Antineuroinflammatory drugs in HIV-associated neurocognitive disorders as potential therapy.

Today, HIV-infected (HIV+) patients can be treated efficiently with combined antiretroviral therapy (cART), leading to long-term suppression of viral load, in turn increasing life expectancy. While cART reduced the occurrence of HIV-associated dementia, the prevalence of subtle forms of HIV-associated neurocognitive disorders (HAND) is unchanged. This is related to persistent immune activation within the CNS, which is not addressed by cART. Pathologic processes leading to HAND consist of the release of proinflammatory cytokines, chemokines, reactive oxygen metabolites and glutamate, and the release of HIV proteins. Some of those processes can be targeted using medications with immunomodulatory and neuroprotective properties such as dimethyl fumarate, teriflunomide, or minocycline. In this review, we will summarize the knowledge about key pathogenic processes involved in HAND and potential therapeutic avenues to target HAND

Analisis Faktor-Faktor yang Memengaruhi Tingkat Kepatuhan Wajib Pajak Orang Pribadi di Lingkungan Kantor Pelayanan Pajak Pratama, Tigaraksa Tangerang

Tax collection is not an easy matter. Active participation from the tax authorities also requires the willingness of the taxpayer. A public reaction can be seen from the taxpayer\u27s willingness to pay taxes. Willingness and awareness to pay taxes represent a value contributed by someone (which has been determined by regulation). Tax is used to finance public expenditures without any direct benefit. Taxpayer\u27s awareness about taxation functions as state funding is needed to improve tax compliance and to determine the level of tax compliance in implementing their tax obligations. Limitation of the scope of this study is the effect of the level of awareness of paying taxes, taxpayer\u27s understanding about tax benefits, tax penalties, and understanding of service quality to the tax authorities of individual taxpayer compliance in the fulfillment of tax obligations, as well as restricted to data obtained through questionnaires received and filled by the individual taxpayer of Tigaraksa Pratama Tax Office area. Data were obtained through questionnaire and processed and analyzed using parametric statistical tests and multiple linear regression with 4 independent variables and one dependent variable resulted in the conclusion that the factors that most influence taxpayer compliance in carrying out its tax liability is the use of sanctions against taxpayers who do not carry out its obligations under applicable legislation

Treatment choices and neuropsychological symptoms of a large cohort of early MS

Objective To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results Of 1,124 patients, with a 2.2: 1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients

Molekulare und virale Determinanten bei HIV-assoziierten neurokognitiven Störungen

Trotz Einführung der kombinierten antiretroviralen Therapie und damit Suppression der Viruslast ist die Prävalenz der neurokognitiven Störungen bei HIV-Patienten unverändert. Nicht die Viruslast, sondern die Interaktionen zwischen Monozyten und Mikroglia scheinen ursächlich für die Störungen, wie in der bystander-hypothesis postuliert. Im Rahmen dieser Dissertation wurde ein Zellkulturmodel aus Mikroglia oder mikroglialen Zellen und monozytären Zellen entwickelt, anhand dessen die Wechselwirkungen im Kontext einer HIV-Infektion untersucht werden konnten. Es konnte gezeigt werden, dass die Aktivierung der Co-Kultur durch die Substanzen Monomethylfumarat und Teriflunomid modifiziert werden konnte, was zu verringerter Neurotoxizität bei primären humanen embryonalen Neuronen führte. Das zeigt die Möglichkeit, bei HIV-Patienten zusätzlich mit immunmodulatorischen Substanzen zu behandeln, um die Aktivierung des Immunsystems, die ursächlich für die neurokognitiven Störungen ist, abzumildern

Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.

BACKGROUND Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking. METHODS We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod. Histology of the sciatic nerve was done to analyze T cell and macrophage cell count, intercellular adhesion molecule (ICAM) and amyloid precursor protein (APP) expression, as well as apoptotic Schwann cell counts. RESULTS Preventive oral treatment with 0.1 mg/kg up to 3 mg/kg fingolimod once daily dissolved in rapeseed oil completely ameliorated clinical neuritis signs. It reduced circulating peripheral blood T cells and infiltrating T cells and macrophages in the sciatic nerve, whereas at the same time, it preserved blood-nerve barrier impermeability. Most importantly, fingolimod showed beneficial properties on the pathogenic process as indicated by fewer apoptotic Schwann cells and a lower amount of amyloid precursor protein indicative of axonal damage at the peak of disease course. CONCLUSIONS Taken together, orally administered low-dose fingolimod showed an impressive immunomodulatory effect in the rat model of experimental autoimmune neuritis. Our current observations introduce fingolimod as an attractive treatment option for neuritis patients

Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection

<div><p>Background</p><p>Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.</p><p>Methods and Findings</p><p>Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53–78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.</p><p>Conclusions</p><p>We conclude that immunmodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.</p></div

Capsaicin-enriched diet ameliorates autoimmune neuritis in rats

Abstract Background Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. Methods We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. Results We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p < 0.01; increase of nerve conduction blocks in control group p < 0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. Conclusion This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies

Dimethyl fumarate induced Nrf2 at the peak of EAN course.

<p>(A) Representative photos of Nrf2 staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg (d-f), 45mg/kg (g-i) and methylcellulose-treated animals (a-c), showing an increase of Nrf2 positive cells for 45mg/kg DMF-treated rats. Pictures a, d and g show nuclear stain (DAPI), pictures b, e and h Nrf2 stain and pictures c, f and i indicate double staining. Scale bars indicate 100μm. (B) Percentage of Nrf2 positive staining per sciatic nerve section measured by immunofluorescent staining on day 16 p.i. from EAN rats (n = 6/group) receiving DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (*p<0,05).</p

Dimethyl fumarate improved proximal and distal nerve conduction.

<p>(A) Representative CMAP (compound motor action potentials) traces during EAN course at days −1 and 16 p.i. showing a conduction block for methylcellulose-treated rats at day 16 p.i. whereas for 45 mg/kg DMF-treated rats no conduction block was recorded. (B) Representative F-wave traces after distal stimulation showing prolonged F-waves latencies only for the methylcellulose-treated group at day 16 p.i. in comparison to day -1. Rats treated with 45mg/kg did not show any significant differences in the F-wave latencies between day -1 and 16 p.i. The black vertical line defines the motor (M) response and the F (F-wave) response latency. On the left of the red vertical line applies the M response regarding distance (horizontally, ms) and vertically (mV) and on the right of the red vertical line applies the F response data (ms, mV), (M: M response, F: F response, D: distance of one side of the dotted lined squares). (C) After proximal and distal stimulation of the sciatic nerve the conduction velocity was calculated. A statistical significant reduction of the MNCV (motor nerve conduction velocity) appeared for the control group and the 15mg/kg group (p<0,0001 ***, n = 10), but no difference in the MNCV was seen for the 45mg/kg DMF treated group indicating a protective role of DMF against demyelination. Mean values and SEM are depicted.</p

Dimethyl fumarate reduced inflammatory infiltrates of T cells and macrophages in sciatic nerves of EAN rats.

<p>(A) Rats were daily force fed with DMF or tap water and 16 days p.i. (at expected disease maximum), sciatic nerves were isolated and stained for CD3⁺ cells (a, b, c) and CD68⁺ cells (macrophages) (d, e, f). Representative photos of sciatic nerves in transverse sections of methylcellulose-treated animals (a and d), 15 mg/kg DMF-treated animals (b and e) and 45mg/kg DMF treated animals (c and f). Scale bars indicate 100μm. (B) Mean numbers of T cells per mm² sciatic nerve sections and B. Mean numbers of macrophages (CD68⁺) per mm² sciatic nerve sections as calculated by immunohistochemistry on day 16 p.i. from EAN rats (n = 6/group) receiving orally DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (** p<0,005, ***p<0,0001). The experiment was repeated 2 times with similar results.</p