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Cleveland, OH, United States

Plaud-Valentin M.,University of Puerto Rico at San Juan | Skolasky R.L.,University of Baltimore | Wojna V.,Neurology Division | Wojna V.,University of Puerto Rico at San Juan | Melendez L.M.,University of Puerto Rico at San Juan
AIDS | Year: 2013

OBJECTIVE: HIV-1-associated neurocognitive disorders (HAND) is triggered by immune activation of brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and cystatins are lysosomal proteins secreted by macrophages and microglia, and may play important roles in neuroregulatory responses. Our laboratory has shown increased secretion and neurotoxicity of cathepsin B from in-vitro HIV-infected monocyte-derived macrophages, and increased expression in postmortem brain tissue with HIV encephalitis and HAND. We hypothesized that cystatin B and cathepsin B could represent potential biomarkers for HAND. METHODS: Monocytes, plasma, and cerebrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for cystatins B and C and cathepsin B expression and activity. RESULTS: Increased cathepsin B and cystatins B and C were found in plasma of HIV-seropositive women. Higher intracellular expression of cathepsin B and cystatin B were found in monocytes from women with HIV-associated dementia (P<0.05). Significant increase in cystatin B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. CONCLUSION: These results demonstrate that dysregulation of cystatin B-cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of cystatin B and cathepsin B in monocytes could be potential candidate biomarkers for HIV dementia, whereas increased cathepsin B and cystatins B and C in plasma are potential candidate markers of chronic HIV-1 activation. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Nataprawira H.M.,Padjadjaran University | Ruslianti V.,Neurology Division | Solek P.,Otolaryngo Neuro otology | Hawani D.,Otolaryngo Neuro otology | And 4 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2016

BACKGROUND: Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis. OBJECTIVE : To assess hearing, visual, motor function, neurological and mental development outcomes in paediatric TBM. METHODS : A retrospective cohort study was conducted among 139 children with TBM registered and treated at the Department of Child Health, Dr Hasan Sadikin Hospital, Bandung, Indonesia, from January 2007 to December 2010. Hearing and visual function, appearance of optic disc, motor function, and neurological and mental development were evaluated. RESULTS : Of a final 128 patients (10 died during hospitalisation, 1 was excluded), 34 (26.5%) died after hospital discharge, the addresses of 58 patients could not be found and 7 parents refused to participate. The remaining 29 patients (16 males, 13 females) were available for evaluation; the mean age was 44 months (range 7-162). Hearing loss and visual impairment were identified in respectively 11/28 and 10/25 patients. Most patients had motor disorders. Delayed neurological and mental development was observed in nearly three quarters of patients, 11 of whom had normal or borderline intelligence quotient. CONCLUS IONS : TBM causes high mortality and sequelae involving hearing and visual impairment, and neurological and mental development.

Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division
Journal of Neurophysiology | Year: 2014

Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25–1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125–1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture. © 2014 the American Physiological Society.

Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division
PLoS ONE | Year: 2013

The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction.

Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division | May P.J.,University of Mississippi | And 3 more authors.
Journal of Neurophysiology | Year: 2015

Rigorous descriptions of ocular motor mechanics are often needed for models of ocular motor circuits. The mouse has become an important tool for ocular motor studies, yet most mechanical data come from larger species. Recordings of mouse abducens neurons indicate the mouse mechanics share basic viscoelastic properties with larger species but have considerably longer time constants. Time constants can also be extracted from the rate at which the eye re-centers when released from an eccentric position. The displacement can be accomplished by electrically stimulating ocular motor nuclei, but electrical stimulation may also activate nearby ocular motor circuitry. We achieved specific activation of abducens motoneurons through photostimulation in transgenic mice expressing channelrhodopsin in cholinergic neurons. Histology confirmed strong channelrhodopsin expression in the abducens nucleus with relatively little expression in nearby ocular motor structures. Stimulation was delivered as 20- to 1,000-ms pulses and 40-Hz trains. Relaxations were modeled best by a two-element viscoelastic system. Time constants were sensitive to stimulus duration. Analysis of isometric relaxation of isolated mouse extraocular muscles suggest the dependence is attributable to noninstantaneous decay of active forces in non-twitch fibers following stimulus offset. Time constants were several times longer than those obtained in primates, confirming that the mouse ocular motor mechanics are relatively sluggish. Finally, we explored the effects of 0.1- to 20-Hz sinusoidal photostimuli and demonstrated their potential usefulness in characterizing ocular motor mechanics, although this application will require further data on the temporal relationship between photostimulation and neuronal firing in extraocular motoneurons. © 2015 the American Physiological Society.

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