserved in order to avoid postoperative deficits. The authors describe a midline, suboccipital approach with the use of intraoperative direct stimulation to identify and preserve functional tissue innervating the palate during the resection of a dorsally exophytic medullary tumor.The video can be found here: https://youtu.be/qbk2DvInO8o.

Intravascular foreign bodies are a known complication of medical and dental procedures. Dental anesthetic needles may be broken off and retained in the oropharynx. These needles have occasionally been reported to migrate through the oral mucosa in to deeper structures. Here we present the case of a 57-year-old man who had a retained dental needle that had migrated into his internal carotid artery. The needle was removed using endovascular techniques. To our knowledge, this is the first report of a retained dental needle being retrieved using this method. We review the literature on intravascular foreign bodies, retained dental needles, and endovascular techniques for retrieval of such foreign bodies.

Purpose This article reports on findings from seven stakeholder focus groups conducted in exploring shared decision making (SDM) between provider and consumer in mental health (MH) treatment in public MH. Basic Procedures Seven focus groups were conducted with stakeholders—consumers, family members, prescribers, MH clinicians, and rural providers. Each of the focus groups was recorded digitally, transcribed into text, and analyzed qualitatively for recurring themes. Main findings Provider barriers to SDM include history of the medical model, MH crises, lack of system support, and time. Consumer-related barriers included consumer competency, fears, insight, literacy, and trauma from past experiences. Information-exchange issues include consumer passivity, whether consumers could be viewed as experts, and importance of adequate history information. New skills needed to practice SDM included provider's knowledge about alternative treatments, mastery of person-first language, and listening skills; consumer's ability to articulate their expert information; and computer skills for both providers and consumers. Outcomes expected from practice of SDM include greater sharing of power between provider and consumer, greater follow-through with treatment plans, greater self-management on the part of consumers, and improved therapeutic alliances. Principal conclusions Implementing SDM in public MH will impact consumers and their families, providers, prescribers, and administrators. More SDM trials in public MH are needed to answer some of the many questions that remain.

Clinical photography requires a regimented system of image acquisition similar to the regimentation needed for dental radiographs. Clinical digital photographic equipment is rapidly advancing. To achieve the best image quality and resolution, digital single-lens reflex systems are necessary. DSLR clinical systems are made of three components: camera body, macro lens, and flash attachment. Other ancillary equipment is necessary to achieve appropriate clinical image reveals and composition. Recommendations are given to assist in the implementation of clinical photography in the dental practice.

This article undertakes to examine the reception of Platonic theories of falsification in the contemporary philosophy of Leo Strauss and his adherents. The aim of the article is to consider the Straussian response to, and interaction with, Platonic ideas concerning deception and persuasion with an emphasis on the arguments found in the Laws. The theme of central interest in this analysis is Plato’s development of paramyth in the Laws. Paramyth entails the use of rhetorical language in order to persuade the many that it is to their advantage to obey certain laws. It does so without explaining in detail why a given law is ethically correct and its use assumes that the audience, on the whole, is not capable of understanding the finer philosophical underpinnings of the law. The so-called ‘noble lie’ of the Republic is also considered in this context. The crucial issue, for Plato if not for Strauss, is whether or not an instance of falsification, however minor, for the purposes of persuasion contains ‘truth-value’, that is, whether it is morally justifiable in terms of ends and means. In terms of Strauss’s reception of Plato, such issues as ancient Hebrew mysticism, Medieval Jewish and Islamic scholarship and Heideggerian Phenomenology figure in the argument. Ultimately, the article finds that Strauss and his followers have constructed a particular view of Platonic ideas that, while unique, is not compatible with their original signification.

The themes of hybris, erôs and mania are interconnected in Plato’s final opus, the Laws, regarding his narrator’s construction of sexually accepted norms for his ‘second-best’, utopian society. This article examines this formulation, its psychological characteristics and philosophical underpinnings. The role and function of his social programme are considered in the context of the Laws and the hypothetical polis outlined therein. However, this particular formulation is not a new development in later Platonic thought. It is, rather, a logical extension of earlier Platonic ideas, expressed in a number of previous dialogues, and brought to bear in the peculiar circumstances of the ‘second-best’ polis. This can be especially observed in relation to the Symposium and Phaedrus. Instead of regarding the construction of sexuality in the Laws as a work in isolation, these earlier ideas are here considered intertextually as part of a broader Platonic continuum.

Ground-based aerosol optical measurements made at near-ambient relative humidity (RH) under clean marine sampling conditions are presented and compared to 1) almost identical optical measurements made at a polluted continental site and 2) optical properties calculated from measured size distributions and Mie theory. The use of Mie theory (which assumes homogeneous spheres) is justified based on the fact that the sea-salt aerosol was measured in a hydrated state. This study focuses on the extinction-to-backscatter ratio S, an optical property required to interpret remote measurements by elastic backscatter lidar. For clean marine conditions, S is found to be 25.4 ± 3.5 sr at 532 nm (central value ± 95% confidence uncertainty). Other optical properties reported include single-scattering albedo, wavelength dependence of scattering, fraction of scattering due to submicrometer particles, and hemispheric-backscatter fraction, as well as the extensive properties (e.g., scattering coefficient) upon which...

Intravascular foreign bodies are a known complication of medical and dental procedures. Dental anesthetic needles may be broken off and retained in the oropharynx. These needles have occasionally been reported to migrate through the oral mucosa in to deeper structures. Here we present the case of a 57-year-old man who had a retained dental needle that had migrated into his internal carotid artery. The needle was removed using endovascular techniques. To our knowledge, this is the first report of a retained dental needle being retrieved using this method. We review the literature on intravascular foreign bodies, retained dental needles, and endovascular techniques for retrieval of such foreign bodies.

Cellular thiols have been proposed to play a protective role in oxidative DNA damage by quenching radical species in solution and by repairing deoxyribose and nucleobase radicals. There is also evidence for participation of thiols in reactions after formation of the DNA radical. Previous studies with neocarzinostatin, a thiol-dependent DNA-cleaving enediyne, revealed that the structure and charge of the activating thiol influence the partitioning of deoxyribose 4'-oxidation reactions between a 3'-phosphoglycolate residue and the alternative 4'-keto-1'-aldehyde abasic site [Kappen, L. S., et al. (1991) Biochemistry 30, 2034-2042; Dedon, P. C., et al. (1992) Biochemistry 31, 1917-1927]. However, interpretation of these results is confounded by the formation of a neocarzinostatin-thiol conjugate that could alter the position of the activated drug in the minor groove and quench drug radicals. Using the DNA-cleaving enediynes calicheamicin gamma(1)(I) and Ø, which are identical except for their trigger moieties, we now present a more definitive study of the role of thiol structure in the partitioning of the deoxyribose 4'-oxidation reaction. In the absence of thiols, calicheamicin Ø, which can undergo hydrolytic or reductive activation, generated 4'-oxidation products consisting of 26% 3'-phosphoglycolate residues, 33% 3'-phosphate-ended fragments, and 41% abasic sites (determined as the 3'-phosphopyridazine derivative). Using a series of thiols of varying size and charge, we found that, at concentrations that do not quench drug or DNA radicals, the negatively charged thiols glutathione and thioglycolate did not significantly affect the baseline proportions of the 4'-oxidation products. However, neutral thiols (O-ethylglutathione, methyl thioglycolate, 2-mercaptoethanol, and dithiothreitol) and, to a greater extent, the positively charged aminoethanethiol inhibited the production of 3'-phosphoglycolate residues with a proportional increase in the number of abasic sites. The effect of the thiols on the quantities of single- and double-stranded DNA lesions produced by calicheamicin gamma(1)(I) was also investigated since 3'-phosphoglycolate residues produced by calicheamicin exist only in double-stranded DNA lesions, and the thiol effects could have resulted from quenching of drug or DNA radicals. These studies revealed that, at thiol concentrations found to alter deoxyribose 4'-oxidation reactions, there was no apparent quenching of drug radicals or repair of DNA radicals. Thus, the effects of the thiols on the deoxyribose 4'-oxidation chemistry are due to reactions with a key intermediate in the phosphoglycolate- and abasic site-generating pathways. These results also suggest that cellular glutathione plays a relatively minor role in the chemistry of deoxyribose 4'-oxidation, which has implications for other oxidative reactions occurring in the minor groove of DNA (e.g., deoxyribose 5'- and 1'-oxidation).

An introduction is given to a new rotating wheelspace test vehicle known as the GE Hot Gas Ingestion Rig (HGIR). This scaled 1.5 stage turbine rig is configured similar to a current generation heavy duty gas turbine. It has a broad spectrum of measurement capability, including radial and circumferential ports for CO2 measurements that are used to measure the sealing effectiveness from candidate rim seal geometries. Engine-matched conditions are presented in a non-dimensional form that demonstrate the value of this fully capable test facility, including static pressure signatures at stage 1 nozzle exit, exit Reynolds number, exit Mach number and rotational Reynolds number. This paper also provides details of the operating conditions and assessment of a thermal steady-state condition achieved consistently throughout each test. Part I of this two-part paper focuses on the geometric details of this new state-of-the-art wheelspace rig, the measurement capabilities currently available and planned, and the results from the baseline geometry. The test data from this test vehicle are used to validate reduced order models, including unsteady CFD models. Details of the CFD modeling and validation are presented in the Part II paper Ding et al. [1]. Measurement uncertainties for all key parameters as well as the repeatability of the test rig to reproduce test conditions are presented to demonstrate the rigor taken in the design and operation of this testing facility.