Functional Expression of Heme Oxygenase-1 in Human Differentiated Epidermis and Its Regulation by Cytokines

Although heme oxygenase-1 (HO-1) is induced in keratinocytes after UV radiation, HO-1 expression during normal epidermal differentiation has not yet been reported. We showed by real-time PCR, western blotting, and ELISA that HO-1 mRNA and protein expression by cultured normal human keratinocytes was upregulated during epidermal differentiation induced by a high-calcium medium. Immunohistochemical staining and in situ hybridization showed the graduated expression of HO-1 in the upper epidermis, which was accompanied by suprabasal HO-1 mRNA expression, and the accumulation of bilirubin (BR) in the stratum corneum. We examined the activation of nuclear factor E2-related factor 2 (Nrf2), which is a pivotal transcription factor for HO-1 expression, by western blotting and by examining the mRNA expression of Nrf2 target genes, and excluded its role in HO-1 expression in epidermal differentiation. Next, we examined the regulation of HO-1 expression by inflammatory cytokines. IL-4 and IL-22 significantly reduced HO-1 mRNA and protein expression, whereas IL-1β, IL-17A, and tumor necrosis factor-α (TNF-α) increased it. Finally, immunohistochemical studies on psoriatic lesional skin showed that HO-1 expression was downregulated in the parakeratotic epidermis, whereas it was retained in the orthokeratotic epidermis. These studies demonstrate that HO-1 is functionally expressed by keratinocytes in parallel with epidermal differentiation and that its expression is independently affected by several cytokines

Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells.

Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

The combination of short-step and wide-based gait is a gait characteristic in progressive supranuclear palsy: a retrospective, cross-sectional study

Purpose Like Parkinson's disease (PD), gait disturbance is a major problem in progressive supranuclear palsy (PSP). Despite limited studies investigating the gait characteristics, we hypothesize that they differ from PD owing to the involvement of different brain lesions. Hence, this study aims to investigate the gait characteristics in patients with PSP by comparing with healthy older adults and patients with PD. Methods We identified 27 PSP patients, 25 PD patients, and 25 neurologically healthy older persons. Using a device that detected the distribution of foot pressure during walking, we analyzed gait variables and measured the walking speed (cm/s), cadence (steps/min), step length (cm), step width (cm), foot angle (degrees), and gait cycle time (s). Additionally, we calculated the coefficient of variation (CV, %) on walking speed and cadence and analyzed the gait characteristics by the PSP subtypes. Results In PSP and PD, the walking speed was slower and the step length was shorter than healthy controls. The CV of cadence in PSP was higher than healthy controls and PD. In PSP, the step width and foot angle were higher than healthy controls and PD. The gait cycle time was longer in PSP and PD than healthy controls. PSP with progressive freezing gait tended to display a faster walking speed. Furthermore, PSP with parkinsonism-resembling idiopathic PD tended to exhibit the larger step width and foot angle compared with PSP-Richardsons syndrome. Conclusion This study suggests that the gait of PSP was unstable with parkinsonism and wide-based, which might be similar to combining features of PD and cerebellar disorders

Reduction in Skeletal Muscle Mass in Progressive Supranuclear Palsy in Comparison with Parkinson’s Disease: A Preliminary Retrospective Longitudinal Study

Progressive supranuclear palsy (PSP) manifests with the loss of skeletal muscle mass, but the longitudinal changes have not been investigated. We studied changes in body composition, including in skeletal muscle mass, in patients with PSP twice, approximately 1 year or more apart, and we compared these measurements with those of patients with Parkinson’s disease (PD). The total number of participants was 42: 10 men had PD, 13 men had PSP, 8 women had PD, and 11 women had PSP. Using a body composition analyzer, we measured such parameters as body mass index (BMI), skeletal muscle mass, basal metabolic rate (BMR), body fat percentage (BFP), and the ratio of extracellular water to total body water. We also calculated the skeletal muscle mass index (SMI). We measured the Barthel index to assess activities of daily living. The Barthel index was lower in patients with PSP than in those with PD at the first evaluation, and it worsened by the time of the second evaluation. In men with PSP, skeletal muscle mass was far more reduced than in those with PD, but no such changes were found among women with either disease. The SMI of men with PSP was correlated significantly with BMI, BMR, BFP, and the Barthel index. Skeletal muscle mass diminished faster in patients with PSP, especially in men, than in patients with PD, probably because of inactivity

Skeletal muscle loss and body composition in progressive supranuclear palsy: A retrospective cross-sectional study

Introduction Skeletal muscle mass loss has been associated with decreased physical performance; however, the body composition characteristics in progressive supranuclear palsy (PSP) are not well understood. We investigated body composition parameters, focusing on skeletal muscle mass, in patients with PSP and compared them with those of healthy older adults. Methods This retrospective cross-sectional study included 39 patients with PSP and 30 healthy older adults (control group). Using a multi-frequency bioelectrical impedance analysis, we measured the skeletal mass index (SMI), basal metabolism, extracellular water/total body water ratio (ECW/TBW), and body fat percentage and examined the relationship between SMI and age, body mass index (BMI) and other body composition parameters. Results The PSP group had a higher rate of low muscle mass (56.4%) than the control group (10.0%), although the ages and BMIs were similar. The leg SMI was lower for the PSP group, while the ECW/TBW was higher for the PSP group. The basal metabolism was lower for the PSP group than for the controls but only in the women. The basal metabolism and BMI showed a significant correlation with SMI in the PSP group. There was a significant correlation between SMI and age, ECW/TBW, and body fat percentage in the PSP group but only in the women. Conclusion This study is the first to show that a high proportion of patients with PSP have low muscle mass. We showed differences in terms of sex in muscle mass loss in women with PSP, which was associated with inactivity and aging

Pseudolymphomatous Folliculitis on the Nose

Pseudolymphomatous folliculitis (PLF), which sometimes mimicks cutaneous lymphoma, is a rare manifestation of cutaneous pseudolymphoma and cutaneous lymphoid hyperplasia. We describe a 57-year-old Japanese woman with PLF on the nose that resembled cutaneous lymphoma clinically. The biopsy specimen revealed dense lymphocytes, especially CD1a+ cells, infiltrated around the hair follicles. Without any additional treatment, her nodule rapidly decreased before we performed a second biopsy for analysis of the clonal gene rearrangement. Though PLF typically behaves as benign lymphohyperplasia, differentiation from cutaneous lymphoma is necessary