Idiopathic hypersomnia with a video recording of a spontaneous sleep attack: A case report.

RATIONALE: Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for its diagnosis due to the lack of symptom recognition. Here, we present a case of idiopathic hypersomnia (IH), a CDH, wherein early diagnosis was aided by a video footage of a spontaneous sleep attack. PATIENT CONCERNS: A 21-year-old man lost consciousness while driving and experienced an accident. He had complained of excessive daytime sleepiness (EDS) over half a year. During his hospitalization for close monitoring of the loss of consciousness, an in-room surveillance camera captured a 14-minutes long spontaneous sleep attack, during which he experienced general muscle weakness and loss of consciousness without warnings or convulsions leading to a fall from the bed. There were no abnormalities in vital signs. DIAGNOSES: There was no significant cataplexy and less than 2 sleep-onset rapid eye movements (SOREM) in 2 sleep latency tests, with a mean sleep latency of 2.1 and 4.6 minutes. Other sleep deprivation syndromes were excluded from differential diagnosis and finally, a diagnosis of IH was confirmed according to the criteria of the Third Edition of the International Classification of Sleep Disorders. During the course of the disease, attention-deficit/hyperactive disorder (ADHD) and a gaming disorder also diagnosed. INTERVENTIONS: Pharmacological treatment with modafinil was administered for IH and methylphenidate for ADHD. Cognitive behavioral therapy was performed for the gaming disorder. OUTCOMES: The EDS improved, and sleep attacks were no longer observed. The disruption of daily life caused by the gaming disorder was also reduced. LESSONS: Video recordings of sleep attacks are beneficial for identifying the cause of loss of consciousness. Home video recordings may be helpful in the early diagnosis of IH.

Divergent Nine-Step Syntheses of Perhydrohistrionicotoxin Analogs and Their Inhibition Activity Toward Chicken α4ß2-Neuronal Nicotinic Acetylcholine Receptors.

Histrionicotoxin (HTX) alkaloids, which are isolated from Colombian poison dart frogs, are analgesic neurotoxins that modulate nicotinic acetylcholine receptors (nAChRs) as antagonists. Perhydrohistrionicotoxin (pHTX) is the potent synthetic analogue of HTX and possesses a 1-azaspiro[5.5]undecane skeleton common to the HTX family. Here, we show for the first time the divergent nine-step synthesis of pHTX and its three stereoisomers from the known aldehyde through a one-step construction of the 1-azaspiro[5.5]undecane framework from a linear amino ynone substrate. Surprisingly, some pHTX diastereomers exhibited antagonistic activities on the chicken α4ß2-neuronal nAChRs that were more potent than pHTX.

Weight loss and functional decline in older Japanese people: A cohort study using large-scale claims data.

BACKGROUND: The association between weight loss and subsequent functional decline is uncertain. The study aims to elucidate the association between weight loss over a year and subsequent functional decline requiring assistance in performing their activities of daily living in older individuals. METHODS: The study used data from the publicly funded Long-Term Care Insurance service in Japan, which provides coverage for long-term care services for individuals unable to perform activities of daily living due to physical or cognitive impairment. The study enrolled people born in or before 1949, who underwent health checkups in both 2014 and 2015. The participants were followed from 2015 to the worsening of functional decline requiring long-term care services, death, or February 28, 2019, whichever occurred first. The risk of subsequent functional decline in each weight loss category was estimated using a Cox regression model adjusted for age, sex, baseline body mass index, smoking, and Charlson comorbidity index. RESULTS: We identified 67,452 eligible individuals from the database. The median follow-up period was 1,284 days. The hazard ratios (95 % confidence interval) of functional decline for -1 %, -2 %, -3 %, -4 %, and ≤-5% weight change compared to 0 % weight change were 1.17 (1.03-1.32), 1.26 (1.11-1.43), 1.29 (1.12-1.49), 1.61 (1.39-1.87), and 1.79 (1.58-1.99), respectively. CONCLUSIONS AND IMPLICATIONS: Older people with weight loss of 1 % or more were at risk of functional decline. Close weight monitoring may serve as an easy and inexpensive means of identifying older individuals at risk of functional decline.

Effect of periodontal therapy on glycaemic control in type 2 diabetes.

AIM: This study aimed to elucidate the impact of periodontal therapy on glycaemic control in individuals with type 2 diabetes and various baseline blood glucose levels using a large-scale claims database from Japan. MATERIALS AND METHODS: Using the JMDC Claims Database, we identified individuals with type 2 diabetes who underwent health check-ups in the fiscal years 2018 or 2019 and were followed up until the next year's health check-up. We conducted a weighted cohort analysis using stabilized inverse probability weights for treatment and censoring to estimate the effect of periodontal therapy on changes in haemoglobin A1c levels within a year. Analysis was done for different baseline haemoglobin A1c categories: 6.5%-6.9%, 7.0%-7.9% and ≥8.0%. RESULTS: Of the 4279 insured persons included in the study, 957 received periodontal therapy. Overall, there was a tendency towards improved glycaemic control among those who received periodontal therapy. Participants with baseline haemoglobin A1c levels of 7.0%-7.9% who received periodontal therapy exhibited significantly better glycaemic control compared with those without dental visits (difference; -0.094 [95% confidence interval: -0.181 to -0.007]). CONCLUSIONS: Periodontal therapy may improve glycaemic control in individuals with diabetes, especially in those with haemoglobin A1c levels ≥7.0%.

Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish.

Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors1,2. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt-planar cell polarity (PCP) signalling pathway to regulate tissue polarity and cell migration3,4. However, it remains unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. In this study, we provide evidence that Wnt5b, together with Ror2, is loaded on long protrusions called cytonemes. Our data further suggest that the active Wnt5b-Ror2 complexes form in the producing cell and are handed over from these cytonemes to the receiving cell. Then, the receiving cell has the capacity to initiate Wnt-PCP signalling, irrespective of its functional Ror2 receptor status. On the tissue level, we further show that cytoneme-dependent spreading of active Wnt5b-Ror2 affects convergence and extension in the zebrafish gastrula. We suggest that cytoneme-mediated transfer of ligand-receptor complexes is a vital mechanism for paracrine signalling. This may prompt a reevaluation of the conventional concept of characterizing responsive and non-responsive tissues solely on the basis of the expression of receptors.

Efficacy of denosumab in the treatment of hypercalcemic renal dysfunction in sarcoidosis: a case report.

A 70-year-old female patient was admitted for close examination and treatment of hypercalcemia (corrected serum calcium levels: 3.04 mmol/L) and renal dysfunction (serum creatinine levels: 254.59 µmol/L). The patient had a history of sarcoidosis, diagnosed based on epithelioid cell granulomas in subcutaneous nodule biopsies, uveitis, and bilateral hilar lymphadenopathy, which had spontaneously remitted 10 years before admission. Because the patient was diagnosed with hypercalcemia associated with recurrent sarcoidosis, prednisone (20 mg/day) was initiated, and its dose was tapered following the decrease in serum calcium and creatinine levels. However, the levels of these parameters increased again when the prednisone dose was reduced to ≤ 4 mg/day. We were concerned about glucocorticoid-induced osteoporosis in the patient but hesitated to use first-line bisphosphonates because of renal dysfunction. Therefore, denosumab was initiated to reduce the risk of hypercalcemia, renal dysfunction, and glucocorticoid-induced osteoporosis. Serum creatinine and corrected serum calcium levels subsequently decreased. The prednisone dose could be reduced following repeated denosumab administration.Thus, denosumab can be a multifaceted, beneficial option for sarcoidosis-induced hypercalcemia, as it alleviates renal dysfunction indirectly by normalizing serum calcium levels, facilitates reduction of the glucocorticoid dose, and ameliorates glucocorticoid-induced osteoporosis.

Proximal Renal Tubular Acidosis Complicated by Severe Hypocalcemia Caused by Malnutrition and Inappropriate Long-term Use of Zoledronate: A Case Report and Review of the Literature.

An 80-year-old man presented with electrolyte abnormalities, particularly hypocalcemia (3.6 mg/dL). He was diagnosed with bone and lymph node metastases from prostate cancer seven years earlier and continuously received goserelin, bicalutamide, and zoledronate. He later developed gradually worsening hypocalcemia, hypokalemia, hypophosphatemia, hypouricemia, renal dysfunction, and weight loss. Urinary potassium and phosphate loss, renal glucosuria, metabolic acidosis, and a low urine pH (5.0) were observed. Given the acquired onset and clinical course, we diagnosed the patient with zoledronate-induced proximal renal tubular acidosis. In the present case, severe hypocalcemia may have been caused by malnutrition and inappropriate long-term use of zoledronate.

Effectiveness of Laparoscopic Adenomyomectomy on Perinatal Outcomes.

Objectives: The objective of this study was to observe the influence of laparoscopic adenomyomectomy on perinatal outcomes. Materials and Methods: The retrospective cohort study included 43 pregnant cases with adenomyosis who did not undergo laparoscopic surgery before pregnancy (nonsurgery group; 26 cases) and did (surgery group; 17 cases). To evaluate the impact of surgery on perinatal outcomes, nine obstetric complications including preterm delivery, hypertensive disorder of pregnancy, placental malposition, oligohydramnios, gestational diabetes mellitus, uterine rupture, abruptio placentae, and postpartum hemorrhage were selected. One obstetric complication was counted as one point (Maximum 9 points for one person). The obstetrical morbidity was compared by adding up the number of relevant events (0-9) between the two groups. Apgar score, umbilical artery pH (UApH), neonatal intensive care unit (NICU) admission, and neonatal death were also examined. Results: The surgery group had a significantly lower prevalence of fetal growth restriction compared to the nonsurgery group (nonsurgery vs. surgery; 26.9%, 7/26 vs. 0%, 0/17: P = 0.031). No differences were found in the morbidity of the nine obstetric complications (19.2%, 45/234 vs. 13.7%, 21/153), gestational weeks (mean ± standard deviation, 37.2 ± 2.4 vs. 36.4 ± 3.2), birth weight (2573.6 ± 557.9 vs. 2555.4 ± 680.8 g), Apgar score (1, 5 min; 8.0 ± 0.7 vs. 7.7 ± 1.2, 8.9 ± 0.6 vs. 8.5 ± 1.8), UApH (7.28 ± 0.08 vs. 7.28 ± 0.06), NICU admission (26.9%, 7/26 vs. 41.2%, 7/17), and neonatal death (0%, 0%) between both groups. Conclusion: Laparoscopic adenomyomectomy may not increase obstetric complications, although attention must be paid to uterine rupture during pregnancy.

Increasing averaging beats improves the test accuracy on Holter-based late potentials in patients with myocardial infarction.

BACKGROUND: The prevalence of Holter-based late potentials (H-LPs) in cases of fatal cardiac events has increased. Although the noise level of H-LP is higher than that of conventional real-time late potential (LP) recording, a procedure to reduce the noise severity in H-LP by increasing the averaging beats has not been investigated. METHODS: We enrolled 104 patients with post-myocardial infarction (MI) and 86 control participants. Among the patients, 30 reported sustained ventricular tachycardia (VT), and the remaining 74 had unrecorded VT. H-LPs were measured twice in all groups to evaluate the efficacy of increasing the averaging beats for H-LPs. Thereafter, the average of LP was calculated at 250 (default setting), 300, 400, 500, 600, 700, and 800 beats. RESULTS: Across all three groups (MI-VT group, MI non-VT group, and control group), the noise levels significantly decreased in consonance with the increase in averaging beats. In the MI-VT group, the H-LP positive rate considerably increased with the increase in the averaging beats from 250 to 800 both at night and daytime. In the MI-VT group, the LP parameters significantly deteriorated, which led to a positive judgment corresponding to the increment of the averaged night and day beats. The H-LP positive rates were unchanged in the MI non-VT and control groups, while the LP parameters remained consistent, despite the increased averaging beats in the MI non-VT and control groups. CONCLUSION: Increasing the calculated averaging beats in H-LPs can improve the sensitivity of predicting fatal cardiac events in patients with MI.

Diurnal Variation in and Optimal Time to Measure Holter-Based Late Potentials to Predict Lethal Arrhythmia after Myocardial Infarction.

Background and Objectives: Holter-based late potentials (LPs) are useful for predicting lethal arrhythmias in organic cardiac diseases. Although Holter-based LPs exhibit diurnal variation, no studies have evaluated the optimal timing of LP measurement over 24 h for predicting lethal arrhythmia that leads to sudden cardiac death. Thus, this study aimed to validate the most effective timing for Holter-based LP testing and to explore factors influencing the diurnal variability in LP parameters. Materials and Methods: We retrospectively analyzed 126 patients with post-myocardial infarction (MI) status and 60 control participants who underwent high-resolution Holter electrocardiography. Among the 126 post-MI patients, 23 developed sustained ventricular tachycardia (VT) (the MI-VT group), while 103 did not (the MI-non-VT group) during the observation period. Holter-based LPs were measured at 0:00, 4:00, 8:00, 12:00, 16:00, and 20:00, and heart rate variability analysis was simultaneously performed to investigate factors influencing the diurnal variability in LP parameters. Results: Holter-based LP parameters showed diurnal variation with significant deterioration at night and improvement during the day. Assessment at the time with the longest duration of low-amplitude signals < 40 µV in the filtered QRS complex terminus (LAS40) gave the highest receiver operating characteristics curve (area under the curve, 0.659) and the highest odds ratio (3.75; 95% confidence interval, 1.45-9.71; p = 0.006) for predicting VT. In the multiple regression analysis, heart rate and noise were significant factors affecting the LP parameters in the MI-VT and control groups. In the non-VT group, the LP parameters were significantly influenced by noise and parasympathetic heart rate variability parameters, such as logpNN50. Conclusions: For Holter-based LP measurements, the test accuracy was higher when the LP was measured at the time of the highest or worst value of LAS40. Changes in autonomic nervous system activity, including heart rate, were factors influencing diurnal variability. Increased parasympathetic activity or bradycardia may exacerbate Holter-based LP parameters.

Anti-ß2-glycoprotein I/HLA-DR Antibody and Adverse Obstetric Outcomes.

Anti-ß2-glycoprotein I/HLA-DR (anti-ß2GPI/HLA-DR) antibody has been reported to be associated with antiphospholipid syndrome and recurrent pregnancy loss (RPL). We conducted a prospective multicenter cross-sectional study aimed at evaluating whether the anti-ß2GPI/HLA-DR antibody is associated with adverse obstetric outcomes and RPL. From 2019 to 2021, serum anti-ß2GPI/HLA-DR antibody levels (normal, <73.3 U) were measured in 462 women with RPL, 124 with fetal growth restriction (FGR), 138 with hypertensive disorders of pregnancy (HDP), 71 with preterm delivery before 34 gestational weeks (preterm delivery (PD) ≤ 34 GWs), and 488 control women who experienced normal delivery, by flow cytometry analysis. The adjusted odds ratios (aORs) of anti-ß2GPI/HLA-DR antibody positivity for adverse obstetric outcomes and RPL were evaluated on the basis of comparisons between the control and each patient group, using multivariable logistic regression analysis. The following were the positivity rates for the anti-ß2GPI/HLA-DR antibody in the patient and control groups: RPL, 16.9%; FGR, 15.3%; HDP, 17.4%; PD ≤ 34 GWs, 11.3%; and the control, 5.5%. It was demonstrated that anti-ß2GPI/HLA-DR antibody positivity was a significant risk factor for RPL (aOR, 3.3 [95% confidence interval {CI} 1.9-5.6], p < 0.001), FGR (2.7 [1.3-5.3], p < 0.01), and HDP (2.7 [1.4-5.3], p < 0.01) although not for PD ≤ 34 GWs. For the first time, our study demonstrated that the anti-ß2GPI/HLA-DR antibody is involved in the pathophysiology underlying FGR and HDP, as well as RPL.

Anti-ß2-glycoprotein I/HLA-DR antibody in infertility.

To evaluate whether anti-ß2-Glycoprotein I/HLA-DR (anti-ß2GPI/HLA-DR) antibody is associated with pathophysiology of infertility, 224 women with infertility were enrolled from July 2020 to December 2021 in this prospective study. The serum levels of anti-ß2GPI/HLA-DR antibody (normal < 73.3 U) were determined in 224 women with infertility. Backgrounds, causes and clinical factors were compared between women with and without anti-ß2GPI/HLA-DR antibody. Forty (17.9 %) of the 224 women tested positive for anti-ß2GPI/HLA-DR antibody. The prevalence of endometriosis was higher in women with anti-ß2GPI/HLA-DR antibody than in women without the antibody (32.5 %, 13/40 vs. 17.4 %, 32/184; P = 0.048). Logistic regression analyses revealed that, among clinical factors and diseases, endometriosis was associated with anti-ß2GPI/HLA-DR antibody positivity in infertile women (adjusted-odds ratio [OR] 3.01, 95 % confidence interval [CI] 1.30-6.99; P = 0.010). Twenty-three (15.5 %) of 148 women who underwent assisted reproductive technology (ART) tested positive for anti-ß2GPI/HLA-DR antibody. The prevalence of recurrent implantation failure (RIF) defined as three or more implantation failures following in vitro fertilization and embryo transfers was higher in women with ART who tested positive for the antibody (43.5 %, 10/23) than in women with ART who tested negative (20.8 %, 26/125; P = 0.032). Logistic regression analyses revealed that RIF was associated with anti-ß2GPI/HLA-DR antibody positivity in women with ART (adjusted-OR 2.92, 95 % CI 1.05-8.11; P = 0.040). Anti-ß2GPI/HLA-DR antibody may be associated with the pathophysiology of infertility, endometriosis and RIF; and can be a potential therapeutic target in infertility.