Pre-Visit Education on Pain Management Options Prior to the First Clinic Visit Improves Chronic Pain Patient Satisfaction with Proposed Treatment Plans.

OBJECTIVE: This study sought to evaluate if actively informing new chronic pain patients about treatment options and setting realistic expectations for care, through the use of a pre-visit informational handout prior to the first clinic visit, improved patient satisfaction with subsequently proposed treatment plans. METHODS: The study was divided into two 3-month periods. During the first 3 months, with our current pain clinic practices in place, new patients (n = 147) were given surveys to establish a baseline of patient satisfaction with treatment plans proposed on their first visit. During the second 3 months, a different group of new patients (n = 156) was given a detailed informational handout which described our clinic's multimodal approach to pain management and therapeutic expectations prior to their visit with a provider. Patient satisfaction with subsequently proposed treatment plans was then assessed and compared with the baseline group. RESULTS: The average patient satisfaction score for the group of patients given the informational handout was 4.21 (on a 5-point Likert scale), compared to an average score of 3.25 for the baseline group (P < .0001, unpaired t-test). 77.6% of patients given the informational handout said their proposed treatment plan met their expectations compared to 46.3% of patients in the baseline group (χ2= 31.61, two-tailed P < .0001). CONCLUSIONS: Patient satisfaction with proposed chronic pain treatment plans was improved when clinic approaches to pain were explicitly outlined and therapeutic expectations were clearly established in the form of an informational handout at the outset of the first visit.

Neuraxial Anesthesia in a Patient With a History of Spontaneous Intracranial Hypotension: A Case Report.

One commonly cited complication of neuraxial techniques is postdural puncture headache. Patients with spontaneous intracranial hypotension may present with a similar constellation of symptoms in the absence of any neuraxial instrumentation. The underlying physiology of spontaneous intracranial hypotension is similar to postdural puncture headache, but cerebrospinal fluid leaks may develop spontaneously at multiple levels of the neuraxis due to a variety of proposed mechanisms. We present a patient with a history of spontaneous intracranial hypotension who underwent a total knee arthroplasty under spinal anesthesia without complication and discuss the pathophysiology, proposed etiologies and treatments, and safety of neuraxial anesthesia in spontaneous intracranial hypotension.

The Expanded Endoscopic Endonasal Approach to Anterior Communicating Artery Aneurysms: A Cadaveric Morphometric Study.

OBJECTIVE: The purpose of this study was to explore the endoscopic endonasal approach to the anterior communicating artery complex. DESIGN: Anatomic, morphometric analysis of human cadaver heads. SUBJECTS: Fifteen latex-injected adult cadaver heads. MAIN OUTCOME MEASURES: The anatomic boundaries of the operative field and the dimensions of exposure of the anterior communicating artery (ACoA) complex were measured and clip placement feasibility was assessed. RESULTS: Exposure of the ACoA and bilateral A1 and A2 segments was accomplished in all 15 cadaver heads. Average length of the exposed ACoA was 3 ± 1 mm, the left A1 was 5 ± 3 mm and right A1 was 5 ± 1 mm, while the A2 segment was 5 ± 2 mm bilaterally. The average distance from the alar floor to the ACoA was 95 mm, while proximal lateral limit measured between the alar floor margins was 36 mm. The distal lateral limit as defined by the distance between the lateral most exposed margins of the chiasm was 19 mm. Clip placement was accomplished for the ACoA and the A1 and A2 segments bilaterally in all specimens. CONCLUSION: The endoscopic, endonasal transtuberculum, transplanum approach is an anatomically feasible alternative to treating select aneurysms of the ACoA complex.

Viability assays for cells in culture.

Manual cell counts on a microscope are a sensitive means of assessing cellular viability but are time-consuming and therefore expensive. Computerized viability assays are expensive in terms of equipment but can be faster and more objective than manual cell counts. The present report describes the use of three such viability assays. Two of these assays are infrared and one is luminescent. Both infrared assays rely on a 16 bit Odyssey Imager. One infrared assay uses the DRAQ5 stain for nuclei combined with the Sapphire stain for cytosol and is visualized in the 700 nm channel. The other infrared assay, an In-Cell Western, uses antibodies against cytoskeletal proteins (α-tubulin or microtubule associated protein 2) and labels them in the 800 nm channel. The third viability assay is a commonly used luminescent assay for ATP, but we use a quarter of the recommended volume to save on cost. These measurements are all linear and correlate with the number of cells plated, but vary in sensitivity. All three assays circumvent time-consuming microscopy and sample the entire well, thereby reducing sampling error. Finally, all of the assays can easily be completed within one day of the end of the experiment, allowing greater numbers of experiments to be performed within short timeframes. However, they all rely on the assumption that cell numbers remain in proportion to signal strength after treatments, an assumption that is sometimes not met, especially for cellular ATP. Furthermore, if cells increase or decrease in size after treatment, this might affect signal strength without affecting cell number. We conclude that all viability assays, including manual counts, suffer from a number of caveats, but that computerized viability assays are well worth the initial investment. Using all three assays together yields a comprehensive view of cellular structure and function.

N-acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress.

The two hit hypothesis of neurodegeneration states that cells that have been severely stressed once are more vulnerable to the negative impact of a second hit. In other words, the toxicity of two hits of severe stress may be synergistic in neurons. We previously developed a two hit model of proteotoxic neurodegeneration using the proteasome inhibitor MG132. In that study, we found that the potent antioxidant N-acetyl cysteine was able to protect against the toxicity associated with dual MG132 hits. N-acetyl cysteine has been shown to ameliorate cognitive deficits in Alzheimer's patients and to reduce the symptoms of blast injury in soldiers. These studies and many others in experimental models of neurodegeneration suggest that N-acetyl cysteine can protect neurons even when they are severely injured. In the present study, we tested the hypotheses that dual hits of hydrogen peroxide and paraquat would elicit synergistic neurodegeneration and that this extreme toxicity would be prevented by N-acetyl cysteine. The findings reveal for the first time that neuronal N2a cells are much more sensitive to oxidative stress from hydrogen peroxide treatment when they have been exposed previously to the same toxin. Two hits of hydrogen peroxide also caused severe loss of glutathione. N-acetyl cysteine attenuated the loss of glutathione and reduced the near-complete loss of cells after exposure to dual hydrogen peroxide hits. The present study supports the notion that N-acetyl cysteine can robustly protect against severe, unremitting oxidative stress in a glutathione-dependent manner.

Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.

In Parkinson's and Alzheimer's diseases, the allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in allocortex.

Rescue from a two hit, high-throughput model of neurodegeneration with N-acetyl cysteine.

Postmortem tissue from patients with neurodegeneration exhibits protein-misfolding stress and reduced proteasome activity. This hallmark burden of proteotoxic stress has led to the term "proteinopathies" for neurodegenerative diseases. Proteinopathies may also be exacerbated by previous insults, according to the two hit hypothesis of accelerated neurodegeneration. In order to model the response to two successive insults in a high-throughput fashion, we exposed the neuronal cell line N2a to two hits of the proteasome inhibitor MG132 and performed three unbiased viability assays. MG132 toxicity was synergistically exacerbated following sequential hits provided the first hit was high enough to be toxic. This accelerated viability loss was apparent by (1) a nuclear and cytoplasmic stain (DRAQ5+Sapphire), (2) immunocytochemistry for a cytoskeletal marker (α-tubulin), and (3) ATP levels (Cell Titer Glo). Ubiquitin-conjugated proteins were raised by toxic, but not subtoxic MG132, and were thus correlated with toxicity exacerbation at higher doses. We hypothesized that levels of autophagic and antioxidant defenses would be reduced with toxic, but not subtoxic MG132, explaining their differential impact on a second hit. However, proteins involved in chaperone-mediated autophagy were raised by toxic MG132, not reduced. Furthermore, inhibiting autophagy enhanced the toxicity of both subtoxic and toxic MG132 as well as of dual hits, suggesting that autophagic removal of cellular debris protected against proteasome inhibition. Two toxic hits of MG132 synergistically decreased the antioxidant glutathione. The glutathione precursor N-acetyl cysteine reversed this glutathione loss and prevented the toxic response to dual hits by all three assays. Dietary supplementation with N-acetyl cysteine benefits Alzheimer's patients and is currently undergoing clinical trials in Parkinson's disease. The present report is the first demonstration that this versatile compound is protective against synergistic loss of viability as well as of glutathione following unrelenting, sequential hits of proteotoxic stress as may occur in the diseased brain.