Efficacy of anifrolumab in long-term intractable alopecia due to discoid lupus erythematosus.

Alopecia associated with lupus erythematosus is broadly classified into reversible nonscarring alopecia seen in the acute phase, such as worsening of systemic lupus erythematosus (SLE) and cicatricial alopecia seen in chronic cutaneous lupus erythematosus represented by discoid lupus erythematosus (DLE). In DLE-induced alopecia, early therapeutic intervention before developing scarring alopecia is important, but the condition is often resistant to conventional treatment. Anifrolumab (ANI), a novel therapeutic agent for SLE that inhibits type I interferon activity, has been shown to be effective against acute skin lesions, including alopecia, in patients with SLE. However, there are very few reports on the effect of ANI on alopecia due to DLE. We report on a 27-year-old Japanese woman with SLE whose alopecia due to chronic DLE was refractory to topical therapy and systemic therapy with oral glucocorticoid, multiple immunosuppressants and belimumab for approximately 8 years after onset, and whose alopecia improved with ANI. ANI can be considered to be an effective treatment option in lupus patients presenting with alopecia due to DLE, even in the chronic refractory stage.

Correlations Between Serum Cytokine Levels and the Use of a Moisturizer in Elderly Women in Accordance with the Improvement of Objective and Subjective Skin Condition.

Purpose: In the skin of elderly people with dryness, the production of inflammatory cytokines tends to be induced under the influence of external stimuli. Therefore, there has been a hypothesis that the deterioration of skin conditions due to aging is linked to systemic inflammation. This study aimed to verify the possibility that the use of moisturizer improves skin condition and suppresses systemic inflammation. Methods: As an open study, the participants (n=75) were randomly assigned to either control group or moisturizer group. Participants in the moisturizer group used a moisturizer called Grafa Moisture Keep Milk MC at least twice a day for four weeks on the entire body below the neck. Objective skin conditions (overall dry skin score, water content of the stratum corneum, and transepidermal water loss) and serum cytokine levels (IL-1α, IL-1ß, IL-4, IL-5, IL-6, IL-8, and TNF-α) were evaluated before and after the study in both groups. Subjective skin condition (questionnaire evaluation) was also assessed in the moisturizer group after the study. Results: Serum IL-6 level was significantly reduced in the moisturizer group (n=16) compared with the control group (n=36). In addition, there was an inverse correlation between serum IL-5 and the subjective moisturizing effect in the questionnaire evaluation, suggesting that the moisturizer improved subjective symptoms of dryness by reducing IL-5 levels. Furthermore, there was a positive correlation between IL-5 and IL-6, indicating that they are regulated by common upstream factors. A significant positive correlation of transepidermal water loss with serum IL-4 levels was also detected. Conclusion: The application of the moisturizer to the entire body not only improved subjective and objective skin condition, it may also reduce the levels of circulating inflammatory cytokines. Umin Clinical Trials Registry: Registration number: UMIN 000052024.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Expression of collagen-related piRNA is dysregulated in cultured dermal fibroblasts derived from patients with scleroderma.

PIWI-interacting RNA (piRNA) is a class of recently discovered small non-coding RNAs. piRNAs derive from an initial transcript encompassing a piRNA cluster via a unique biosynthesis process, interact with PIWI proteins, bind to specific targets, and recruit chromatin modifiers to enable transcriptional repression. Abnormal expression of PIWI proteins and piRNAs has been reported in some human cancers, with participation of some PIWI/piRNAs complexes in tumorigenesis and association with cancer prognosis. Their expression in patients with systemic sclerosis (SSc) has not been widely elucidated. PIWI/piRNAs and their role in the pathogenesis of collagen accumulation in SSc was therefore investigated; no difference was found in the PIWIL1-4 levels between normal and cultured SSc dermal fibroblasts. Among piRNAs predicted to target SSc-related molecules, we first found significant piR-32364 up-regulation in SSc dermal fibroblasts, likely due to intrinsic TGF-ß signaling. Forced piR-32364 overexpression in normal fibroblasts significantly reduced COL1A1 expression both at mRNA and protein levels, but not COL1A2. Thus, piR-32364 overexpression in SSc fibroblasts may be the negative feedback against collagen up-regulation, which could suggest the potential of piRNAs as a therapeutic target.

Saliva contact during infancy and allergy development in school-age children.

Background: Parent-child saliva contact during infancy might stimulate the child's immune system for effective allergy prevention. However, few studies have investigated its relation to allergy development in school-age children. Objective: We sought to investigate the relationship between parent-child saliva contact during infancy and allergy development at school age. Methods: We performed a large multicenter cross-sectional study involving Japanese school children and their parents. The self-administered questionnaires including questions from the International Study of Asthma and Allergies in Childhood were distributed to 3570 elementary and junior high school children in 2 local cities. Data were analyzed for the relationship between saliva contact during infancy (age <12 months) and the risk of allergy development, specifically eczema, allergic rhinitis, and asthma. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. Results: The valid response rate was 94.7%. The mean and median age of children was 10.8 ± 2.7 and 11 (interquartile range, 9-13) years, respectively. Saliva contact via sharing eating utensils during infancy was significantly associated with a lower risk of eczema (odds ratio, 0.53; 95% CI, 0.34-0.83) at school age. Saliva contact via parental sucking of pacifiers was significantly associated with a lower risk of eczema (odds ratio, 0.24; 95% CI, 0.10-0.60) and allergic rhinitis (odds ratio, 0.33; 95% CI, 0.15-0.73), and had a borderline association with the risk of asthma in school-age children. Conclusions: Saliva contact during infancy may reduce the risk of developing eczema and allergic rhinitis in school-age children.

Analysis of skin aging patterns using a facial imaging system in patients with atopic dermatitis.

BACKGROUND: There are few studies on skin aging in patients with atopic dermatitis (AD). OBJECTIVES: To clarify the characteristics of facial skin aging in AD patients. MATERIALS & METHODS: Using facial images obtained by a digital imaging system (VISIA evolution), we compared the severity scores for 10 aging signs in 53 women in the AD group and 29 women in the healthy control group, all 35-49 years old. RESULTS: The severity scores for fine lines on the forehead, periorbital wrinkles, nasolabial folds, and texture of the mouth contour were significantly higher in the AD group than in the controls. However, in order to exclude a direct effect of dermatitis at the time of measurement, cases with signs of AD at the evaluation site were excluded from the AD group (defined as the AD [non-lesion] group), revealing no statistical significance between the AD (non-lesion) group and the healthy control group for any of the 10 facial signs. Age subset analysis showed that for individuals in their late 40s, the AD (non-lesion) group exhibited significantly higher scores for crow's feet wrinkle and nasolabial fold compared to the healthy control group. Furthermore, these two scores correlated with one other, suggesting that they may be induced by the same factors. CONCLUSION: The results of this study show that skin aging associated with AD is prominent in areas prone to transient wrinkling by frequent blinking and speaking or facial expressions. Understanding of the need for appropriate AD treatment from a cosmetic perspective may increase patient adherence.

Glycoprotein M6A upregulation detected by transcriptome analysis controls the proliferation of keloidal fibroblasts.

Hypertrophic scars and keloids are fibroproliferative disorders caused by abnormal wound healing. Their exact cause has not been found, but abnormalities during the wound healing process including inflammatory, immune, genetic, and other factors are thought to predispose an individual to excessive scarring. In the present study, we performed transcriptome analysis of established keloid cell lines (KEL FIB), focusing on gene expression analysis and fusion gene detection for the first time. For gene expression analysis, fragments per kilobase per million map read values were calculated, which were validated by real-time PCR and immunohistochemistry. Fusion genes were predicted by transcriptome sequence, and validated by Sanger sequence and G-banding. As a result, GPM6A was shown in the expression analysis to be upregulated in KEL FIB compared with normal fibroblasts. The GPM6A upregulation in KEL FIB was confirmed by real-time PCR, and GPM6A messenger ribonucleic acid expression was consistently significantly elevated in the tissues of hypertrophic scar and keloid compared to normal skin. Immunohistochemistry also revealed that the number of fibroblast-like spindle-shaped cells positive for GPM6A was significantly increased in keloidal tissues. GPM6A inhibition by small interfering ribonucleic acid significantly reduced the number of KEL FIB. On the other hand, although we hypothesized that fusion genes are involved in the pathogenesis of keloids, the transcriptome analysis could not prove the presence of fusion genes in KEL FIB. Taken together, GPM6A upregulation may have an inducible effect on cell proliferation in keloidal fibroblasts. GPM6A can be a novel therapeutic target in hypertrophic scars and keloids. The inflammatory nature may be more prominent in the pathogenesis of keloids, rather than being skin tumors, as proposed by Ogawa et al. Future studies using several cell lines will be required.

Clinical evaluation of needle-free electronic pneumatic hyaluronic acid injection treatment for facial atrophic acne scars: A prospective, randomized comparative trial.

Acne scars are common but difficult to treat, and an effective new treatment strategy is desired. This prospective, split-face randomized controlled trial was designed to compare the safety and efficacy of needle-free electronic pneumatic hyaluronic acid injection (EPI-HA) treatment for acne scars. Thirty Japanese subjects with moderate to severe facial atrophic acne scars underwent EPI-HA treatment on a randomized side of their face. Three treatment sessions were carried out at 1-month intervals, and the subjects were followed-up for 3 months after the final treatment. Three months after the final treatment, 48.3% of treated sides met the criteria for success, compared with 0% for the control sides (P < 0.0001). Rolling type scars were much improved compared with boxcar types and icepick types. Satisfaction (or better) was reported by 55.2% of subjects at the 3-month follow-up after the final treatment, which was similar to the physicians' assessment. Three-dimensional in vivo imaging analysis detected significant difference in scar reductions between the treated and control sides in the mean scar area, scar depth, and maximum depth of the biggest scar at 1 and 3 months after the final treatment (all P < 0.05). In conclusion, EPI-HA treatment significantly improved rolling facial atrophic acne scars in our Japanese subjects, with minimal side effects.

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors.

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

Analysis of cytokine profiles in sera of single and multiple infantile hemangioma.

Infantile hemangiomas (IH) are benign vascular tumors that are common in infancy. They vary in growth, size, location, and depth, and although most lesions are relatively small, approximately one fifth of patients have multiple lesions. Risk factors for IH include female sex, low birth weight, multiple gestation, preterm birth, progesterone therapy, and family history, but the mechanism that causes multiple lesions is unclear. We hypothesized that blood cytokines are involved as a cause of multiple IHs, and tried to prove this using sera and membrane arrays from patients with single and multiple IHs. Serum samples were obtained from five patients with multiple lesions and four patients with a single lesion, none of which had received any treatment. Serum levels of 20 cytokines were measured using human angiogenesis antibody membrane array. Four of the 20 cytokines (bFGF, IFN-γ, IGF-I, and TGF-ß1) were higher in the patients with multiple lesions than in those with single lesion, with statistically significant difference (p < 0.05). Notably, signal for IFN-γ was evident in all cases with multiple IHs, but was absent in cases with single IH. Although not significant, there was mild correlation between IFN-γ and IGF-I (r = 0.64, p = 0.065), and between IGF-I and TGF-ß1 (r = 0.63, p = 0.066). bFGF levels were strongly and significantly correlated with the number of lesions (r = 0.88, p = 0.0020). In conclusion, blood cytokines could act as a cause of multiple IHs. This is a pilot study with a small cohort, so further large-scale studies are necessary.

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

Arm heating to relieve Raynaud's phenomenon in systemic sclerosis: A single-arm multicentre prospective clinical trial.

OBJECTIVES: Raynaud's phenomenon, one of the major symptoms of systemic sclerosis (SSc), is difficult to treat. Although it is empirically considered that warming is a beneficial technique, there is no supportive evidence. We conducted a multicentre study to evaluate whether continuous heating of the arm alleviates Raynaud's phenomenon in SSc. METHODS: A pair of disposable warmers was applied to the upper arm near the elbow of patients with SSc. Two weeks of non-warmer application were followed by 2 weeks of warmer application, which was repeated twice. The Raynaud Condition Score (RCS), number of episodes, and duration of Raynaud's phenomenon were recorded. The differences in the mean RCS, frequency, and duration of Raynaud's phenomenon between the warmer application and non-application periods were analysed. RESULTS: Twenty-eight patients were included in the analysis. The average RCS was 1.98 and 2.66 during the warmer application and non-application periods, respectively. The change between the two periods was statistically significant by paired t-test. In addition, the frequency and total duration of Raynaud's phenomenon in the warmer application period were significantly lower than those in the non-application period. CONCLUSIONS: Heating of the upper arm near the elbow is effective in alleviating Raynaud's phenomenon in SSc.

Nevus of Ota on the auricle successfully treated with Q-switched ruby laser.

Nevus of Ota is a dermal melanocytosis that consists of blue-brown spots, patches and plaques along the distribution of the first and second branches of trigeminal nerve. The efficacy of Q-switched ruby laser treatment against nevus of Ota on dark skin has not been described. The present case, a 2-month-old Indonesian girl, showed rare auricular involvement. Because ear has complicated steric structure, whose skin is sensitive and thin, pain and inflammatory reaction are inevitable. We discussed the difficulty of laser treatments on auricular lesions.

The clinical significance of dupilumab-induced blood eosinophil elevation in Japanese patients with atopic dermatitis.

This study aims to clarify the clinical significance of dupilumab-induced elevation of blood eosinophil in Japanese patients with atopic dermatitis (AD). Eosinophil elevation was defined as ≥ 5% increase of eosinophil percentage within one year after dupilumab initiation. Seven patients (15.7%) were shown to have eosinophil elevation, six of whom developed dupilumab-associated conjunctivitis (DAC) and were accompanied with DAC more frequently than those without eosinophil elevation, with statistically significant difference. Eosinophil percentage resolved spontaneously in all seven patients, including the one without DAC, despite the continuation of dupilumab treatment. None of the patients with eosinophil elevation had cardiac or pulmonary complications attributable to the hypereosinophilia. The patients with eosinophil elevation were all male. Furthermore, none of four patients in whom efficacy of dupilumab was < 25% showed eosinophil elevation. Childhood onset tended to be more common in patients with the elevation of eosinophil. This study suggests that most eosinophil elevation is associated with DAC, and that the eosinophil ratio is a biomarker for DAC.

Elevated Alpha 1(I) to Alpha 2(I) Collagen Ratio in Dermal Fibroblasts Possibly Contributes to Fibrosis in Systemic Sclerosis.

Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.

Dupilumab Improves Pruritus in Netherton Syndrome: A Case Study.

The patient was a 26-year-old male. He had red and scaling skin of the entire body since birth, as well as an elevated level of serum IgE. Genetic testing revealed a mutation in the SPINK5 gene, which had confirmed the diagnosis with Netherton syndrome. He has had significant pruritis since birth, and subsequently had symptoms of sleeping disorders and concentration difficulty throughout the day. Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. Dupilumab has been administered for one year without any adverse events or recurrence of symptoms. Although studies have previously described cases who used dupilumab for Netherton syndrome, reported effects have been limited or transient. Additional studies are needed to confirm the effect of dupilumab for Netherton syndrome, which currently lack any effective treatment strategies.

Forearm porphyrin levels evaluated by digital imaging system are increased in patients with systemic sclerosis compared with patients in pre-clinical stage.

We hypothesized that changes in skin characteristics on the forearm could be useful for early diagnosis of systemic sclerosis (SSc). We used VISIA digital imaging system to investigate this possibility for the first time. Twenty-eight Japanese patients who were diagnosed with typical or very early diagnosis of SSc (VEDOSS) were enrolled in this study, and ten age- and gender-matched patients with other disorders were included as a control group. Eight skin characteristics were analyzed. Our method of evaluating forearm skin characteristics was shown to be reproducible. The scores of WRINKLES, TEXTURE, PORES, and PORPHYRINS were higher in SSc subjects with sclerotic forearm skin (SSc forearm+; 11.004, 5.116, 3.230, and 0.084, respectively) and those without (SSc forearm-: 11.915, 4.898, 2.624, 0.0616, respectively) than in the non-SSc control subjects (10.075, 4.496, 2.459, 0.0223, respectively). Also, the scores of SPOTS, TEXTURE, PORES, UV SPOTS, BROWN SPOTS, and PORPHYRINS were elevated in SSc forearm+ (3.182, 5.116, 3.230, 5.761, 6.704, 0.084, respectively) and SSc forearm- patients (2.391, 4.898, 2.624, 9.835, 5.798, 0.0616, respectively) compared with those with VEDOSS (2.362, 4.738, 2.234, 5.999, 4.898, 0.0169, respectively). We found statistical significance in the difference in score of PORPHYRINS between SSc forearm- and VEDOSS groups (p = 0.044), and between SSc forearm+ and VEDOSS groups (p = 0.012). Therefore, they can be used to differentiate VEDOSS from early or mild SSc cases, which is sometimes clinically problematic. Our study also suggests that the porphyrin research will lead to a better understanding of SSc pathogenesis.

Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors.

BACKGROUND: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. METHODS: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. RESULTS: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. CONCLUSION: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-centre, randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.

ISSVA Classification of Vascular Anomalies and Molecular Biology.

Vascular anomalies include various diseases, which are classified into two types according to the International Society for the Study of Vascular Anomalies (ISSVA) classification: vascular tumors with proliferative changes of endothelial cells, and vascular malformations primarily consisting of structural vascular abnormalities. The most recent ISSVA classifications, published in 2018, detail the causative genes involved in many lesions. Here, we summarize the latest findings on genetic abnormalities, with the presentation of the molecular pathology of vascular anomalies.