α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies.

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.

Cross-sectional surveillance study of long COVID in Toyonaka city, Osaka prefecture, Japan.

BACKGROUND: As the COVID-19 epidemic continues, concerns about long-term health impacts, specifically long COVID, persist. While the prevalence and symptomatology of long COVID have been explored in various global contexts, large-scale cohort studies in Japan remain limited, especially after the advent of the Omicron variant. METHODS: In this observational study, 4,047 residents with a history of COVID-19 living in Toyonaka City, Osaka Prefecture, were assessed for long COVID symptoms using the VOICE mobile application and a paper survey. Respondents provided demographic and health information, as well as information regarding COVID-19 infection and subsequent symptoms. A Cox proportional hazard regression model was used to estimate the multivariable-adjusted hazard ratios and 95 % confidence intervals for overall morbidity of long COVID symptoms. RESULTS: The survey found that 5.2 % of participants reported the persistence of one or more symptoms at 30 days post-onset. Fatigue was the most commonly reported symptom (1.75 %), followed by hair loss (1.41 %), and cough (1.28 %). Factors associated with an increased risk of experiencing long COVID symptoms included BMI, severe illness during the acute phase, and infection with certain COVID-19 variant strains, including Alpha, Delta, and Omicron. However, the incidence rate of long COVID appears to be decreasing with the dominance of the Omicron variant. CONCLUSIONS: This large-scale study from Toyonaka City suggests a 5.2 % prevalence rate for persistent COVID-19 symptoms 4 weeks post-infection, potentially indicating a lower prevalence of long COVID in Japanese populations after the rise of the Omicron variant.

The number of erupted teeth as a risk factor for dental caries in eighteen-month-old children: a cross­sectional study.

BACKGROUND: Dental caries is one of the most common chronic diseases worldwide, affecting lifelong as well as children. Therefore, it is important to clarify factors related to early childhood caries (ECC) in a younger population in terms of caries prevention. However, the prevalence of ECC is low in developed countries in the twenty-first century and a large-scale survey is needed to clarify the risk factors. Furthermore, earlier tooth eruption is not taken into consideration in most studies of ECC, even though it may be a factor of ECC. The present study investigated the prevalence and risk factors of dental caries in children aged 18 months in a core city of Japan. METHODS: Findings from a total of 7351 children aged 18 months were analyzed. Anthropometric measurements of height and weight, as well as an oral examination and a microbiological caries-risk test, were performed. Additionally, a structured interview sheet was provided to the parents or guardians. Findings of dental caries at 18 months of age were evaluated using a logistic regression model. RESULTS: Of the enrolled children, 1.2% had experienced dental caries. Multivariable logistic regression analysis results indicated a significant association with dental caries at 18 months of age for the following factors: second child (OR = 1.78; 95% CI:1.08-2.93, P < 0.05), third and later child (OR = 2.08; 95% CI:1.12-3.89, P < 0.05), 12 or fewer erupted teeth (OR = 0.47; 95% CI:0.24-0.96, P < 0.05), 17 or more erupted teeth (OR = 4.37; 95% CI:1.63-11.7, P < 0.01), Cariostat score (+ + +) (OR = 3.99; 95% CI:1.29-12.31, P < 0.05), daily eating before bed (OR = 2.62; 95% CI: 1.55-4.45, P < 0.001), three or more snacks per day (OR = 2.03; 95% CI:1.15-3.58, P < 0.05), and breastfeeding (OR = 3.30; 95% CI:2.00-5.44, P < 0.001). CONCLUSIONS: These results suggest that the number of erupted teeth, as well as birth order, eating habits, and breastfeeding, are significant factors in dental caries occurrence at 18 months of age.

Challenge to improve Japan's deplorable HPV vaccination rate by local government actions.

AIM: In Japan, in 2013, following reports of several alleged adverse reactions in young girls following vaccination, the previously successful national human papillomavirus infection (HPV) vaccination program collapsed rapidly. In the 8 years since vaccination rates have hovered near zero. In October of 2020, in an attempt to mitigate this lingering disaster, the Japanese Ministry of Health, Labor, and Welfare (MHLW) agency finally revised its HPV vaccination informational leaflet that was designed to be distributed by local governments nationwide. Prior to this revision, Toyonaka City, in Japan's Osaka province, had already begun sending out their own unique leaflet to girls in the targeted 6th-10th grades. As a preview of how MHLW's revised leaflet might eventually succeed, we have studied the HPV vaccination results from Toyonaka City's experiment. METHOD: This study was a population-based analysis that compared the monthly rates of new vaccinations in girls of a targeted grade school age group. We looked at rates before and after the leaflets were sent by Toyonaka City's Division of Health Promotion and Senior Services. RESULTS: The vaccination rates between April 2020 and March 2021 were improved across all grades; 1.2% in 6th grade (p = 0.000185), 2.5% in 7th grade (p < 0.0001), 3.5% in 8th grade (p < 0.0001), 6.8% in 9th grade (p < 0.0001), and a remarkable 16.5% in 10th grade (p < 0.0001). CONCLUSION: When a local government sends an HPV informational leaflet targeted at young girls, it can significantly improve their HPV vaccination rates.

[HLA-mismatched bone marrow transplantation with post-transplant cyclophosphamide for pediatric patients with aplastic anemia].

Post-transplant cyclophosphamide (PTCy) has improved the efficacy of HLA-mismatched hematopoietic cell transplantation (HCT) by decreasing the risk of graft-versus-host disease (GVHD) and nonrelapse mortality. If an HLA-matched donor is not available, GVHD prophylaxis with PTCy can also be used for HLA-mismatched HCT in patients with pediatric aplastic anemia (AA). We report two cases of pediatric AA that were treated with HLA-mismatched HCT with reduced-intensity conditioning and PTCy. We administered 50 mg/kg/day Cy for GVHD prophylaxis on days 3 and 4, and tacrolimus and mycophenolate mofetil (or methotrexate) were initiated from day 5. In both the cases, the time to engraftment was favorable and GVHD and infection were controllable. PTCy probably allows us to expand donor candidates in pediatric AA when an HLA-matched donor is not available; however, further studies regarding optimal conditioning regimens and late complications are required.

Clinical and Echocardiographic Impact of Tafazzin Variants on Dilated Cardiomyopathy Phenotype in Left Ventricular Non-Compaction Patients in Early Infancy.

BACKGROUND: Left ventricular non-compaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium and numerous prominent trabeculations, and is often associated with dilated cardiomyopathy (DCM). Variants in the gene encoding tafazzin (TAZ) may change mitochondrial function and cause dysfunction of many organs, but they also contribute to the DCM phenotype in LVNC, and the clinical and echocardiographic features of children with this phenotype are poorly understood. Methods and Results: We enrolled 92 DCM phenotype LVNC patients and performed next-generation sequencing to identify the genetic etiology. Ten TAZ variants were identified in 15 male patients (16.3%) of the 92 patients, including 3 novel missense substitutions. The patients with TAZ variants had a higher frequency of early onset of disease (92.3% vs. 62.3%, P=0.0182), positive family history (73.3% vs. 20.8%, P=0.0001), and higher LV posterior wall thickness Z-score (8.55±2.60 vs. 5.81±2.56, P=0.0103) than those without TAZ variants, although the mortality of both groups was similar. CONCLUSIONS: This study provides new insight into the impact of DCM phenotype LVNC and emphasizes the clinical advantages available for LVNC patients with TAZ variants.

[Three cases of human herpesvirus-6 encephalopathy showing hyperperfusion in the acute phase on SPECT].

Brain hypoperfusion observed on single-photon emission computed tomography (SPECT) is a typical finding in the acute phase of human herpesvirus-6 (HHV-6) encephalopathy. However, from 2004 to 2010, we encountered three cases of HHV-6 encephalopathy in which hyperperfusion in the area of the brain lesion was observed on SPECT performed within 48 hours after disease onset. The hyperperfusion in the brain was followed by hypoperfusion in the recovery phase. These cases suggest that hyperperfusion may appear in damaged areas prior to the hypoperfusion that is normally associated with HHV-6 encephalopathy.

Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis.

PURPOSE: PRRT2 mutations were recently identified in benign familial infantile epilepsy (BFIE) and infantile convulsions with paroxysmal choreoathetosis (ICCA) but no abnormalities have so far been identified in their phenotypically similar seizure disorder of benign convulsions with mild gastroenteritis (CwG), while mutations in KCNQ2 and KCNQ3 have been recognized in benign familial neonatal epilepsy (BFNE). The aim of this study was to identify PRRT2 mutations in infantile convulsions in Asian families with BFIE and ICCA, CwG and BFNE. METHODS: We recruited 26 unrelated Japanese affected with either BFIE or non-familial benign infantile seizures and their families, including three families with ICCA. A total of 17 Japanese and Taiwanese with CwG, 50 Japanese with BFNE and 96 healthy volunteers were also recruited. Mutations of PRRT2 were sought using direct sequencing. RESULTS: Heterozygous truncation mutation (c.649dupC) was identified in 15 of 26 individuals with benign infantile epilepsy (52.1%). All three families of ICCA harbored the same mutation (100%). Another novel mutation (c.1012+2dupT) was found in the proband of a family with BFIE. However, no PRRT2 mutation was found in either CwG or BFNE. CONCLUSIONS: The results confirm that c.649dupC, a truncating mutation of PRRT2, is a hotspot mutation resulting in BFIE or ICCA regardless of the ethnic background. In contrast, PRRT2 mutations do not seem to be associated with CwG or BFNE. Screening for PRRT2 mutation might be useful in early-stage differentiation of BFIE from CwG.

Pulse methylprednisolone with gammaglobulin as an initial treatment for acute Kawasaki disease.

Approximately 15-20% of patients with Kawasaki disease (KD) are not responsive to high-dose intravenous gammaglobulin (IVIG). We have previously reported a predictive method for identifying IVIG-non-responsive patients (high-risk KD patients). We determined the safety and effectiveness of pulse methylprednisolone with high-dose IVIG (mPSL+IVIG) as a primary treatment for high-risk KD patients. Sixty-two high-risk KD patients were treated with pulse methylprednisolone 30 mg/kg over 2 h, followed by IVIG 2 g/kg over 24 h (mPSL+IVIG group) and were compared with a historical control group of 32 high-risk patients treated with IVIG 2 g/kg alone at the participating hospitals before this study was opened (IVIG group). High-risk patients were identified with at least two of three predictors (C-reactive protein >or=7 mg/dL, total bilirubin >or=0.9 mg/dL or aspartate aminotransferase >or=200 IU/L). Sixty-six percent (95% confidence interval [CI] 54-78%) of patients had a prompt defervescence in the mPSL+IVIG group compared with 44% (95% CI 26-62%) for the IVIG group (p=0.048). Coronary artery lesions were observed in 24.2% (95% CI 13.2-35.2%) and 46.9% (95% CI 28.6-65.2%) of patients in the mPSL+IVIG and IVIG groups, respectively (p=0.025). This is the first report showing that mPSL+IVIG is effective and safe as a primary treatment for high-risk KD patients.

Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity.

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by numerous excessively trabeculations and deep intertrabecular recesses. This study was performed to investigate Japanese LVNC patients for disease-causing mutations in a series of selected candidate genes. DNA was isolated from the peripheral blood of 79 cases including 20 familial cases and 59 sporadic cases. DNA samples were screened for mutations in the genes encoding G4.5 (TAZ), alpha-dystrobrevin (DTNA), alpha1-syntrophin (SNTA1), FK506 Binding protein 1A (FKBP1A or FKPB12: FKBP1A), and LIM Domain Binding protein 3 (Cypher/ZASP: LDB3), using single-strand conformational polymorphism analysis and DNA sequencing. DNA variants were identified in 6 of the 79 cases, including four familial cases and two sporadic cases. A splice acceptor mutation of intron 8 in TAZ (IVS8-1G>C) was identified in one family with isolated LVNC, resulting in deletion of exon 9 from mRNA. In a sporadic case of isolated LVNC and Barth syndrome (BTHS), a 158insC in exon 2 of TAZ resulting in a frame-shift mutation was identified. A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC. A 163G>A polymorphism was identified in LDB3, which changed a valine to isoleucine (V55I) in one patient with isolated LVNC. In addition, in a family with nonisolated LVNC, a 362C>T mutation was identified in DTNA. LVNC, like other forms of inherited cardiomyopathy, is a genetically heterogeneous disease, associated with variable clinical symptoms and can be inherited as an autosomal or X-linked recessive disorder.

[Clinical efficacy of shortened ACTH therapy --an individualized method for minimization of adverse effects--Part 1. The short-term outcome].

To minimize adverse effects and to get good efficacy of ACTH therapy against West syndrome, we tried a new 2-steps therapeutic protocol consisting of the shortened ACTH therapy and the additional ACTH therapy. In a prospective multi-institutional study, 20 patients with newly diagnosed West syndrome who had failed to respond to high-dose vitamin B6 and zonisamide were treated by this shortened ACTH therapy. Synthetic corticotropin (ACTH-Z 0.025 mg/kg/dose, max 0.25 mg) was administrated intramuscularly seven times on every other day for 14 days. At 1 month after discontinuing corticotropin, spasms and hypsarrhythmia disappeared in 10/20 (50%) and 13/17 (59%) patients respectively. Subsequently, 9 out of the 10 patients with persistent spasms received additional therapy for 1 or 2 weeks with daily intramuscular ACTH-Z, which was tapered off over a few weeks. Including the additional ACTH therapy, the disappearance of spasms and hypsarrhythmia were found in 13 patients (65%) and 13 patients (76%). Adverse effects during the shortened ACTH therapy were fewer than additional ACTH therapy but not statistically significant. Severe adverse effects were not observed in both ACTH therapy. In the 2-steps therapeutic protocol according to the response to ACTH, favorable results were obtained in seizure control, EEG findings and the degree of adverse effects.

Impaired vascular endothelium-dependent relaxation in Henoch-Schönlein purpura.

Few reports have focused on vascular endothelial function in children with Henoch-Schönlein purpura (HSP). The purpose of the present study was to assess endothelial function and to follow serial changes from the acute to convalescent phases in children with HSP. Forearm flow-mediated vasodilation was evaluated in 21 patients with HSP, aged 4.0-10.3 years (median 6.2 years), and in 14 control subjects. Vascular dimension, mean velocity, and flow volume were measured by ultrasonography in brachial artery before and after hyperemia, and during incremental infusions of nitroglycerin (0.5, 1.0 microg/kg per min). In the controls, significant increases in dimension, mean velocity, and flow volume were observed in reactive hyperemia ( P<0.01). In contrast, patients in the acute phase of HSP showed a flow velocity profile indicating a highly resistant forearm circulation, and significantly attenuated responses after hyperemia ( P<0.01 vs. control), whereas the responses to nitroglycerin were well preserved. In addition, the impaired hyperemic responses recovered in the convalescent phase, with no significant differences compared with controls. These results clearly suggest that forearm vascular endothelium-dependent relaxation was attenuated in patients with acute HSP.

Serum KL-6 level in newborns with meconium aspiration syndrome.

BACKGROUND: It has been reported that serum KL-6 increases in babies with progressing chronic lung disease (CLD). However, there have been few reports assessing KL-6 in meconium aspiration syndrome (MAS). KL-6 was measured in neonates with respiratory diseases including MAS. METHODS: Thirty-eight neonates with respiratory disease were enrolled in the study. These patients were classified into three groups, 14 patients with respiratory distress syndrome (RDS), 14 with MAS, and 10 with transient tachypnea of the newborn (TTN). The control group consisted of 12 healthy neonates. KL-6 levels were measured 1 day (median) after the birth. In the RDS group, measurement was repeated just prior to 36 weeks' postmenstrual age. RESULTS: The levels of KL-6 were 116 +/- 40 U/mL in the RDS, 281 +/- 138 U/mL in the MAS, and 106 +/- 41 U/mL in the TTN groups. KL-6 levels were significantly higher in the MAS group than in the control group (134 +/- 71 U/mL; P < 0.01). In addition, the levels were significantly higher in those with severe MAS than those with mild MAS (P < 0.05). In patients with RDS, KL-6 increased in patients who developed CLD (P < 0.05), while KL-6 levels did not change in those who did not develop CLD. CONCLUSION: These data confirm the high level of KL-6 in CLD, and suggest that KL-6 is increased in MAS.