局所麻酔薬による筋毒性は悪性高熱症の素因の有無に関わらず同等である

内容の要旨, 審査の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Genetic screening for malignant hyperthermia and comparison of clinical symptoms in Japan

Malignant hyperthermia (MH) is an anaesthetic complication that causes an abnormal hypermetabolic state. RYR1 encoding ryanodine receptors of the sarcoplasmic reticulum and CACNA1S encoding α subunits of dihydropyridine receptors are known to be associated with MH pathogenicity. We performed genetic screening using next-generation sequencing to evaluate the prevalence of genes associated with MH pathogenicity and clinical symptoms. This was a retrospective cohort study wherein next-generation sequencing data of 77 families diagnosed with MH predisposition by calcium-induced calcium release (CICR) tests from 1995 to 2019 was used to search for RYR1 and CACNA1S variants. Furthermore, the clinical symptoms and predisposition tests in participants with RYR1 and CACNA1S variants were compared. In the 77 families, 44.2%, 7.8%, and 48.1% individuals had RYR1, CACNA1S, and neither RYR1 nor CACNA1S variants, respectively. Clinically significant differences were found in the maximum body temperature, maximum elevated body temperature for 15 min, creatinine kinase level, and CICR rate between the RYR1 and CACNA1S groups. The prevalence of pathogenic CACNA1S variants appears to be prominent in Japan. The severity of clinical symptoms and the CICR rate were greater in individuals with RYR1 variants than in those with CACNA1S variants, likely due to more direct regulation of calcium levels by ryanodine receptors than by dihydropyridine receptors. Genetic analysis of MH in future studies may help identify other genes associated with MH, which will further clarify the relationship between genotypes and MH symptoms and contribute to safer anaesthesia practice.This study was supported by a Grant-in-Aid for Young Scientists (grant number: 17K16733 to Y.N. and 20K17783 to R.K.) from the Japan Society for the Promotion of Science and by the Takeda Science Foundation (H.K.)

HSP47 levels determine the degree of body adiposity

Shin J., Toyoda S., Okuno Y., et al. HSP47 levels determine the degree of body adiposity. Nature Communications 14, 7319 (2023); https://doi.org/10.1038/s41467-023-43080-x.Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances

Writing errors in ALS related to loss of neuronal integrity in the anterior cingulate gyrus

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neuron and various cognitive deficits including writing errors. (11)C-flumazenil (FMZ), the positron emission tomography (PET) GABA(A) receptor ligand, is a marker of cortical dysfunction. The objective of this study was to investigate the relationship between cognitive deficits and loss of neuronal integrity in ALS patients using (11)C-FMZ PET. Ten patients with ALS underwent both neuropsychological tests and (11)C-FMZ-PET. The binding potential (BP) of FMZ was calculated from (11)C-FMZ PET images. There were no significant correlations between the BP and most test scores except for the writing error index (WEI), which was measured by the modified Western Aphasia Battery - VB (WAB-IVB) test. The severity of writing error was associated with loss of neuronal integrity in the bilateral anterior cingulate gyrus with mild right predominance (n=9; x=4mm, y=36mm, z=4mm, Z=5.1). The results showed that writing errors in our patients with ALS were related to dysfunction in the anterior cingulate gyrus

Anesthetic management of cesarean section in COVID-19-positive pregnant women in Japan: Three case reports and review of the literature

Cesarean delivery may be performed if a pregnant woman develops coronavirus disease 2019 (COVID-19) in the prenatal period; however, perioperative management is controversial. Herein, we report the anesthetic management of cesarean sections in three pregnant women with COVID-19. In addition, we reviewed the literature on perioperative anesthesia management in pregnant women with COVID-19. Three pregnant women between the 37th and 38th weeks of gestation developed COVID-19 and were transferred to our hospital for cesarean section. Intraoperative spinal anesthesia was administered, and postoperative analgesia included intravenous morphine. Postoperatively, all patients were administered anticoagulant therapy. We used a negative pressure-controlled operating room for the cesarean sections, and the staff used Level 3 personal protective equipment with N95 masks, face shields, double gloves, full-body gowns, and shoe covers. None of the operating room staff, including the anesthesiologist, were infected with COVID-19 due to patient care. Spinal anesthesia, rather than general anesthesia, is recommended for cesarean sections in pregnant women with COVID-19. In addition to the risk of thrombosis, it is necessary to manage anesthesia in pregnant women infected with COVID-19 while considering accessibility to the ward for postoperative management and familiarity of ward staff

Impact of proficiency in the transcatheter aortic valve implantation procedure on clinical outcomes: a single center retrospective study

Abstract Background We used transcatheter aortic valve implantation (TAVI) procedure time to investigate the association between surgical team maturity and outcome. Methods Among patients who underwent TAVI between October 2015 and November 2019, those who had Sapien™ implanted with the transfemoral artery approach were included in the analysis. We used TAVI procedure time and surgery number to draw a learning curve. Then, we divided the patients into two groups before and after the number of cases where the sigmoid curve reaches a plateau. We compared the two groups regarding the surveyed factors and investigated the correlation between the TAVI procedure time and survey factors. Results Ninety-nine of 149 patients were analysed. The sigmoid curve had an inflection point in 23.2 cases and reached a plateau in 43.0 cases. Patients in the Late group had a shorter operating time, less contrast media, less radiation exposure, and less myocardial escape enzymes than the Early group. Surgical procedure time showed the strongest correlation with the surgical case number. Conclusion The number of cases required for surgeon proficiency for isolated Sapien™ valve implantation was 43. This number may serve as a guideline for switching the anesthesia management of TAVI from general to local anesthesia