A new therapeutic strategy with istradefylline for postural deformities in Parkinson’s disease

Aim of the study. Postural deformities are common in Parkinson’s disease (PD) patients. Several treatment options have been reported, but responses to these treatments appear unpredictable. Istradefylline is a novel drug for PD. Cases of PD patients whose postural deformities were improved after withdrawal of dopamine agonists and initiation of istradefylline are presented. Materials and Methods. Four consecutive patients with postural deformities including antecollis, Pisa syndrome, and camptocormia were recruited and treated with istradefylline in combination with withdrawal of dopamine agonists, which are possible causes of postural deformities. Results. The dopamine agonists were discontinued an average of 26 months after the development of the postural deformities, and istradefylline was initiated an average of 1.3 months after dopamine agonist withdrawal. Three patients with preserved paraspinal muscle volume showed good responses to the treatment regimen at least two months after dopamine agonist withdrawal. Conclusions and clinical Implications. Postural deformities caused by dopamine agonists generally improve less than two weeks after dopamine agonist withdrawal. Given the response time in the present study, the response was unlikely to be caused solely by dopamine agonist withdrawal. Istradefylline can be a potential therapeutic option; however, appropriate selection of patients for treatment with istradefylline is warranted

Impaired Healing of a Cutaneous Wound in an Inducible Nitric Oxide Synthase-Knockout Mouse

Background. We investigated the effects of loss of inducible nitric oxide synthase (iNOS) on the healing process of cutaneous excisional injury by using iNOS-null (KO) mice. Population of granulation tissue-related cell types, that is, myofibroblasts and macrophages, growth factor expression, and reepithelialization were evaluated. Methods. KO and wild type (WT) mice of C57BL/6 background were used. Under general anesthesia two round full-thickness excision wounds of 5.0 mm in diameter were produced in dorsal skin. After specific intervals of healing, macroscopic observation, histology, immunohistochemistry, and real-time reverse transcription-polymerase chain reaction (RT-PCR) were employed to evaluate the healing process. Results. The loss of iNOS retards granulation tissue formation and reepithelialization in excision wound model in mice. Detailed analyses showed that myofibroblast appearance, macrophage infiltration, and mRNA expression of transforming growth factor b and of collagen 1α2 were all suppressed by lacking iNOS. Conclusions. iNOS is required in the process of cutaneous wound healing. Lacking iNOS retards macrophage invasion and its expression of fibrogenic components that might further impair fibrogenic behaviors of fibroblasts

Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19–deficient mice

Tight junction (TJ)–like structures have been reported in Schwann cells, but their molecular composition and physiological function remain elusive. We found that claudin-19, a novel member of the claudin family (TJ adhesion molecules in epithelia), constituted these structures. Claudin-19–deficient mice were generated, and they exhibited behavioral abnormalities that could be attributed to peripheral nervous system deficits. Electrophysiological analyses showed that the claudin-19 deficiency affected the nerve conduction of peripheral myelinated fibers. Interestingly, the overall morphology of Schwann cells lacking claudin-19 expression appeared to be normal not only in the internodal region but also at the node of Ranvier, except that TJs completely disappeared, at least from the outer/inner mesaxons. These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological “sealing” function of Schwann cells

Insights into gene expression profiles induced by Socs3 depletion in keratinocytes

Specific deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes can cause severe skin inflammation with infiltration of immune cells. The molecular mechanisms and key regulatory pathways involved in these processes remain elusive. To investigate the role of Socs3 in keratinocytes, we generated and analyzed global RNA-Seq profiles from Socs3 conditional knockout (cKO) mice of two different ages (2 and 10 weeks). Over 400 genes were significantly regulated at both time points. Samples from 2-week-old mice exhibited down-regulation of genes involved in keratin-related functions and up-regulation of genes involved in lipid metabolism. At week 10, multiple chemokine and cytokine genes were up-regulated. Functional annotation revealed that the genes differentially expressed in the 2-week-old mice play roles in keratinization, keratinocyte differentiation, and epidermal cell differentiation. By contrast, differentially expressed genes in the 10-week-old animals are involved in acute immune-related functions. A group of activator protein-1–related genes were highly up-regulated in Socs3 cKO mice of both ages. This observation was validated using qRT-PCR by SOCS3-depleted human keratinocyte–derived HaCaT cells. Our results suggest that, in addition to participating in immune-mediated pathways, SOCS3 also plays important roles in skin barrier homeostasis

Insights into gene expression profiles induced by Socs3 depletion in keratinocytes.

Specific deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes can cause severe skin inflammation with infiltration of immune cells. The molecular mechanisms and key regulatory pathways involved in these processes remain elusive. To investigate the role of Socs3 in keratinocytes, we generated and analyzed global RNA-Seq profiles from Socs3 conditional knockout (cKO) mice of two different ages (2 and 10 weeks). Over 400 genes were significantly regulated at both time points. Samples from 2-week-old mice exhibited down-regulation of genes involved in keratin-related functions and up-regulation of genes involved in lipid metabolism. At week 10, multiple chemokine and cytokine genes were up-regulated. Functional annotation revealed that the genes differentially expressed in the 2-week-old mice play roles in keratinization, keratinocyte differentiation, and epidermal cell differentiation. By contrast, differentially expressed genes in the 10-week-old animals are involved in acute immune-related functions. A group of activator protein-1-related genes were highly up-regulated in Socs3 cKO mice of both ages. This observation was validated using qRT-PCR by SOCS3-depleted human keratinocyte-derived HaCaT cells. Our results suggest that, in addition to participating in immune-mediated pathways, SOCS3 also plays important roles in skin barrier homeostasis

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naive patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P = 0.0008) and progression-free survival (P = 0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm-3 (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (≥4500 mm-3, n = 204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (≥4500 mm-3, n = 184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis

Molecular mechanism of crown root initiation and the different mechanisms between crown root and radicle in rice

Monocot plants produce numerous adventitious (crown) roots. The plant hormone auxin has positive effects on crown root formation, while cytokinin suppresses it. We have demonstrated that auxin-induced CROWN ROOTLESS5 (CRL5) regulates crown root initiation in rice through the induction of OsRR1, a negative regulator of cytokinin signaling. CRL5 overexpressing calli formed adventitious roots, although CRL5 overexpressing plants did not induce ectopic roots, suggesting that CRL5, which promotes de novo root initiation, might function only in de-differentiated cells. A radicle initiated normally in a crl5 mutant, in spite of the defect in crown root initiation, whereas crown roots, but not a radicle, were produced in a radicleless1 (ral1) mutant. A crl5 ral1 double mutant displayed an additive phenotype, showing that the formation of each root is regulated by different genetic mechanisms in rice