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Sézary syndrome involving the intestinal tract (j,k) Histological investigation of the specimens of the subtotal colon excision showed submucosal infiltration of atypical lymphocytes with mitotic figures without lymphoepithelial lesion. Histopathological examination of biopsy specimens from erythema on the back showed superficial and perivascular infiltration of mononuclear cells with mild atypia in the dermis (Fig. c, d). [Extracted from the article]

Objectives: There is a lack of quantitative and objective methods for measuring skin hardness. This study aimed to verify whether SOFTGRAM, a device that can measure elastic modulus using the Hertz elastic contact theory, could be used to evaluate skin hardness in systemic sclerosis (SSc)., Methods: Skin score according to the modified Rodnan total skin thickness score and elastic modulus of the skin using SOFTGRAM were measured for 20 patients with SSc and 20 healthy controls on 8 parts of the body, both of the cheeks, forearms, fingers, and hands. Five observers shared to measure skin score 320 times (40 participants × 8 parts). Elastic modulus was measured 1600 times (40 participants × 8 parts × 5 times each). As an additional examination to compare differences between observers, the skin score of another healthy control was measured 40 times (5 observers × 8 parts). Elastic modulus was measured 200 times (5 observers × 8 parts × 5 times each)., Results: There was a significant correlation between elastic modulus and skin score (correlation coefficient=0.67, p<0.001) and a significant difference in elastic modulus (8 parts: healthy controls vs. limited cutaneous SSc vs. diffuse cutaneous SSc: 22.6±15.7 vs. 32.0±27.7 vs. 44.8±39.8, p<0.001). Intraobserver reliabilities were sufficient in 6 out of 7 observers; however, interobserver was less satisfactory., Conclusions: This study showed the practicality of SOFTGRAM as an accurate measurement method of skin hardness but also revealed points to be improved. More studies are needed to find an accurate measurement method of skin hardness.

Competing Interests: There are no conflicts of interest.

The association between immunoregulatory cytokines, such as interleukin (IL)-10 or IL-35, and dipeptidyl peptidase-4 inhibitor (DPP4i)-related bullous pemphigoid (BP) has not been evaluated. Serum IL-10 and IL-35 levels were measured in 39 patients with BP (24 males and 15 females; 6 DPP4i-related and 33 DPP4i-unrelated BP patients) and 10 healthy controls. The number of CD26 + cells in the dermis around bulla on sections was counted immunohistochemically for 12 patients (six patients with DPP4i-related BP and six randomly sampled patients with DPP4i-unrelated BP). Patients with DPP4i-related BP had lower levels of serum eosinophils (DPP4i-related vs. DPP4i-unrelated BP: 476.1 ± 234.0 vs. 911.3 ± 948.8/μL; p = 0.537) and a higher rate of infiltrating CD26 + cells (32.9 ± 7.1% vs. 15.7 ± 4.4%; p = 0.01). There were no significant differences in serum IL-10 (6.77 ± 0.24 vs. 6.84 ± 0.20 pg/mL), serum IL-35 (2.63 ± 0.17 vs. 2.63 ± 0.21 pg/mL), serum anti-BP180NC16a antibodies (67.31 ± 37.4 vs. 76.18 ± 54.59 U/mL) and Bullous Pemphigoid Disease Area Index before treatment in this study. Serum IL-10 and IL-35 levels do not increase in patients with BP and may not be a candidate for a therapeutic target for BP. An increase in CD26 + cells might be associated with DPP4i-related BP., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS-causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

Objective: For patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), early medical intervention would be desirable. This study analyzed the real-world, single-center use of nintedanib for CTD-ILD patients., Methods: Patients with CTD who received nintedanib from January 2020 to July 2022 were enrolled. Medical records review and stratified analyses of the collected data were conducted., Results: Reduction in the percentage of predicted forced vital capacity (%FVC) was seen in the elderly group (>70 years; P = .210), males (P = .027), the late group who started nintedanib >80 months after confirmation of an ILD disease activity (P = .03), the severe %DLco (diffusing capacity for carbon monoxide as a percentage of predicted) group (<40%; P = .20), the group who had extensive pulmonary fibrosis at the beginning of nintedanib (pulmonary fibrosis score >35%), and the low-dose group (nintedanib 50-100 mg/d; P = .40). %FVC did not decrease by >5% in the young group (<55 years), the early group who started nintedanib within 10 months after confirmation of an ILD disease activity, and the group whose pulmonary fibrosis score at the beginning of nintedanib was <35%., Conclusion: It is important to diagnose ILD early and start antifibrotic drugs with proper timing for cases in need. It is better to start nintedanib early, especially for patients at risk (>70 years old, male, <40% DLco, and >35% areas of pulmonary fibrosis)., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Context: Few reports focused on the sex differences in alopecia areata (AA) treated with steroid pulse therapy., Aims: This study aimed to investigate the association between the clinical outcomes and distinction of gender in AA patients treated with steroid pulse therapy., Settings and Design: This study retrospectively investigated 32 cases (15 males and 17 females) treated with steroid pulse therapy at the Department of Dermatology at the Shiga University of Medical Science between September 2010 and March 2017., Methods and Material: The administration of corticosteroid was 500 mg methylprednisolone intravenous infusion for 3 consecutive days. Patients were followed up approximately once a month until March 2017., Statistical Analysis Used: The respective data were analyzed by examining and comparing males and females. Statistical analysis was performed using t -test and χ 2 test., Results: There were no significant differences in periods from the onset of AA to the administration of steroid pulse therapy ( P = 0.2), the degree of severity ( P = 0.37) and improved rate ( P = 0.0772) between males and females. In contrast, the remission rate was 20% (3 of 15 males) and 71% (12 of 17 females), which was statistically significant ( P = 0.0042). Previous reports have also shown a significant difference in the remission rate between males and females (males: 32 of 114; females: 51 of 117; P = 0.014)., Conclusions: Despite the limitations of a small sample size including the previous reports ( n = 261), female patients with AA would have better outcomes than male patients after steroid pulse therapy., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Dermatology.)

Stride intervals in human walking fluctuate from one stride to the next, exhibiting statistical persistence. This statistical property is changed by aging, neural disorders, and experimental interventions. It has been hypothesized that the central nervous system is responsible for the statistical persistence. Human walking is a complex phenomenon generated through the dynamic interactions between the central nervous system and the biomechanical system. It has also been hypothesized that the statistical persistence emerges through the dynamic interactions during walking. In particular, a previous study integrated a biomechanical model composed of seven rigid links with a central pattern generator (CPG) model, which incorporated a phase resetting mechanism as sensory feedback as well as feedforward, trajectory tracking, and intermittent feedback controllers, and suggested that phase resetting contributes to the statistical persistence in stride intervals. However, the essential mechanisms remain largely unclear due to the complexity of the neuromechanical model. In this study, we reproduced the statistical persistence in stride intervals using a simplified neuromechanical model composed of a simple compass-type biomechanical model and a simple CPG model that incorporates only phase resetting and a feedforward controller. A lack of phase resetting induced a loss of statistical persistence, as observed for aging, neural disorders, and experimental interventions. These mechanisms were clarified based on the phase response characteristics of our model. These findings provide useful insight into the mechanisms responsible for the statistical persistence of stride intervals in human walking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TN declared a shared affiliation with the author SA to the handling editor at time of review., (Copyright © 2022 Okamoto, Obayashi, Kokubu, Senda, Tsuchiya and Aoi.)

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

In this study, dermoscopy was applied to determine the site of skin biopsy in cases of palmoplantar pustulosis (PPP) with invisible tiny pustules or vesicles. Fifty-two clinically diagnosed PPP patients (11 men and 41 women) were observed by a dermoscope and underwent skin biopsy. Nineteen patients had visible pustules, whereas 33 had no visible pustules. Pustules were detected by a dermoscope on palmoplantar lesions in 17 of the 33 PPP patients. In contrast, 16 patients showed no presence of pustules or vesicles observed by a dermoscope. In this group, biopsy specimens were taken from scaly lesions. Out of the 16 patients, 10 histologically showed pustules in the epidermis. We finally detected pustules for 46 patients among 52 who were clinically diagnosed with PPP. As a result, we detected pustules in PPP for 19 patients on "inspection", and 36 patients on "inspection and dermoscopy", and 46 patients on "inspection, dermoscopy, and biopsy". Dermoscopy is significantly useful comparing the detection rate (inspection, 0.41; inspection and dermoscopy, 0.78; p = 0.0003; using χ 2 -test). In addition, we also should learn from the results that the detection rate goes down to 0.78 without a biopsy. Thus, dermoscopy is certainly a useful tool for invisible pustules and also undetectable pustules to detect pustules in PPP. Moreover, we objectively showed that "inspection, dermoscopy, and biopsy" are the best way to make a PPP diagnosis., (© 2021 Japanese Dermatological Association.)

Genetic variants in Granulin (GRN), which encodes the secreted glycoprotein progranulin (PGRN), are associated with several neurodegenerative diseases, including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer's disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying factors that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration and could reveal novel potential therapeutic targets. Here, we report that modulation of the endocytosis/lysosomal pathway via reduction of Nemo-like kinase (Nlk) in microglia, but not in neurons, can alter total brain Pgrn levels in mice. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through the endocytosis/lysosomal pathway, specifically in microglia. Furthermore, genetic interaction studies in mice showed that Nlk heterozygosity in Grn haploinsufficient mice further reduces Pgrn levels and induces neuropathological phenotypes associated with PGRN deficiency. Our results reveal a mechanism for Pgrn level regulation in the brain through the active catabolism by microglia and provide insights into the pathophysiology of PGRN-associated diseases.

Trimethoprim-sulfamethoxazole (TMP/SMX) combination is used for the prophylaxis of Pneumocystis pneumonia (PCP). Although TMP/SMX is frequently used in dermatology for cases treated with corticosteroids and/or immunosuppressants, it is often difficult to continue the administration of TMP/SMX due to adverse events. There are only a few reported studies on the prophylaxis of PCP in dermatology. This is the first review focused on adverse events of TMP/SMX among patients with dermatological diseases compared with previous reports. In this study, we retrospectively investigated 132 cases treated with TMP/SMX and examined the adverse events. Adverse events occurred in 32 cases (24.2%) and the incidence in this study was higher than in previous reports. Thrombocytopenia occurred in 17 cases (12.5%), which was the most frequent adverse event. The possible causes of adverse events were that the standard dose of TMP/SMX may be excessive for most Japanese, in addition to the long administration period, and the concomitant use of corticosteroids and/or immunosuppressants in almost all cases. We must consider the risks of PCP and adverse events of TMP/SMX in each case. It is desirable to examine possible administration methods that can be continued by adjusting the dose and interval of TMP/SMX., (© 2021 Japanese Dermatological Association.)

Passive dynamic walking is a model that walks down a shallow slope without any control or input. This model has been widely used to investigate how humans walk with low energy consumption and provides design principles for energy-efficient biped robots. However, the basin of attraction is very small and thin and has a fractal-like complicated shape, which makes producing stable walking difficult. In our previous study, we used the simplest walking model and investigated the fractal-like basin of attraction based on dynamical systems theory by focusing on the hybrid dynamics of the model composed of the continuous dynamics with saddle hyperbolicity and the discontinuous dynamics caused by the impact upon foot contact. We clarified that the fractal-like basin of attraction is generated through iterative stretching and bending deformations of the domain of the Poincaré map by sequential inverse images. However, whether the fractal-like basin of attraction is actually fractal, i.e., whether infinitely many self-similar patterns are embedded in the basin of attraction, is dependent on the slope angle, and the mechanism remains unclear. In the present study, we improved our previous analysis in order to clarify this mechanism. In particular, we newly focused on the range of the Poincaré map and specified the regions that are stretched and bent by the sequential inverse images of the Poincaré map. Through the analysis of the specified regions, we clarified the conditions and mechanism required for the basin of attraction to be fractal.

Passive dynamic walking is a useful model for investigating the mechanical functions of the body that produce energy-efficient walking. The basin of attraction is very small and thin, and it has a fractal-like shape; this explains the difficulty in producing stable passive dynamic walking. The underlying mechanism that produces these geometric characteristics was not known. In this paper, we consider this from the viewpoint of dynamical systems theory, and we use the simplest walking model to clarify the mechanism that forms the basin of attraction for passive dynamic walking. We show that the intrinsic saddle-type hyperbolicity of the upright equilibrium point in the governing dynamics plays an important role in the geometrical characteristics of the basin of attraction; this contributes to our understanding of the stability mechanism of bipedal walking.

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.