Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.

Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg2+-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders.

Novel ITPA variants identified by whole genome sequencing and RNA sequencing.

Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.

Mesoterricola silvestris gen. nov., sp. nov., Mesoterricola sediminis sp. nov., Geothrix oryzae sp. nov., Geothrix edaphica sp. nov., Geothrix rubra sp. nov., and Geothrix limicola sp. nov., six novel members of Acidobacteriota isolated from soils.

Forty-eight Acidobacteriota strains were isolated from soils and sediments in Japan. Among them, six representative strains, designated W79T, W786T, Red222T, Red802T, Red803T, and Red804T, were subjected to the taxonomic classification. These six strains are Gram-stain-negative, non-spore-forming, rod-shaped, and facultative anaerobic bacterium that can reduce ferric iron. Phylogenetic and phylogenomic trees based on 16S rRNA genes and multiple single-copy gene sequences showed that strains Red222T, Red802T, Red803T, and Red804T formed a cluster with the type strains of Geothrix species, but strains W79T and W786T created an independent cluster from any other type strains. The former four strains shared 97.95-99.08% similarities of 16S rRNA gene sequence with the type strains of the genus Geothrix, whereas the latter two strains 94.86-95.49% similarities. The average amino acid identity of strains W79T and W786T were <63 % to any other type strains, which were below the genus delineation thresholds. Moreover, colonies of these two strains were white, while those of the other four isolated strains were reddish-yellow as well as the type strain Geothrix fermentans H-5T. Although the known type strains of Geothrix species have been reported to be non-motile, five strains (W79T, W786T, Red222T, Red803T, and Red804T) except for strain Red802T displayed motility. Furthermore, multiple genomic, phylogenetic, and phenotypic features supported the discrimination between these isolated strains. Based on the study evidence, we propose these six isolates as novel members within the Acidobacteriota/Holophagae/Holophagales/Holophagaceae, comprising two novel species of a novel genus, Mesoterricola silvestris gen. nov., sp. nov., and Mesoterricola sediminis sp. nov., and four novel species of the genus Geothrix: Geothrix oryzae sp. nov., Geothrix edaphica sp. nov., Geothrix rubra sp. nov., and Geothrix limicola sp. nov.

Pharmacokinetic variability of vancomycin in patients with nosocomial meningitis.

WHAT IS KNOWN AND OBJECTIVE: High doses of vancomycin are required early in the treatment of nosocomial meningitis. However, the dosage is often reduced later during treatment, irrespective of renal function. This study was designed to investigate the pharmacokinetic variability of vancomycin and the associated factors throughout the treatment course for patients with nosocomial bacterial meningitis. METHODS: This study included 17 patients who received vancomycin for nosocomial bacterial meningitis at the Tokyo Women's Medical University Yachiyo Medical Center from April 2013 to May 2020. All patients had their serum vancomycin concentrations and cerebrospinal fluid (CSF) parameters measured within 7 days of initiating treatment (early period) and after 8 days (later period) of treatment. RESULTS AND DISCUSSION: The relative error between the predicted serum vancomycin concentration and the measured value was significantly higher in the later period than in the early period. In 13 patients who did not have their dosing interval shortened, the vancomycin dosage/serum vancomycin concentration/estimated glomerular filtration rate (D/C/eGFR) ratio significantly decreased in the later period. Moreover, the rate of change in the D/C/eGFR ratio significantly correlated with that in the CSF protein and C-reactive protein levels. WHAT IS NEW AND CONCLUSION: This study suggests that the clinical condition and inflammatory response of a patient with meningitis influence the pharmacokinetics of vancomycin. Therefore, the vancomycin dosage for the treatment of nosocomial bacterial meningitis must be adjusted according to changes in the clinical condition and renal function of the patient, necessitating careful therapeutic drug monitoring.

Local Control of Squamous Cell Carcinoma of the Cervix Treated with CT-based Three-dimensional Image-Guided Brachytherapy with or without Central Shielding.

The purposes of this retrospective study were to analyze local control of squamous cell carcinoma of the cervix treated with computed tomography (CT)-based image-guided brachytherapy (IGBT), as well as the factors affecting local control. A total of 39 patients were analyzed. The prescribed dose to the pelvis was 45-50 Gy with or without central shielding (CS). IGBT was delivered in 1-5 fractions. The total dose for high-risk clinical target volume (HR-CTV) was calculated as the biologically equivalent dose in 2-Gy fractions. The median follow-up period was 29.3 months. The 2-year overall survival and local control rates were 97% and 91%, respectively. In univariate analysis, the dose covering 90% of the HR-CTV (D90) and tumor size were found to be significant factors for local control. The cutoff values of tumor size and D90 for local control were 4.3 cm (area under the curve [AUC] 0.75) and 67.7 Gy (AUC 0.84) in the CS group and 5.3 cm (AUC 0.75) and 73.7 Gy (AUC 0.78) in the group without CS, respectively. However, though the local control of CT-based IGBT was favorable, the results suggested that the dose required for tumor control may differ depending on the presence of CS.

Short-lasting unilateral neuralgiform headache attacks with ispilateral facial flushing is a new variant of paroxysmal extreme pain disorder.

BACKGROUND: We encountered a 5-year-old girl who had short-lasting, severe, unilateral temporal headaches with ipsilateral lacrimation, nasal congestion and rhinorrhoea, and facial flushing after severe attacks. Family history revealed similar short-lasting, severe headaches in an older brother, younger sister, mother, maternal aunt, and maternal grandfather's brother. METHODS: We performed routine laboratory examinations and electrophysiological and radiological studies for three children, and whole-exome sequencing to determine the genetic causality in this family. RESULTS: Focal hyperperfusion of the right trigeminal root entry zone was seen during a right-sided attack in one child, while left-sided temporal headache attacks were provoked by bilateral electrical stimulation of the upper extremities in another. We identified a novel SCN9A mutation (NM_002977: c.5218G>C, p.Val1740Leu) in all affected family members, but not in any of the unaffected members. SCN9A encodes the voltage-gated sodium-channel type IX alpha subunit known as Na(v)1.7. CONCLUSIONS: Gain-of-function mutations in Na(v)1.7 are well known to cause paroxysmal extreme pain disorder (PEPD), a painful Na-channelopathy characterized by attacks of excruciating deep burning pain in the rectal, ocular, or jaw areas. The SCN9A mutation suggests that our patients had a phenotype of PEPD with a predominant symptom of short-lasting, severe, unilateral headache.

Meiothermus ruber H328 enhances the production of membrane vesicles for feather degradation.

The thermophilic bacterium Meiothermus ruber H328 aggressively degrades chicken feathers. When feathers were added to culture medium, the cells significantly exfoliated membrane vesicles from the outer membrane as observed by electron microscopy of ultrathin sections. This is the first report of membrane vesicle production associated with keratinolytic activity by Meiothermus sp.

Characteristics of risk factors for acute kidney injury among inpatients administered sulfamethoxazole/trimethoprim: a retrospective observational study.

BACKGROUND: Sulfamethoxazole/trimethoprim (SMX/TMP) potentially increases the serum creatinine levels, resulting in acute kidney injury (AKI). However, the clinical characteristics of the AKI associated with SMX/TMP and the risk factors for its development have not been fully characterized. METHODS: A retrospective cohort observational analysis was conducted on adult inpatients who started SMX/TMP treatment at the Tokyo Women's Medical University, Yachiyo Medical Center, from April 2018 to March 2020. The primary outcome was AKI, defined as an increase in serum creatinine level of ≥ 50% from baseline. Multivariate logistic regression analysis was used to determine the risk factors for the AKI associated with SMX/TMP. RESULTS: Of the 281 patients, 32 (11.4%) developed AKI. The multivariate logistic regression analysis identified that body mass index (BMI) (odds ratio [OR] = 0.86, 95% confidence interval [95% CI] 0.76-0.97, p < 0.01), presence of hypertension (OR = 2.69, 95% CI 1.11-6.49, p = 0.02), SMX/TMP daily dose (OR = 1.16, 95% CI 1.03-1.30, p = 0.02), and concomitant loop diuretic use (OR = 2.91, 95% CI 1.08-7.78, p = 0.04) were the associated risk factors for AKI in patients who were administered SMX/TMP. CONCLUSIONS: This study showed that low BMI, hypertension, high-dose SMX/TMP, and concomitant loop diuretic use increased the risk of AKI in patients administered SMX/TMP. Clinicians should consider monitoring the renal function in patients at a high risk of AKI.

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients.

INTRODUCTION: We aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT). METHODS: We retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2-4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT. RESULTS: The present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2-27.2) mg/kg. The CPHT was 13.4 (8.6-18.9) µg/mL 2-4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7-14.2) and 5.8 (3.7-10.0) µg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6-15.4) µg/mL at 5 mg/kg and 13.9 (5.7-31.0) µg/mL at 7.5 mg/kg. CONCLUSIONS: In pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5-7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.

Community-based lifestyle modification of cardiovascular disease risks in middle-aged Japanese: a 27-month update.

Lifestyle modification is the cornerstone of preventive management for people with cardiovascular disease risks, such as obesity, hypertension, dyslipidemia and diabetes. This study investigated the effect of a 27-month community-based lifestyle intervention on the reduction of cardiovascular disease risks in middle-aged Japanese. Of 549 participants with cardiovascular disease risk factors of overweight, hypertension, dyslipidemia or diabetes enrolled in this non-randomized controlled study, 397 participants aged 39-71 years old completed all 3 serial surveys at baseline, 15 months and 27 months. For the intervention group (39 males and 174 females), 31 specific interventions including individual counselling and group sessions were conducted. The control group (64 males and 120 females) only received 7 newsletters providing health information and results of health checkups. Multiple logistic regression analysis adjusted for sex, each baseline risk category and age category showed that the proportion of those who were overweight or showed dyslipidemia risk were significantly lower in the intervention group only at 27 months [Odds ratio (OR): 0.43 (95% CI 0.20-0.94), OR: 0.43 (95% CI 0.21-0.87), respectively] and the proportion of those showing diabetes risk was significantly lower in the intervention group at both 15 months [OR: 0.42 (95% CI 0.18-0.97)] and 27 months [OR: 0.56 (95% CI 0.32-0.99)]. In conclusion, the 27-month community-based lifestyle modification of cardiovascular disease risks shows significant reductions in risks of diabetes, overweight and dyslipidemia in middle-aged Japanese.

Fifteen-month lifestyle intervention program to improve cardiovascular risk factors in a community population in Japan.

Morbidity and mortality associated with cardiovascular disease remain primary public health problems in Japan. We developed a large-scale community-based 15-month intervention program, and evaluated its long-term effects on improving lifestyle and cardiovascular risk. Of 549 participants, 436 (46 males and 186 females in intervention group and 72 males and 132 females in control group) completed the study. The intervention program consisted of a 6-month program including 15 sessions, with one lecture and individual counseling, two workshops and nutrition educations, and nine exercises (total 29 hours) and a 9-month maintenance program including 4 sessions of individual counseling, workshop, nutrition, and exercise (total 7 hours). Changes from the baseline to 15 months were significantly different between intervention and control groups by gender: the proportion of subjects who walked more than 6,000 steps/day (+39% vs. +2% for males; +17% vs. +1% for females), exercised more than 20 min/day and 3 times/week (+22% vs. +1% for males; +22% vs. +8% for females), ate vegetables at every meal (+18% vs. +4% for females), and consumed less salt (+9% vs. +3% for females); and the changes in body weight (-1.0 vs. -0.1 kg for males; -1.8 vs. -0.6 kg for females). Other changes detected only in females were body mass index (-0.8 vs. -0.3 kg/m(2)), systolic blood pressure (-6.6 vs. -2.4 mmHg), total cholesterol (-2.2 vs. +1.5 mg/dl), and the total risk scores (-0.5 vs. -0.1 points). The 15-month intervention program effectively improves and maintains lifestyle and cardiovascular risk, with greater effects of the long-term intervention in females.

High attendance at a lifestyle intervention program is important to reduce risks related to metabolic syndrome in middle-aged Japanese.

Evaluating attendance at health education programs is important to obtain a more comprehensive evaluation of the program impact. This study investigated whether attendance at a lifestyle intervention program in a community setting would reduce risks related to metabolic syndrome. Of 545 subjects with risks related to metabolic syndrome, i.e. overweight, hypertension, dyslipidemia or diabetes, participated in this non-randomized control study, 389 subjects aged 40-71 years completed the surveys at baseline and 27 months. Intervention group (39 males and 168 females) was provided 3 individual counseling plus 28 group sessions conducted monthly on average, whereas control group (64 males and 118 females) received only 7 health information newsletters by mail. Intervention group was subcategorized into two groups according to the median attendance (87.1%): 106 subjects with high attendance (93.8 +/- 4.7%) and 101 subjects with low attendance (68.6 +/- 16.0%). Logistic regression analyses adjusted for age and baseline value showed that among males, the proportion with dyslipidemia risk was lower only in high attendance group compared with that in control group at 27 months [Odds ratio (OR): 0.11 (95%CI 0.02 - 0.51)] and among females, the proportion of overweight was lower only in high attendance group [OR: 0.24 (95%CI 0.07 - 0.81)]. In females, the mean total risk score calculated by adding the number of the 4 risks present decreased only in high attendance group (p < 0.001). In conclusion, high attendance at a lifestyle intervention program impacts the reduction of risks related to metabolic syndrome in a Japanese community setting.

Influence of Peer Reactions and Student Attitudes on Student Deviance: Differences Between Japan and the United States.

The current study examines the cross-cultural applicability of Akers' social learning theory in explaining why Japanese commit fewer deviant acts than Americans. It is predicted that deviance would be less common in Japan because Japanese have less favorable attitudes toward deviance, which in turn are attributable to less favorable peer reactions to deviance. Analyses of comparable survey data from college students in Japan (N = 583) and the United States (N = 615) provide mixed support for our arguments. As expected, Japanese students had less favorable attitudes toward deviance because they had peers who reacted less favorably to deviance. Contrary to expectation, however, even after controlling for student attitudes toward deviance and peer reactions to deviance, the initially large difference between the two samples in student deviance remained significant. This was at least partly because, in Japan, compared with the United States, peer reactions and student attitudes had significantly less influence on student deviance.

Asymmetric total synthesis of (-)-leuconoxine via chiral phosphoric acid catalyzed desymmetrization of a prochiral diester.

The asymmetric total synthesis of (-)-leuconoxine has been achieved. The desymmetrization of a prochiral diester using a chiral phosphoric acid catalyst produced a highly enantioenriched lactam with excellent yield. The ring construction featuring an intramolecular N-acyliminium cyclization and the one-step pyrrolidone formation using Bestmann's ylide was successfully accomplished.