An Acute Disseminated Encephalomyelitis-Like Illness in the Elderly: Neuroimaging and Neuropathology Findings.

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system (CNS) that classically occurs in children and adolescents. It characteristically presents with acute inflammation, resulting in demyelination, often following an infectious disease. ADEM has been described in adult patients, but the incidence in the adult and especially elderly population is low. CASES: We describe five older adults (age 57 to 85) who presented with acute neurological symptoms. Three patients presented with an infectious illness preceding the event, 4 patients were encephalopathic, and oligoclonal bands (OCBs) were negative in all tested cases. The clinical scenario and imaging studies suggested alternative diagnoses, such as metastasis, primary CNS tumor, or stroke. Two patients had contrast enhancing lesions, two other patients had lesions with restricted diffusion on diffusion-weighted imaging. Neuropathologic diagnostic from biopsy or autopsy was eventually conclusive, showing perivascular zones of myelin loss with relative axonal sparing in all five cases. CONCLUSION: Each of these patients was found to have pathological findings of acute demyelination on tissue diagnosis, suggesting ADEM or ADEM-like disease. The initial presentation and imaging was pointing toward other diagnoses. Broad differential diagnosis is important, especially for older patients, and pathological proof might be warranted for a conclusive diagnosis.

Use and Outcomes of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients ≥90 Years of Age.

BACKGROUND AND PURPOSE: Intravenous tissue-type plasminogen activator (tPA) is a proven treatment for acute ischemic stroke, but there has been limited evaluation among patients aged ≥90 years. METHODS: We analyzed data from the Get With The Guidelines-Stroke national quality improvement registry from January 2009 to April 2013. Frequency, determinants, and outcomes of tPA use were compared among patients aged ≥90 and 3 younger age groups (18-64, 65-79, and 80-89 years). RESULTS: Among 35 708 patients from 1178 sites who arrived within 2 hours of time last known well and received tPA, 2585 (7.2%) were ≥90 years. Compared with younger patients, the rate of tPA use among patients without a documented contraindication was lower among patients aged ≥90 years (67.4% versus 84.1% in 18-89-year olds; P<0.0001). Discharge outcomes among individuals aged ≥90 years included discharge to home or acute rehabilitation in 31.4%, independent ambulation at discharge in 13.4%, symptomatic hemorrhage in 6.1%, and in-hospital mortality or hospice discharge in 36.4%. On multivariable analysis, good functional outcomes generally occurred less often and mortality more often among patients aged ≥90 years. The risk of symptomatic hemorrhage was increased compared with patients <65 years but was not significantly different than the risk in 66- to 89-year olds. CONCLUSIONS: The use of intravenous tPA among those aged ≥90 years is lower than in younger patients. When fibrinolytic therapy is used, the risk of symptomatic hemorrhage is not higher than in 66- to 89-year olds; however, mortality is higher and functional outcomes are lower.

Poor Hypertension Control and Longer Transport Times Are Associated with Worse Outcome in Drip-and-Ship Stroke Patients.

BACKGROUND: The "drip-and-ship" paradigm is an important treatment modality for acute ischemic stroke (AIS) patients who do not have immediate access to a comprehensive stroke center (CSC). Intravenous thrombolysis is initiated at a primary stroke center followed by expeditious transfer to a CSC. We sought to determine factors associated with poor outcomes in drip-and-ship AIS patients transferred to a CSC. METHODS: This study is a retrospective analysis of 130 consecutive drip-and-ship patients transferred by ambulance to a single CSC between July 2012 and June 2014. Multiple patient and transport factors were analyzed. Transport blood pressure (BP) control was considered inadequate if the systolic BP was greater than 180 mmHg and/or diastolic BP was greater than 105 mmHg upon CSC arrival. Poor patient outcome was defined as discharge to hospice or expiry, a discharge modified Rankin Scale (mRS) score higher than 2, or symptomatic intracerebral hemorrhage (ICH). RESULTS: There was a significant association between inadequate BP control upon CSC arrival and in-hospital mortality or discharge to hospice (P < .0007). Arrival BP was not associated with the risk of post-thrombolysis symptomatic ICH. Longer transport time was significantly associated with a poorer mRS score at discharge (P < .0174) and death (P < .0351). CONCLUSIONS: Post-thrombolysis BP guideline violations and longer transport times during drip-and-ship transfers were significantly associated with poor outcome. Guidelines for strict transport BP management and alternative modes of transfer for longer-distance transports may be warranted.

Ischemic and Hemorrhagic Strokes due to Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: We report a case of ischemic and hemorrhagic strokes occurring almost simultaneously in a patient diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) previously known as Churg-Strauss vasculitis. To our knowledge, this is the first known case. METHODS: A 59-year-old man presented with a 2-month history of bilateral leg weakness, difficulty ambulating, and dyesthesias. While in the hospital, he developed acute right hand weakness, and magnetic resonance imaging of the brain revealed multiple, bilateral ischemic infarcts. After a few days, he acutely became unresponsive and was found to have a large left frontal hematoma and underwent emergent hematoma evacuation. His weakness was unexplained by the infarcts based on location and so a peripheral process was suspected. RESULTS: Nerve conduction studies showed severe axonal sensorimotor neuropathy. A sural nerve biopsy showed necrotizing vasculitis, consistent with EGPA. CONCLUSIONS: EGPA is the rarest of the antineutrophilic cytoplasmic antibody vasculitides. The peripheral nervous system is frequently involved, but the central nervous system can also be affected. The vasculitis damages the vessel walls, which leads either to stenosis or to dilatation, resulting in ischemic or bleeding consequences which can occur simultaneously, such as in this case. Caution should be exercised when prescribing antiplatelet therapy to such patients.

Mechanism of acute ischemic stroke in patients with severe middle cerebral artery atherosclerotic disease.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is one of the most common causes of ischemic stroke worldwide. Although the pathogenesis of cerebral infarct in ICAD has been reported from autopsy series, the mechanism of stroke is not well known. This study used baseline perfusion imaging and diffusion-weighted imaging (DWI) or computerized tomography (CT) imaging to help identify the mechanism of stroke in ICAD involving the middle cerebral artery (MCA). METHODS: We retrospectively reviewed baseline CT or magnetic resonance (MR) perfusion studies and diffusion-weighted MR imaging or CT scans in patients with severe symptomatic MCA stenosis. Perfusion scans were classified according to stage of perfusion deficit, and the acute stroke patterns were categorized as borderzone, cortical, or perforating artery infarcts according to DWI or noncontrast CT. RESULTS: Fifteen patients were included in this analysis. All 15 patients had some type of borderzone infarct. Six had borderzone infarct only, 4 had borderzone and cortical infarcts, and 5 had borderzone, cortical, and perforating artery infarcts. Thirteen of the 15 patients had baseline perfusion deficits. CONCLUSIONS: In patients with severe MCA ICAD, the mechanism of stroke is multifactorial, but hemodynamic insufficiency plays a significant role. This finding is important in selecting a subgroup of patients who may benefit from revascularization.

Pain and relaxation (review).

The modern notion of pain and its clinical management, along with its physiological origins, is of exceeding interest to both clinicians and basic science researchers. While much is known about the control of pain via non-steroidal anti-inflammatory medications or comparative exogenous analgesics, little is known about the interplay between pain perception and its relationship with catecholamine molecules. We believe that the perception of pain and the body's self-attempt to alleviate it utilizing conventional homeostatic mechanisms via endogenous opiate release is mediated by key catecholamines, and that this effect is further modulated by nitric oxide. We further propose a new paradigm which links pain, endogenous opiates, and the catecholamines in a unique robust fashion demonstrating a complex symbiotic signaling system.

Role of amygdala in mediating sexual and emotional behavior via coupled nitric oxide release.

Although the anatomical configuration of the amygdala has been studied a great deal, very little research has been conducted on understanding the precise mechanism by which this emotional regulatory center exerts its control on emotional and sexual behavior. By applying research methodology from the Neuroscience Research Institute, State University of New York, College at Old Westbury, we intended to demonstrate that much of the mediated effects of the amygdala, specifically the regulation of the male and female sexual response cycles, as well as related emotional considerations, exert their effects coupled to nitric oxide (NO) release. Furthermore, by using current anatomical and histological data, we demonstrated that amygdalar tissue rich in endocannabinoid and opiate, as well as catecholamine, receptors could exert its neurochemical effects within an NO-mediated paradigm. This paradigm, together with the existence of estrogen and androgen signaling within the amygdala, further lends credence to our theoretical framework. We begin with a brief anatomical and functional review of amygdalar function, and then proceed to demonstrate its relationship with NO.

Nitric oxide as a possible mechanism for understanding the therapeutic effects of osteopathic manipulative medicine (Review).

Throughout the history of medicine we have seen the progression of medical therapies from the empirical to the counter-intuitive, with much pressure being placed upon the scientific community to distinguish the two. This exercise has proven the effectiveness of numerous modern therapeutic techniques that have been adapted into modern medicine with remarkable success. While it is certain that many of these techniques yield beneficial results, the mechanisms by which these results are achieved have not been fully realized. In the present report, we consider the case of osteopathic manipulative medicine (OMM), which represents a therapeutic technique developed over a century ago as a means of non-invasive treatment for numerous ailments. Our intention is to use current findings from our laboratory, as well as those of our colleagues in the area of nitric oxide (NO) research to explain the mechanism through which osteopathic manipulations aid the patient. These reports demonstrate that fluidic motions applied to vascular and nerve tissue in a manner comparable to manipulations can cause a remarkable increase in NO concentration within the blood and vasculature. These findings combined with the overwhelming amount of research into the beneficial effects of constitutive NO provide a dynamic theoretical framework to explain the therapeutic effects of OMM.

Music alters constitutively expressed opiate and cytokine processes in listeners.

BACKGROUND: Listening to music as a means of inducing a sense of calm and relaxation has been known for some time. Although these effects are robust, little research has been conducted into exploring the underlying neurochemical changes, which must occur to provide an individual with these objective sensations. MATERIAL/METHODS: In the current report we utilize an AB design to explore observed differences in blood plasma signaling molecules in pre- and post music listening groups when compared with controls. We focus chiefly on cytokines, as well as peripheral blood mononuclear cells and polymorphonuclear cells. We utilized reverse transcription followed by real-time polymerase chain reactions to determine relative mRNA expression for the mu opiate receptor gene. Using high pressure liquid chromatography coupled to electrochemical detection as well as nano electrospray ionization double quadrupole orthogonal acceleration time of flight-mass spectrometry we determined opiate alkaloid levels. RESULTS: Our findings are two-fold: with regard to mu opiate receptor expression, mononuclear cells showed a statistically significant increase in subjects in the music group compared to the control. Plasma morphine levels were found to be non-significantly lower in subjects after listening to music when compared to control subjects whereas morphine 6 glucuronide levels increased slightly, suggesting morphine's conversion to morphine 6 glucuronide. IL- 6 levels were significantly lower as well whereas IL-1b, IL-10 and cortisol values were unchanged. CONCLUSIONS: Taken together, it appears that music-listeners exhibit plasma signal molecule changes consistent with the physiological changes associated with the reported actions of music, i.e, lower blood pressure.

17-beta estradiol down regulates ganglionic microglial cells via nitric oxide release: presence of an estrogen receptor beta transcript.

OBJECTIVES: In earlier studies we have demonstrated that 17-beta-estradiol and an estrogen cell surface receptor can be found on various human cells where they are coupled to nitric oxide release. We also demonstrated the presence of estrogen signaling in Mytilus edulis ganglia. In the present report, we sought to determine a function for these ganglionic estrogen receptors, transcending a reproductive role for estrogen. MATERIAL & METHODS: Ganglionic microglial egress from excised pedal ganglia was examined microscopically following pharmacological treatments designed to determine a role for 17-beta-estradiol in microglial regulation via nitric oxide. Additionally, we examined the tissue by RT-PCR and sequence analysis for the estrogen receptor beta gene. RESULTS: In ganglia incubated with varying concentrations of 17-beta-estradiol-BSA there is a significant drop in microglial egress at the 24 hour observation period (58.7 +/- 7.4 vs. 17-beta-estradiol-BSA exposed = 14.7 +/- 1.5; P<0.01), which can be antagonized by tamoxifen and significantly diminished by L-NAME, a nitric oxide synthase inhibitor. By RT-PCR and sequence analysis Mytilus edulis pedal ganglia was found to express a 266 bp fragment of the estrogen receptor-beta gene, which exhibits 100% sequence identity with the human counterpart. CONCLUSION: These data suggest that 17-beta-estradiol-BSA is working on estrogen cell surface receptors since 17-beta-estradiol-BSA does not enter the cytoplasm and that these receptors are coupled to constitutive nitric oxide release. This study demonstrates that 17-beta-estradiol can down regulate microglial fMLP induced activation and activation following ganglionic excision.

The presence of 17-beta estradiol in Mytilus edulis gonadal tissues: evidence for estradiol isoforms.

OBJECTIVES: In earlier studies, we demonstrate that 17-beta -estradiol and an estrogen cell surface receptor can be found on various human cells, i.e., vascular endothelial, monocytes, and granulocytes, where they are coupled to nitric oxide release. We further demonstrated this phenomenon in the marine mussel Mytilus edulis ganglionic tissues. In the present report we sought to determine if estrogen can be found in M. edulis reproductive tissues. MATERIAL & METHODS: We determined the presence of 17-beta -estradiol via high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA) in the animals gonads. This substance was further identified via nanoelectro-spray ionization quadrupole time of flight mass spectrometry (Q-TOF-MS). RESULTS: 17-beta -estradiol was identified and quantified in Mytilus gonads. Interestingly, we also determined that estradiol isoforms also were present in this tissue. CONCLUSION: These data demonstrate that 17-beta-estradiol and an estradiol isoform is present in M. edulis gonadal tissues, suggesting that they have functions related to reproduction. This further suggests that estrogen's association with reproductive activities has a long evolutionary history and that this association began in invertebrates.

The effects of auditory perception and musical preference on anxiety in naive human subjects.

BACKGROUND: The use of music as a method of relieving anxiety has been studied extensively by researchers from varying disciplines. The abundance of these reports focused on which genre of music best aided in the relief of stress. Little work has been performed in the area of auditory preference in an attempt to ascertain whether an individual's preferred music type aids in their anxiety reduction at levels greater than music that they have little or no propensity for. MATERIAL/METHODS: In the present report we seek to determine whether naive human subjects exposed to music of their preference show a decrease in anxiety, as measured by systolic and diastolic blood pressure values. We furthermore contrast these values to those obtained during non-preferred music listening. RESULTS: We found statistically significant reduction of anxiety levels only when subjects were exposed to their preferred musical selections. CONCLUSIONS: Students participating in the study already had knowledge of what genre of music would best relax them. It is our belief, that within the general population, many people do not have this self understanding. We conclude that music therapy may provide a mechanism for this self-understanding and subsequently help alleviate anxiety and stress.

Religion and its effects on crime and delinquency.

This review is an attempt to explore the relationship between two complex areas of behavioral research, namely that of religion and crime and delinquency. We will also examine supporting research from the area of physiological belief and relaxation systems as a means of understanding the posited negative correlation between religiosity and crime. Our central thesis is that ones level of participation in religious activities is negatively correlated to participation in criminal activity. While this central tenant seems straightforward there are a number of methodological issues that need to be addressed. In particular we need to operationally define the terms religiosity and delinquency. By reviewing archival research we hope to help substantiate the negative correlation between religion and crime, as well as explain a possible mechanism for this relationship.

Risk factors for breast cancer and the prognosis of African American women: estrogen's role.

Archival reports demonstrate that black females are in the minority of reported breast cancer cases, yet are given a significantly poorer prognosis than their white counterparts. Numerous studies have been conducted in an attempt to explain this discrepancy. In the past, socio-economic variables such as economic status and access to adequate health care have been the focus of attention. More recently there has been a shift to understanding the racial differences in genotype, as well as hormones related to tumor growth. In the present report, we explore the effects of increased estrogen levels as a precursor to the detrimental effects of breast cancer in African American women when compared to Caucasian women. Furthermore we will explore the effects of increased estrogen levels on the apoptotic events of p53 and Bcl-2 proteins. We conclude with a discussion regarding the antagonistic behavior of varying isoforms of estrogen receptors, and their relationship to nitric oxide (NO) as a free radical. The main focus of this paper is to address the many carcinogenic pathways that are instigated by estrogen and those which may be linked to obesity. By determining the relative concentration of estrogen and related proteins within black and white populations we hope to better understand the above mentioned disparity.

Sound therapy induced relaxation: down regulating stress processes and pathologies.

The use of music as a means of inducing positive emotions and subsequent relaxation has been studied extensively by researchers. A great deal of this research has centered on the use of music as a means of reducing feelings of anxiety and stress as well as aiding in the relief of numerous pathologies. The precise mechanism responsible for these mediated effects has never been truly determined. In the current report we propose that nitric oxide (NO) is the molecule chiefly responsible for these physiological and psychological relaxing effects. Furthermore this molecules importance extends beyond the mechanistic, and is required for the development of the very process that it mediates. Nitric oxide has been determined to aid in the development of the auditory system and participate in cochlear blood flow. We show that NO is additionally responsible for the induced exhibited physiological effects. We proceed to outline the precise neurochemical pathway leading to these effects. Furthermore we explore the interrelationship between the varying emotion centers within the central nervous system and explain how the introduction of music can mediate its effects via NO coupled to these complex pathways.

The nongenomic protective effects of estrogen on the male cardiovascular system: clinical and therapeutic implications in aging men.

Although the preponderance of studies investigating the effects of estrogen on vasomotor tone and function have focused on women, a number of recent studies have intriguingly shown that estrogen's rapid vasodilatory properties is also preserved in men. Unlike classical steroid transcription mediated pathways, estrogen's acute vasodilatory effect is mediated by calcium dependent cell surface estrogen receptors that stimulate constitutive endothelial nitric oxide synthase (eNOS) activity. The transient release of eNOS derived nitric oxide exerts profound physiological effects on the vasculature exerting a state of cellular inhibition (i.e. vasodilation). Thus, the partial or complete attenuation of this rapid signaling system can promote endothelial dysfunction, an early pathophysiological event in atherosclerotic development. Consequently, human males experiencing age-related declines in testosterone and aromatase derived estradiol plasma levels may lose a vital cardioprotective mechanism that preserves proper endothelial function. Therapeutic strategies to preserve basal nitric oxide levels through the maintenance of normal physiological estradiol levels may confer cardiovascular benefits to aging males.

Music as an aid in the development of the social self.

The development of the social self has been a topic of interest to developmental psychologists for some time. With the recent emphasis placed on the effect of the nuclear family and its increasing paucity, researchers have been even more pressed to develop alternate means to aid in the social effects of family and subsequently enhance a child's assertion of independence. In our paper we explore some of the possible ways by which developmental learning occurs, most notably by implicit or unconscious acquisition. We further provide some historical background explaining the emergence of this unconscious learning. Once we understand the process by which this learning occurs and the historical context in which it operates we can put forth our hypothesis. We suggest that an effective way of aiding or supplementing the role of the family is by providing a theoretical family unit. Specifically we propose that participation in musical or band related activities aids in the emergence of adolescence independence and a healthy self concept.

Mechanisms of knowledge learning and acquisition.

The mechanism by which knowledge enters into memory has been a source of debate for some time. Theorists have proposed several models that aim at explaining the sequence of events from the perception of a stimulus, to its entrance into long-term storage. Much of this work was prompted by early research into the nuances of classical conditioning where it was first firmly established that organisms are capable of detecting covariations of stimuli within their environment. Subsequent work in the field has shown that these covariations form the basis for the mental representation of our surroundings, as well as the basis of learning. Work within the field of classical conditioning, along with the advance of computer technology and neuroscience has made these architectural models even more complex. Furthermore, experiments designed to support some of these proposed models have revealed that there are several conditions that can either aid or inhibit the transition of information into permanent storage. In this review we explore a number of these models, along with some classic critiques that have been levied against them. We also provide some history into the form of knowledge, termed 'implicit knowledge', as well as some of the proposed mechanisms of implicit knowledge acquisition. We conclude by exploring the newly proposed theoretical framework within which implicit learning theory operates.