Burst spinal cord stimulation for the treatment of cervical dystonia with intractable pain: A pilot study

Shimizu, T.; Maruo, T.; Miura, S.; Kimoto, Y.; Ushio, Y.; Goto, S.; Kishima, H. Burst Spinal Cord Stimulation for the Treatment of Cervical Dystonia with Intractable Pain: A Pilot Study. Brain Sci. 2020, 10, 827

Effects of a non-cyclodextrin cyclic carbohydrate on mouse melanoma cells: Characterization of a new type of hypopigmenting sugar.

Cyclic nigerosyl nigerose (CNN) is a cyclic tetrasaccharide that exhibits properties distinct from other conventional cyclodextrins. Herein, we demonstrate that treatment of B16 melanoma with CNN results in a dose-dependent decrease in melanin synthesis, even under conditions that stimulate melanin synthesis, without significant cytotoxity. The effects of CNN were prolonged for more than 27 days, and were gradually reversed following removal of CNN. Undigested CNN was found to accumulate within B16 cells at relatively high levels. Further, CNN showed a weak but significant direct inhibitory effect on the enzymatic activity of tyrosinase, suggesting one possible mechanism of hypopigmentation. While a slight reduction in tyrosinase expression was observed, tyrosinase expression was maintained at significant levels, processed into a mature form, and transported to late-stage melanosomes. Immunocytochemical analysis demonstrated that CNN treatment induced drastic morphological changes of Pmel17-positive and LAMP-1-positive organelles within B16 cells, suggesting that CNN is a potent organelle modulator. Colocalization of both tyrosinase-positive and LAMP-1-positive regions in CNN-treated cells indicated possible degradation of tyrosinase in LAMP-1-positive organelles; however, that possibility was ruled out by subsequent inhibition experiments. Taken together, this study opens a new paradigm of functional oligosaccharides, and offers CNN as a novel hypopigmenting molecule and organelle modulator

Burst Spinal Cord Stimulation for the Treatment of Cervical Dystonia with Intractable Pain: A Pilot Study

Pain is the most common and disabling non-motor symptom in patients with cervical dystonia. Here, we report four patients with painful cervical dystonia in whom burst spinal cord stimulation (SCS) in the cervical region produced sustained and significant improvements in both dystonic pain and motor symptoms. Further studies need to be performed to investigate the clinical efficacy of burst SCS for patients with cervical dystonia

NK-4 exerts selective regulatory effects on the activation and function of allergy-related Th2 cells

<div><p>NK-4 is the main component of the antiallergic drug Lumin, which has been in popular usage since the early 1950s. In this study, we examined whether NK-4 exerts a regulatory effect on the activation and effector function of Th2 cells. NK-4 inhibited IL-4 production by anti-CD3ε mAb-stimulated BALB/c mouse spleen cells, whereas NK-4 had little effect on IFN-γ production. IL-4 and IL-5 secretion by anti-CD3ε mAb- or antigen-stimulated Th2 cells (D10.G4.1) was abrogated by NK-4 without affecting cell numbers, whereas IFN-γ secretion by activated Th1 cells was unchanged. Mechanistic analysis revealed that NK-4 inhibited mRNA expression of the Th2-associated transcription factors GATA-3 and NFATc1 in anti-CD3ε mAb-stimulated D10.G4.1 cells. Regarding the regulation of Th2 cell effector functions, NK-4 inhibited the secretion of eotaxin and thymus and activation-regulated chemokine (TARC) by normal human dermal fibroblasts in response to IL-4 and/or TNF-α. NK-4 achieved TARC attenuation comparable to what is observed with suplatast tosilate, an antiallergic drug that selectively inhibits Th2 cytokine production, at 14-fold lower concentrations of suplatast tosilate. Dexamethasone increased TARC production by 2.2- to 2.6-fold of control cultures. NK-4 successfully inhibited the STAT6 signaling pathway, suggesting a potential mechanism for down-regulating chemokines expression. In addition, NK-4 abrogated IL-4-driven modulation of cytokine production profile in human monocytic THP-1 cells from proinflammatory to anti-inflammatory response, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. These results suggest that NK-4 could prevent IL-4-driven polarization to alternatively activated macrophages, which are proposed to have pathogenic roles in allergic asthma. The importance of Th2 cytokines and chemokines in the development and progression of type 2 inflammatory disorders has been highlighted by recent advance in our understanding the immunological mechanism underlying allergic disease. Our results support the use of NK-4 as a reasonable therapeutic option to alleviate Th2-mediated allergic inflammation.</p></div

Chemical structure of NK-4.

<p>Chemical structure of NK-4.</p

NK-4 down-regulates secretion of TARC by NHDF stimulated with both IL-4 and TNF-α.

<p>NHDF were stimulated with 10 ng/ml IL-4 and 5 ng/ml TNF-α in the presence or absence (control) of varying concentrations of NK-4, dexamethasone or FK-506 (A) for 48 h at 37°C. In experiments comparing NK-4 with suplatast tosilate (B), NHDF were exposed to test articles for 15 min before stimulation with IL-4 and TNF-α. TARC levels in the cultures of NHDF without stimulation were below detectable limits. Results are the means ± S.D. of triplicate cultures. Results are representative of three independent experiments with similar results. **<i>p</i> < 0.01 compared with control cultures.</p

NK-4 suppresses the mRNA expression of the Th2-associated transcription factors GATA-3 and NFATc1.

<p>Total RNA was extracted from D10.G4.1 cells (2 x 10⁶ cells) stimulated with immobilized anti-CD3ε mAb (8 μg/ml) in the presence or absence (control) of NK-4 for 6 h at 37°C. First-strand cDNA was synthesized using reverse transcriptase, as described in the Materials and Methods. Expression levels of GATA-3 (A), NFATc1 (B) and c-Maf (C) were analyzed by real-time PCR. 18S rRNA expression levels were used for normalization. Results are given as changes in gene expression relative to the mean values of the control. Results are the means ± S.D. of three independent experiments. *<i>p</i> < 0.05, compared with control cultures.</p

NK-4 selectively down-regulates Th2 cytokine production by antigen-stimulated established Th2 cells.

<p>Th1 clone #4 (2.5 x 10⁴ cells/well) were stimulated with OVA (200 μg/ml) and MMC-treated BALB/c mouse spleen cells (1.2 x 10⁶ cells/well) in the presence or absence (control) of varying concentrations of NK-4 for 48 h at 37°C in 96-well plates (A). D10.G4.1 cells (2.5 x 10⁴ cells/well) were stimulated with MMC-treated C57BL/6 mouse spleen cells (1.2 x 10⁶ cells/well) (B and C). Concentrations of IFN-γ (A), IL-4 (B) and IL-5 (C) in culture supernatants were measured by ELISA. Results are the means ± S.D. of triplicate cultures. Results are representative of three independent experiments with similar results. **<i>p</i> < 0.01 compared with control cultures.</p