Advancements and challenges in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.

Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults.

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Beat-to-beat blood pressure variability, hippocampal atrophy, and memory impairment in older adults.

Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

Short-term blood pressure variability and brain functional network connectivity in older adults.

Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.

Sacramental meditation.

The group practice called "sacramental meditation" relies on sacred objects and spontaneous imagination to prepare its participants for spiritual experience. The meditation object is likened to an icon. The practice is compared with Loyola's "spiritual exercises" and the therapeutic technique of "active imagination'. Fowler's theory of faith development is used to show the forms of symbolic awareness that occur during a meditation. The theory, the method, and the effects of sacramental meditation are reviewed.

Blood pressure variability, central autonomic network dysfunction and cerebral small vessel disease in APOE4 carriers.

Background: Increased blood pressure variability (BPV) is a risk factor for cerebral small vessel disease (CSVD) and neurodegeneration, independent of age and average blood pressure, particularly in apolipoprotein E4 (APOE4) carriers. However, it remains uncertain whether BPV elevation is a cause or a consequence of vascular brain injury, or to what degree injury to the central autonomic network (CAN) may contribute to BPV-associated risk in APOE4 carriers. Methods: Independently living older adults (n=70) with no history of stroke or dementia were recruited from the community and underwent 5 minutes of resting beat-to-beat blood pressure monitoring, genetic testing, and brain MRI. Resting BPV, APOE genotype, CSVD burden on brain MRI, and resting state CAN connectivity by fMRI were analyzed. Causal mediation and moderation analysis evaluated BPV and CAN effects on CSVD in APOE4 carriers (n=37) and non-carriers (n=33). Results: Higher BPV was associated with the presence and extent of CSVD in APOE4 carriers, but not non-carriers, independent of CAN connectivity (B= 18.92, P= .02), and CAN connectivity did not mediate the relationship between BPV and CSVD. In APOE4 carriers, CAN connectivity moderated the relationship between BPV and CSVD, whereby BPV effects on CSVD were greater in those with lower CAN connectivity (B= 36.43, P= .02). Conclusions: Older APOE4 carriers with higher beat-to-beat BPV exhibit more extensive CSVD, independent of average blood pressure, and the strength of CAN connectivity does not mediate these effects. Findings suggest increased BPV is more likely a cause, not a consequence, of CSVD. BPV is more strongly associated with CSVD in APOE4 carriers with lower rsCAN connectivity, suggesting CAN dysfunction and BPV elevation may have synergistic effects on CSVD. Further studies are warranted to understand the interplay between BPV and CAN function in APOE4 carriers.

Mercury in tadpoles collected from remote alpine sites in the southern Sierra Nevada mountains, California, USA.

Amphibians in alpine wetlands of the Sierra Nevada mountains comprise key components of an aquatic-terrestrial food chain, and mercury contamination is a concern because concentrations in fish from this region exceed thresholds of risk to piscivorous wildlife. Total mercury concentrations were measured in whole tadpoles of the Sierra chorus frog, Pseudacris sierra, two times at 27 sites from high elevations (2786-3375 m) in the southern Sierra Nevada. Median mercury concentrations were 14 ng/g wet weight (154 ng/g dry weight), which were generally low in comparison to tadpoles of 15 other species/location combinations from studies that represented both highly contaminated and minimally contaminated sites. Mercury concentrations in P. sierra were below concentrations known to be harmful in premetamorphic tadpoles of another species and below threshold concentrations for risk to predaceous wildlife. Concentrations in tadpoles were also lower than those observed in predaceous fish in the study region presumably because tadpoles in the present study were much younger (1-2 months) than fish in the other study (3-10 years), and tadpoles represent a lower trophic level than these fish. Mercury concentrations were not related to distance from the adjacent San Joaquin Valley, a source of agricultural and industrial pollutants.

Analysis of shared underlying mechanism in neurodegenerative disease.

In this review, the relationship between bioenergetics, mitochondrial dysfunction, and inflammation will be and how they contribute to neurodegeneration, specifically in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) will be reviewed. Long-term changes in mitochondrial function, autophagy dysfunction, and immune activation are commonalities shared across these age-related disorders. Genetic risk factors for these diseases support an autophagy-immune connection in the underlying pathophysiology. Critical areas of deeper evaluation in these bioenergetic processes may lead to potential therapeutics with efficacy across multiple neurodegenerative diseases.

Effect of Race on Prediction of Brain Amyloidosis by Plasma Aß42/Aß40, Phosphorylated Tau, and Neurofilament Light.

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aß42/Aß40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups. METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aß42/Aß40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aß42/Aß40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively. RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aß42/Aß40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aß42/Aß40 status with the plasma biomarkers was as follows: Aß42/Aß40, 0.86 (95% CI 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aß42/Aß40 status with plasma Aß42/Aß40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aß42/Aß40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aß42/Aß40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings. DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aß42/Aß40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.

Brain and psyche in early Christian asceticism.

This study is an 11-part investigation of the psychology and neuropsychology of early Christian asceticism as represented by Evagrius Ponticus (AD 345-399), the tradition's first ascetical theologian and possibly its mosfinfluential. Evagrius's biography is reviewed in the first section. The living circuinstaii and perceptual consequences of desert asceticism are considered in the second. Penitence, dispassion, and the mysticism of "pure prayer" are discussed in the third. Austerities are addressed in the fourth section, particularly fasting, prostrations, and prolonged standing. Ascetical perspectives on sleep, dreams, and the hypnogogic state are analyzed in the fifth. The depressive syndrome of acedia is discussed in the sixth. Evagrius's reports of auditory, olfactory, and visual hallucinations are analyzed in the seventh. Multiple complementary interpretations of demonic phenoniena are developed in the eighth section. Evagrius's psychotherapy for anger is reviewed in the ninth. Interpersonal relations among ascetics are considered in the tenth section. The study concludes with a summary.

Medication Adherence: Expanding the Conceptual Framework.

Interventions targeting traditional barriers to antihypertensive medication adherence have been developed and evaluated, with evidence of modest improvements in adherence. Translation of these interventions into population-level improvements in adherence and clinical outcomes among older adults remains suboptimal. From the Cohort Study of Medication Adherence among Older adults (CoSMO), we evaluated traditional barriers to antihypertensive medication adherence among older adults with established hypertension (N = 1,544; mean age = 76.2 years, 59.5% women, 27.9% Black, 24.1% and 38.9% low adherence by proportion of days covered (i.e., PDC <0.80) and the 4-item Krousel-Wood Medication Adherence Scale (i.e., K-Wood-MAS-4 ≥1), respectively), finding that they explained 6.4% and 14.8% of variance in pharmacy refill and self-reported adherence, respectively. Persistent low adherence rates, coupled with low explanatory power of traditional barriers, suggest that other factors warrant attention. Prior research has investigated explicit attitudes toward medications as a driver of adherence; the roles of implicit attitudes and time preferences (e.g., immediate vs. delayed gratification) as mechanisms underlying adherence behavior are emerging. Similarly, while associations of individual-level social determinants of health (SDOH) and medication adherence are well reported, there is growing evidence about structural SDOH and specific pathways of effect. Building on published conceptual models and recent evidence, we propose an expanded conceptual framework that incorporates implicit attitudes, time preferences, and structural SDOH, as emerging determinants that may explain additional variation in objectively and subjectively measured adherence. This model provides guidance for design, implementation, and assessment of interventions targeting sustained improvement in implementation medication adherence and clinical outcomes among older women and men with hypertension.

Spatial patterns of atmospherically deposited organic contaminants at high elevation in the southern Sierra Nevada mountains, California, USA.

Atmospherically deposited contaminants in the Sierra Nevada mountains of California, USA have been implicated as adversely affecting amphibians and fish, yet little is known about the distributions of contaminants within the mountains, particularly at high elevation. The hypothesis that contaminant concentrations in a high-elevation portion of the Sierra Nevada decrease with distance from the adjacent San Joaquin Valley was tested. Air, sediment, and tadpoles were sampled twice at 28 water bodies in 14 dispersed areas in Sequoia and Kings Canyon National Parks (2,785-3,375 m elevation; 43-82 km from Valley edge). Up to 15 chemicals were detected frequently in sediment and tadpoles, including current- and historic-use pesticides, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. Only beta-endosulfan was found frequently in air. Concentrations of all chemicals detected were very low, averaging in the parts-per-billion range or less in sediment and tadpoles, and on the order of 10 pg/m3 for beta-endosulfan in air. Principal components analysis indicated that chemical compositions were generally similar among sites, suggesting that chemical transport patterns were likewise similar among sites. In contrast, transport processes did not appear to strongly influence concentration differences among sites, because variation in concentrations among nearby sites was high relative to sites far from each other. Moreover, a general relationship for concentrations as a function of distance from the valley was not evident across chemical, medium, and time. Nevertheless, concentrations for some chemical/medium/time combinations showed significant negative relationships with metrics for distance from the Valley. However, the magnitude of these distance effects among high-elevation sites was small relative to differences found in other studies between the valley edge and the nearest high-elevation sites.

Assessing the impact of drug courts on provider-directed marketing efforts by manufactures of medications for the treatment of opioid use disorder.

BACKGROUND: Opioid use disorder (OUD) has become an increasingly consequential public health concern, especially in the United States where 47,600 opioid overdose deaths occurred in 2017 (Scholl, Seth, Kariisa, Wilson, & Baldwin, 2019). Medications for OUD (MOUD) are effective for decreasing opioid-related morbidity and mortality, including within the criminal justice system (Hedrich et al., 2012; Medications for Opioid Use Disorder Save Lives, 2019; Moore et al., 2019).While a stronger evidence base exists for agonist MOUD than for antagonist MOUD, a national study of drug courts found that half prohibited agonist MOUD (Matusow et al., 2013).Furthermore, recent media reports suggest that the pharmaceutical manufacturer of an antagonist MOUD has marketed its product towards drug court judges (Goodnough & Zernike, 2017; Harper, 2017). However, no study to date has systematically examined the relationship between MOUD marketing practices and drug courts. This ecological study examines the association at the county level between MOUD manufacturer payments to prescribers and drug court locations. METHOD: We extracted provider-directed payments from Centers for Medicare and Medicaid Services (CMS)'s Sunshine Act Open Payments data 2014-2017, isolating those records mentioning any MOUD. We compared provider-directed payments for two major MOUDs: buprenorphine and extended-release naltrexone, in counties with and without drug courts. RESULTS: The presence of any adult drug courts in the county is associated with a 7.86 percentage-point increase in the likelihood of providers in that county receiving any MOUD-related payments (about 22.46% of the sample mean, p<0.001) and with a 10.70% increase in the amount of these payments per 1000 county residents (p<0.001). The association between other forms of drug courts such as juvenile drug courts and Driving-Under-the-Influence courts (DUI) courts are less significant and slightly smaller in magnitude compared to those of adult drug courts. We did not find significant difference between payments by the manufacturer of Vivitrol and manufacturers of Zubsolv, Bunavail, and Suboxone (oral forms of buprenorphine). CONCLUSIONS: Our results show an ecological association at the county level between MOUD manufacturer payments to prescribers and drug court presence. However, we did not examine a causal association between these variables.

Comparison of pressurized liquid extraction and matrix solid-phase dispersion for the measurement of semivolatile organic compound accumulation in tadpoles.

Analytical methods capable of trace measurement of semivolatile organic compounds (SOCs) are necessary to assess the exposure of tadpoles to contaminants as a result of long-range and regional atmospheric transport and deposition. The present study compares the results of two analytical methods, one using pressurized liquid extraction (PLE) and the other using matrix solid-phase dispersion (MSPD), for the trace measurement of more than 70 SOCs in tadpole tissue, including current-use pesticides. The MSPD method resulted in improved SOC recoveries and precision compared to the PLE method. The MSPD method also required less time, consumed less solvent, and resulted in the measurement of a greater number of SOCs than the PLE method.

Relaxation of forces needed to distract cervical vertebrae after discectomy: a biomechanical study.

STUDY DESIGN: In vitro and in vivo biomechanical stress measurements are made of the intervertebral disc segment distraction force during anterior cervical discectomy. OBJECTIVE: The purpose of this study is to determine the short-term force relaxation of the native intervertebral disc segment and to determine the short-term force relaxation of the segment after removal of the intervertebral disc, as is commonly performed in anterior cervical discectomy with fusion and arthroplasty. SUMMARY OF BACKGROUND DATA: No published data examine the issue of intraoperative distraction force of the cervical intervertebral disc segment. This is a novel research in this area. METHODS: In vitro and in vivo studies under institutional review board approval were performed to determine the mechanical behavior of the normal and diseased cervical functional spinal unit. Seven in vitro and 11 in vivo spines were studied. Strain measurements between distracting Caspar-type pins were made before, at various points during, and after discectomy to assess how removal of the disc and other spinal components affects the force-displacement behavior of the spinal unit. RESULTS: The in vitro data show progressive reduction in force needed for distraction after discectomy and uncovertebral joint resection. Greatest reduction is noted after discectomy. The in vivo data indicate that, on average, the cervical functional spinal unit requires 20 N less force to achieve the same degree of distraction after removal of the intervertebral disc. CONCLUSIONS: A sharp reduction in the strain across the intervertebral space occurs after distraction. The removal of the cervical intervertebral disc significantly reduces the viscoelastic response of the cervical motion segment. The long-term force used to stabilize intervertebral grafts or implants is less than what is achieved at the time of distraction. The exact magnitude of the resultant force on graft or device at a given distraction force is unknown and would depend also upon fit.

The short-term effects of electrosurgical ablation on proinflammatory mediator production by intervertebral disc cells in tissue culture.

BACKGROUND CONTEXT: Percutaneous discectomy can be performed by a variety of methods. One method, electrosurgical ablation, has been shown in a chronic animal model to alter the expression of inflammatory cytokines in degenerated discs. PURPOSE: To determine whether electrosurgical ablation has an acute direct effect on proinflammatory mediator production by disc cells. STUDY DESIGN: A short-term in vitro study using normal and interleukin (IL)-1alpha stimulated porcine disc cells cultured in alginate gel to evaluate the biochemical effects of electrosurgical ablation. METHODS: Porcine annulus and nucleus cells were embedded into alginate gels and cultured using control culture media or IL-1alpha-treated media for 6 days before ablation treatment. Treated gels were ablated by using a radiofrequency-based electrosurgical device for 5 seconds and cultured an additional 3 or 6 days. IL-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), nitric oxide (NO), and heat shock protein-70 (Hsp70) levels in culture medium were measured. Levels were normalized to DNA and compared between ablated and shams. RESULTS: For normal annulus cells, there were no significant changes in cytokine levels between ablation and sham groups. For normal nucleus cells, ablation produced significantly greater levels of IL-8 at 3 days and 6 days, Hsp70 at 3 days but not 6 days, and NO at 6 days. PGE2 was also increased at 3 days and 6 days but not significantly. For IL-1-stimulated annulus cells, IL-6 and NO in the ablation group were decreased at 3 days relative to the control group. However, IL-6, IL-8, PGE2, and Hsp70 were significantly increased in the 6-day ablation group. For degenerated nucleus cells, IL-6, IL-8, and TNF-alpha were significantly decreased in the ablation group at both 3 days and 6 days. Ablation resulted in reduced PGE2 at 3 days but not 6 and reduced Hsp70 and NO at 6 days. CONCLUSIONS: The results show that electrosurgical ablation has an acute direct effect on proinflammatory mediator production by disc cells. The effect produced depends on disc cell phenotype, the mediator, and time. These direct biologic effects may be a mechanism of pain relief after percutaneous discectomy using electrosurgical ablation. However, the measured responses are limited to the short-term (1 week), and the existence of a prolonged effect remains to be determined.

Polyopic heautoscopy: Case report and review of the literature.

Heautoscopy, i.e., the encounter with one's double, is a multimodal illusory reduplication of one's own body and self. In its polyopic form, more than one double is experienced. In the present article, we review fourteen published cases of polyopic heautoscopy and describe in detail the case of a 41-year-old man with polyopic heautoscopy resulting from a tumor in the insular region of the left temporal lobe. Our case is illustrative in several respects: (1) The patient's five doubles were all confined to the right hemispace. Laterality in this case is discussed with reference to previous cases of unilateral heautoscopy after focal brain damage, which generally do not show a hemispatial or hemispheric bias. (2) The patient's psychological affinity with his doubles, and also the extent of their echopraxia of his movements, decreased as a function of their perceived spatial distance from the patient's body, corroborating previous observations of associations between spatial and psychological phenomenologies during autoscopic phenomena. (3) While classical heautoscopy (the reduplication of a single body and self) is considered a breakdown in the integrative processes that enable us to identify our self with our body, the phenomenon of polyopic heautoscopy (a multiplication of body and self) points to the multiple mappings of the body, whose disintegration may give rise to the illusory experience of multiple selves.