Receptor for Advanced Glycation End Product, Organ Crosstalk, and Pathomechanism Targets for Comprehensive Molecular Therapeutics in Diabetic Ischemic Stroke.

Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes-ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain-kidney-muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing-emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE-RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory-antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients.

Mononeuritis Multiplex as Initial Manifestation of Pure Neuritic Leprosy-A Forgotten Cause: Clinical, Electrodiagnostic and Pathologic Correlations.

Despite being common, polyneuropathy remains a diagnostic challenge for most clinicians. Mononeuritis multiplex (MM) refers to involvement of several or many peripheral nerves at the same or different points in time by a disease process. This report describes a case of an atypical presentation of Hansen's disease (HD) as mononeuritis multiplex in the left lower limb with corresponding radiographic, electrodiagnostic, and histopathological data that confirmed pure neuritic leprosy (PNL). We reiterate that although the incidence of PNL is exceedingly low characterized by nerve involvement without the characteristic cutaneous stigmata, leprosy is still the commonest cause of MM in the Indian sub-continent.This report underscores the crucial need for a heightened multi-disciplinary awareness of this "forgotten and uncommon" presentation of PNL. It is imperative that the treating physician should also understand the various neurological presentations, both mimics and chameleons, of this treatable disease to prevent permanent neuropathic injury and disability.

Selective Hand Motor Cortex Lesions Masquerading as "Pseudoperipheral Nerve Palsy".

Strategic cortical lesions involving the hand motor cortex (HMC) presenting acutely as distal upper limb pure motor weakness certainly do need to be differentiated on clinical grounds from "pseudoperipheral palsy." This rare phenotype can imitate peripheral motor nerve deficits and should not be easily overlooked. The isolated "central hand and finger weakness" presenting as an acute onset of varying combinations such as pseudomedian, pseudoradial, and/or pseudoulnar nerve palsy is intriguing to the novice. In literature, this phenotype has been reported solely to result from cortical cerebral infarction and documented to occur in <1% of all ischemic strokes. The apropos of six "unforgettable patients" here highlights the heterogeneous pathophysiologic etiologies and mechanisms that included not only the conventional stroke risk factors but also hyperhomocysteinemia, common carotid artery thrombosis due to hyperhomocysteinemia and severe iron-deficiency anemia, biopsy-proven giant cell arteritis (GCA), cerebral metastasis, and dilated cardiomyopathy-related left ventricular thrombosis. Physicians and neurologists alike, as clinicians, need to be familiar with the peculiarities and clinical presentations of central hand control network cortical lesions.

Hyperacute Paraplegia and Neurovascular (Immuno Vasculotoxic) Catastrophe of Nicolau Syndrome: Primum Non nocere.

A case of Nicolau syndrome (NS) in a 36-year-old adult taking an unusual and devastating hyperacute irreversible paraplegia after an intramuscular injection of benzathine penicillin as a part of routine chemoprophylaxis of her rheumatic heart disease is reported. Although this syndrome is a considerably rare, iatrogenic and underappreciated dermatologic entity, we reiterate in this report, its extracutaneous systemic potential for a catastrophic neurovascular phenomenon and morbidity as well as its possible preventive measures. The apoplectiform onset of T10 flaccid areflexic paraplegia, with the cutaneous hallmark of "embolia cutis medicamentosa" was corroborated by magnetic resonance imaging evidence of centromedullary complete cord involvement from T10 to conus medullaris. Combination therapy with pulse methylprednisolone, low-molecular-weight heparin, and pentoxifylline infusion proved unsuccessful. The skin biopsy and direct immunofluorescence revealed features were consistent with NS with overlap features of leukocytoclastic vasculitis, hitherto not reported. The literature of this preventable and iatrogenic disorder is reviewed, and plausible etiology is discussed.

Preventing "Neurophobia": Remodeling Neurology Education for 21st-Century Medical Students through Effective Pedagogical Strategies for "Neurophilia".

Neurology has a reputation, particularly as a complex "head-to-toe" discipline for undergraduate medical students. Neurophobia syndrome, a global phenomenon, fundamentally stems from pedagogical deficiencies during the undergraduate curriculum, the lack of vertical integration between basic neurosciences and clinical bedside neurology, the lack of clinical reasoning exercises, cognitive heuristics, and clinical problem-solving, errors in diagnostic competence, and hyposkilia. This ultimately results in poor clinical competence and proficiency in clinical neurology and causes attrition in nurturing a passion for learning the neurology discipline. This article explores plausible factors that contribute to the genesis of neurophobia and multifaceted strategies to nurture interest in neurosciences and provide possible solutions to demystify neurology education, especially the need for evidence-based educational interventions. Remodeling neurology education through effective pedagogical strategies and remedial measures, and using the Miller's pyramid, would provide a framework for assessing clinical competence in clinical bedside neurology. Technology-enhanced education and digital classrooms would undoubtedly stamp out neurophobia in medical students of the 21st century. It will not frighten off another generation of nonneurologist physicians to empower them to hone expertise in order to tackle the increasing burden of neurological disorders in India. Furthermore, promoting neurophilia would facilitate the next generation of medical students in pursuing career options in neurology which would be quintessential not only in closing India's looming neurologist workforce gap but also in fostering interest in research imperatives in the next generation of medical students.

A Viral Polymyositis Masquerade: Life-Threatening Case of Juvenile Dermatomyositis Complicated by Systemic Capillary Leak Syndrome.

This is a case report of an 8-year-old boy who developed an atypical, rare subphenotype of autoimmune inflammatory acute juvenile dermatomyositis (JDM), initially masquerading as viral polymyositis (PM)-like presentation, that was complicated by a hitherto unreported fulminant, life-threatening pediatric systemic capillary leak syndrome (SCLS). We highlight the close differential between viral PM and JDM, the baffling clinical syndromic constellation of hypotension with hemoconcentration - a "shock"-like syndrome, hypoalbuminemia without albuminuria, and generalized edema with the atypical JDM presentation, and stress crucial need to implement early aggressive, multipronged immunomodulatory treatment along with intensive fluid resuscitation which saved the life, this patient from a stormy, and turbulent 4-week clinical illness. This is the first published case description in the current literature of the association of an aggressive subphenotype of JDM and life-threatening pediatric SCLS. This report opens the Pandora's Box to explore the genetic and pathomechanisms of both disorders.

Simultaneous Determination of Impurities of Atazanavir and Ritonavir in Tablet Dosage Form by Using Reversed-Phase Ultra Performance Liquid Chromatographic Method.

A simple, rapid, selective and stability indicating reversed phase-ultra performance liquid chromatography method was developed and validated for the simultaneous quantification of process related and degradation impurities present in Atazanavir and Ritonavir tablets. The two proposed drug components and their respective impurities were separated using Acquity BEH C18 (100 mm × 2.1 mm), 1.7 µ column at a flow rate of 0.4 mL/min. Buffer used as Mobile phase-A which consists of 0.01 M monobasic potassium hydrogen phosphate adjusted the pH to 3.6 and acetonitrile is used as organic modifier (mobile phase-B). The detector wavelength of 240 nm was used for quantifying the impurities. Both the drug components along with their impurities were eluted within a runtime of 18 min. The performance of the developed method was checked by validating the method according to the requirements of International Conference on Harmonization for parameters such as specificity, precision, linearity, ruggedness, accuracy, sensitivity (limit of detection (LOD) and limit of quantitation (LOQ)) and robustness. Linearity and range were established from LOQ level to 150% level. Accuracy of the method was demonstrated from LOQ level to 150% level. The developed stability indicating method is capable for determination of impurities of Atazanavir and Ritonavir in combined tablet dosage form as well as individual dosage forms also. The reported method enables lesser solvent consumption and reduces time and cost of the analysis in quality control laboratory.

Temporal arteritis presenting as hand motor cortex infarction: A report from India

@#This is the first Indian case report of a biopsy proven temporal arteritis that presented as acute ischemic stroke. The 60 year old woman presented with an isolated pure motor flaccid fractional weakness of the left distal hand, as a rare stroke chameleon due to isolated infarction of the ‘hand motor cortex’ area. The hand motor cortex infarction masquerades as ‘pseudoperipheral palsy’.

"All that spikes is not fits", mistaking the woods for the trees: the interictal spikes--an "EEG chameleon" in the interface disorders of brain and mind: a critical review.

Recent research into mammalian cortical neurophysiology, after 6 decades of Berger's seminal work on electroencephalography, has shifted the older concept of interictal epileptiform activity (IEA) away from that of a mere electrographic graphoelement of relevance to diagnostic implications in epilepsy. Instead, accumulating information has stressed the neuropsychological implications, cognitive and/or behavioral consequence of these electrophysiological events, which are the phenotypic expression of aberrations of actual biophysical cellular function. We feel that this review is germane to neuropsychiatry, however, a rather neglected area of research. There is a great scope for brain-behavior-EEG research in the future that can be complimented by other techniques of "neurobehavioral electrophysiology". This review does not address the "pearls, perils and pitfalls" in the use of EEG in epilepsy, but critically and systematically reappraises the published electroencephalographic correlates of human behavior. We reiterate that epileptiform and other paroxysmal EEG dysrhythmias unrelated to clinical seizures do have neuropsychological, cognitive and/or behavioral implications as seen in the various neuropsychiatric and neurobehavioral disorders discussed in this article. IEA and EEG dysrhythmias should neither be ignored as irrelevant nor automatically attributed to epilepsy. The relevance of these EEG aberrations in the disorders of the brain-mind interface extend beyond epilepsy, and may be an electrophysiological endophenotype of aberrant neuronal behavior indicative of underlying morpho-functional brain abnormalities. Magnetoencephalography (MEG), data fusion models (EEG-fMRI-BOLD), transcranial magnetic stimulation (TMS), evoked potentials (EP); intracranial electrophysiology, and EEG neurofeedback complemented by current functional neuroimaging techniques (fMRI and PET) would certainly help in further understanding the broader relationship between brain and behavior.

Is the pathology of corticobasal syndrome predictable in life?

Corticobasal syndrome (CBS) has been associated with a heterogeneous spectrum of pathologies with an increasing number of reports of Alzheimer's type pathology. There is, however, no means of predicting pathology of CBS in vivo at present. We compared the clinical features of patients presenting with CBS who have either pathologic changes of classic corticobasal degeneration (CBD) or Alzheimer's disease (AD) at post-mortem to identify predictors of the specific pathological processes in life. Twelve patients with CBS were followed prospectively; six had AD and six had classic CBD neuropathology. After review of the presenting clinical features, we identified nine potential predictor variables, compared their frequency in the two groups, and performed a discriminant function analysis. Initial episodic memory complaints and poor performance on the combined orientation-memory subtest of the Addenbrooke's Cognitive Examination (ACE) reliably predicted AD pathology while varying combinations of early frontal-lobe type behavioral symptoms, nonfluent language disturbance, orobuccal apraxia, and utilization behavior predicted CBD pathology ante-mortem. CBS is frequently associated with Alzheimer's disease pathology. Early episodic memory impairment versus early behavioral symptomatology appears to best predict AD or CBD pathology in life.

Electroencephalographic cerebral dysrhythmic abnormalities in the trinity of nonepileptic general population, neuropsychiatric, and neurobehavioral disorders.

Subclinical electroencephalographic epileptiform discharges in neurobehavioral disorders are not uncommon. The clinical significance and behavioral, diagnostic, and therapeutic implications of this EEG cerebral dysrhythmia have not been fully examined. Currently the only connotation for distinctive epileptiform electroencephalographic patterns is epileptic seizures. Given the prevailing dogma of not treating EEGs, these potential aberrations are either disregarded as irrelevant or are misattributed to indicate epilepsy. This article reappraises the literature on paroxysmal EEG dysrhythmia in normative studies of the "healthy" nonepileptic general populations, neuropsychiatry, and in neurobehavioral disorders. These EEG aberrations may be reflective of underlying morpho-functional brain abnormalities that underpin various neurobehavioral disturbances.

The spectrum of dementia: frequency, causes and clinical profile. A national referral hospital-based study in Oman.

BACKGROUND AND OBJECTIVE: There is a paucity of epidemiological data on dementia in the Arabian Peninsular region, particularly Oman. To determine the spectrum, clinical profile, and the behavioral manifestations of dementia in Omani patients evaluated at a tertiary referral hospital. METHODS: We retrospectively reviewed the demographic and clinical spectrum of 116 patients with probable dementia diagnosed in this center. The diagnosis of dementia was made according to DSM-IV criteria, and staged according to the Clinical Dementia Rating scale. Exclusion criteria included psychiatric disorders, cranial trauma, cerebral tumors, and mild cognitive impairment. The vascular risk patterns and behavioral data were analyzed. RESULTS: Alzheimer's disease was observed to be the commonest dementia subtype seen in 61 patients (52.6%), while 24.1% had vascular dementia and 9.5% constituted frontotemporal lobar degeneration. Early onset dementia was seen in 45% and potentially reversible dementia constituted 8.6%. Behavioral and psychopathological disturbances in dementia appear to be universal with certain differentiating features between the three major subtypes of dementia. CONCLUSIONS: This is the first published report of dementia from Oman. Dementia is an important health problem not only of the elderly but also of the young population in Oman.

Frontotemporal dementia in Oman: cognitive behavioural profile and neuroimaging characteristics; a prospective hospital-based study.

Frontotemporal dementia is increasingly recognised as an important cause of early-onset dementia and is considered to be the second commonest neurodegenerative dementia after Alzheimer's disease. We describe the cognitive, behavioural profile and neuroimaging characteristics of 6 patients with frontal variant of Frontotemporal dementia that were evaluated at the cognitive behavioural clinic at this tertiary referral teaching hospital. All patients underwent clinical, neuropsychological, structural/functional neuroimaging, and laboratory evaluations. The male to female ratio was 1:1; mean age of onset was 54 years, and the mean duration of symptoms were 30 months. The mean scores for Addenbrooke's cognitive examination, Frontal Assessment Battery, and Mini-Mental State Examination were 70.5, 6.33 and 23.6 respectively. The mean VLOM ratio was 2.04. MRI revealed significant asymmetrical regional frontal/temporal atrophy supplemented by the evidence of circumscribed hypoperfusion in SPECT imaging. We conclude that a combination of behavioural and cognitive assessment using short bedside tests, along with structural and functional neuroimaging does facilitate early identification, and increase the diagnostic specificity of Frontotemporal dementia.

The neuropsychiatry and multisystem features of the Smith-Magenis syndrome: a review.

Smith-Magenis Syndrome (SMS) is a complex, pediatric, neurobehavioral, contiguous gene syndrome ascribed to interstitial microdeletion of chromosome 17, band 11.2. The syndrome is characterized by distinctive behavioral, neurocognitive, and neuropsychiatric abnormalities. This genetically mediated disorder of mental retardation prompts behavioral researchers to examine the links between genes, brain, and behavior in order to solve the gene-behavior puzzle and the genotype/phenotype correlation. In this article, the authors review literature on behavioral profile and its associated psychopathologies, cognitive profiles, multisystem abnormalities, and genetic correlates that highlight the complexities of the disorder.

The insular lobe of Reil--its anatamico-functional, behavioural and neuropsychiatric attributes in humans--a review.

There is considerable clinical and experimental research to explore the anatamico-functional correlations of the limbic lobe to establish its relevance in modern neuroscience. The insula being a pivotal structure in the concept of the greater limbic lobe, we have attempted to highlight in this review the topographical anatomy and development, the remarkable heterogeneity of the insular cortical architecture, the widespread multifaceted spectrum of functional connectivity patterns and how this is translated to its behavioural specialisation in humans. The insula serves as an intergration cortex for multimodal convergence of distributed neural networks such as the somesthetic-limbic, insulo-limbic, insulo-orbito-temporal and the prefrontal-striato-pallidal-basal forebrain. This provides the conceptual framework to facilitate functional and clinical considerations relevant to the various behavioural and neuropsychiatric disorders outlined in this review. The functional role of the insula in these disorders with particular reference to the current functional neuroimaging data has been also reviewed in this article.

Optical scattering (TAOS) by tire debris particles: preliminary results.

Tire debris particles from low severity laboratory wear tests have been investigated by the TAOS optical scattering facility at Yale University. The incident wavelength is 532 nm. After the TAOS event some particle samples have been imaged by a scanning electron microscope and microanalyzed. The TAOS intensity patterns recorded within a solid angle in the backward sector have been processed by cluster analysis and compared with the patterns computed by a T-matrix code. Preliminary agreement has been found between TAOS data and the particle models (size, shape, refractive index). The purpose of the investigation is to obtain signatures of the material, based on its TAOS pattern.