Opsoclonus-myoclonus syndrome following long-term use of cyclosporine

<p><b>Background:</b> Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS).</p> <p><b>Case details:</b> A 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably.</p> <p><b>Conclusion:</b> This is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity.</p

Additional file 1 of Acute ischemic stroke in Tsutsugamushi: understanding the underlying mechanisms and risk factors

Supplementary Material

Decoding the Parkinson’s Symphony: PARIS, Maestro of Transcriptional Regulation and Metal Coordination for Dopamine Release

Parkin interacting substrate (PARIS) is a pivotal transcriptional regulator in the brain that orchestrates the activity of various enzymes through its intricate interactions with biomolecules, including nucleic acids. Notably, the binding of PARIS to insulin response sequences (IRSs) triggers a cascade of events that results in the functional loss in the substantia nigra, which impairs dopamine release and, subsequently, exacerbates the relentless neurodegeneration. Here, we report the details of the interactions of PARIS with IRSs via classical zinc finger (ZF) domains in PARIS, namely, PARIS(ZF2–4). Our biophysical studies with purified PARIS(ZF2–4) elucidated the binding partner of PARIS, which generates specific interactions with the IRS1 (5′-TATTTTT, Kd = 38.9 ± 2.4 nM) that is positioned in the promoter region of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). Mutational and metal-substitution studies demonstrated that Zn(II)–PARIS(ZF2–4) could recognize its binding partner selectively. Overall, our work provides submolecular details regarding PARIS and shows that it is a transcriptional factor that regulates dopamine release. Thus, PARIS could be a crucial target for therapeutic applications

Langerhans cells prevent subbasal nerve damage and upregulate neurotrophic factors in dry eye disease

<div><p>The functional role of Langerhans cells (LCs) in ocular surface inflammation and nerve damage in dry eye (DE) disease has yet to be determined. This study was performed to investigate this relationship through both clinical study on DE patients and in vivo mouse models with induced DE disease. In a cross-sectional case-control study (54 eyes of DE patients; 34 eyes of control patients), average cell density, area, and process length of LCs were measured using confocal microscopy. Data were analyzed to determine whether changes in LCs are correlated with subbasal nerve plexus (SNP) parameters (nerve density, beading, and tortuosity). In DE patients, SNP density marginally decreased and nerve beading and tortuosity were significantly increased compared to the control group. The total number of LCs significantly increased in DE patients, and some LCs with elongated processes were found to be attached to nerve fibers. Interestingly, nerve loss and deformation were correlated with inactivation of LCs. In an <i>in vivo</i> experiment to elucidate the role of LCs in ocular surface inflammation and corneal nerve loss, we used a genetically modified mouse model (CD207-DTR) that reduced the population of CD207 (Langerin) expressing cells by injection of diphtheria toxin. In CD207-depleted mice with DE disease (CD207-dDTR+DE), corneal nerves in the central region were significantly decreased, an effect that was not observed in wild-type (WT)+DE mice. In CD207-dDTR+DE mice, infiltration of CD4+, CD19+, CD45+, and CD11b+ cells into the ocular surface was increased, as confirmed by flow cytometry. Increased IL-17 and IFN-γ mRNA levels, and decreased expression of neurotrophic factors and neurotransmitters, were also found in the CD207-dDTR+DE mice. These data support a functional role for LCs in negatively regulating ocular surface inflammation and exhibiting a neuroprotective function in DE disease.</p></div

Increased inflammatory cell infiltration in LC-depleted mice by DE induction.

<p>(A) Flow cytometry was performed in WT, CD207-dDTR, WT+DE, and CD207-dDTR+DE mice. Cornea samples with limbal tissues were secured and prepared for FACS analysis using anti-CD45-FITC, anti-CD11b-APC, anti-CD4-FITC, and anti-CD19-PE-Cy7 as described in Materials and Methods. At least four mice were included in each group and the experiment was repeated three times. (B) Data were represented as mean ± SD (*: p<0.05, **: p<0.01, ***: p<0.0001 by Student’s t-test).</p

Analysis by flow cytometry of CD207+ and CD11c+ cell recruitment in the cornea and conjunctiva after DE induction.

<p>(A) Comparison of CD207+ cell density between the conjunctiva (Conj) and cornea by DE induction. After DE induction, corneal tissues were separated from the conjunctiva for comparison of CD11c and CD207 cell frequencies between the two tissues. A minimum of four mice were included in each group, and the experiment repeated four times. Data are represented as mean ± SD (*: p<0.05, ***: p<0.001 Student t-test). (B) At 10 days post diphtheria toxin injection for CD207-DTR mice, the loss of CD207+ cells in skin, lung, and ocular surface were determined. The experiment was repeated three times and representative flow cytometry data are presented. (C) Comparison of CD207+ and CD11c+ cell population changes in ocular surface by DE induction and CD207-deletion in CD207-DTR mice. At least four mice were included in each group, and the experiment was repeated four times. Representative FACS study data are displayed.</p

Reduction of corneal nerves in CD207-dDTR+DE mice.

<p>(A-C) After 7 days of DE induction of WT mice and CD207-dDTR mice, immunostaining for βIII tubulin (green) on a corneal flap mount was performed and compared with a non-DE induced control (CONT). (A) Low magnification (× 40) photo images. White arrowheads indicate corneal nerves on limbal area with larger diameter (>20 μm) and yellow arrows indicate mid-corneal nerve leashes. (B) High magnification (× 100 upper row and × 200 lower row) images were taken. (C) Limbal and paracentral corneal nerve leashes were compared using ImageJ software in high magnification images between CONT, WT+DE and CD207-dDTR+DE mice. Yellow arrowheads mark the small nerve fibers on the superficial surface of limbal area. At least five mice were included in each group, and nerve length was measured and is represented as mean ± SD. Dashed white line: limbal margin, Cj: conjunctiva, NS: no statistical significance, ***; p<0.0001, One-way ANOVA with Dunnett’s post-hoc test.</p

Reduced expression of DE-induced neurotrophic factors by LC depletion.

<p>(A) Determination of NGF, CGRP and SP mRNA levels after LC depletion in CD207-DTR mice (CD207-dDTR). (B) Changes in corneal erosion scores for WT+DE and CD207-dDTR+DE (C) NGF, BNGF, CGRP and SP protein levels between WT+DE and CD207-dDTR+DE mice. Data are represented as mean ± SD (*: p<0.05, **: p<0.01, ***: p<0.0001 by Student’s t-test).</p