Nicotinamide mononucleotide (NMN) alleviates the poly(I:C)-induced inflammatory response in human primary cell cultures.

NMN is the direct precursor of nicotinamide adenine dinucleotide (NAD+) and is considered as a key factor for increasing NAD+ levels and mitochondrial activity in cells. In this study, based on transcriptome analysis, we showed that NMN alleviates the poly(I:C)-induced inflammatory response in cultures of two types of human primary cells, human pulmonary microvascular endothelial cells (HPMECs) and human coronary artery endothelial cells (HCAECs). Major inflammatory mediators, including IL6 and PARP family members, were grouped into coexpressed gene modules and significantly downregulated under NMN exposure in poly(I:C)-activated conditions in both cell types. The Bayesian network analysis of module hub genes predicted common genes, including eukaryotic translation initiation factor 4B (EIF4B), and distinct genes, such as platelet-derived growth factor binding molecules, in HCAECs, which potentially regulate the identified inflammation modules. These results suggest a robust regulatory mechanism by which NMN alleviates inflammatory pathway activation, which may open up the possibility of a new role for NMN replenishment in the treatment of chronic or acute inflammation.

Posterior reversible encephalopathy syndrome associated with mild COVID-19 infection in a 9-year-old child: A case report and literature review.

The neurologic complications associated with the coronavirus disease 2019 (COVID-19) is becoming more prevalent in children after the appearance of the Omicron strain. An association between COVID-19 and posterior reversible encephalopathy (PRES) has been consistently reported in adults, but little information is available in the pediatric age group. There are only few case reports of COVID-19-related PRES in children, and all of these patients were either on some type of immunomodulatory medications or whose general condition was severe. The present case, a 9-year-old Japanese boy, who had no fever but vomited several times from days 1-4 of a COVID-19 infection had an afebrile seizure on the 8th day of his illness. The patient had no history of hypertension, and had not previously been administered any immunosuppressive drugs before or during the period of his COVID-19 infection. On admission, his physical findings were unremarkable, except for a high blood pressure. The results obtained by brain computed tomography and magnetic resonance imaging were consistent with PRES. The patient recovered with no sequelae after treatment with antihypertensive drugs. Further investigations did not suggest any underlying disease that could have caused the transient hypertension. Although PRES is relatively rare in children, pediatricians should keep in mind that this syndrome can be complicated, even in children with mild COVID-19 infections.

Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex.

Astrocytes are one of the most abundant cell types in the mammalian brain. They play essential roles in synapse formation, maturation, and elimination. However, how astrocytes migrate into the gray matter to accomplish these processes is poorly understood. Here, we show that, by combinational analyses of in vitro and in vivo time-lapse observations and lineage traces, astrocyte progenitors move rapidly and irregularly within the developing cortex, which we call erratic migration. Astrocyte progenitors also adopt blood vessel-guided migration. These highly motile progenitors are generated in the restricted prenatal stages and differentiate into protoplasmic astrocytes in the gray matter, whereas postnatally generated progenitors do not move extensively and differentiate into fibrous astrocytes in the white matter. We found Cxcr4/7, and integrin ß1 regulate the blood vessel-guided migration, and their functional blocking disrupts their positioning. This study provides insight into astrocyte development and may contribute to understanding the pathogenesis caused by their defects.

Acrodysostosis and pseudohypoparathyroidism (PHP): adaptation of Japanese patients with a newly proposed classification and expanding the phenotypic spectrum of variants.

Objective: This study aimed to report on 15 Japanese patients with acrodysostosis and pseudohypoparathyroidism (PHP) and analyze them using the newly proposed classification of the EuroPHP network to determine whether this classification system is suitable for Japanese patients. Design: We divided the patients into three groups based on hormone resistance, the number of fingers with short metacarpals, the existence of cone-shaped epiphyses and gene defects. Methods: We carried out clinical, radiological and genetic evaluations of two patients in group A (iPPSD5), six patients in group B (iPPDS4) and seven patients in group C (iPPSD2). Results: Group A consisted of two siblings without hormone resistance who had the most severe bone and physical developmental delays. PDE4D gene defects were detected in both cases. Group B consisted of six patients who showed hormone resistance without hypocalcemia. Short metacarpal bones with corn-shaped epiphyses were observed in all patients. In two cases, PRKAR1A gene defects were detected; however, their clinical and radiological features were not identical. The facial dysmorphism and developmental delay were less severe and PRKAR1A gene defects were detected in case B-3. Severe facial dysmorphism and deformity of metacarpal bones were observed, but no gene defect was detected in case B-1. Group C consisted of seven patients with PHP1a, four of whom had maternally inherited heterozygous inactivating mutations in one of the GNAS genes. The clinical and radiological features of the patients in group C were not identical either. Conclusions: The newly proposed classification is suitable for Japanese patients; however, heterogeneities still existed within groups B and C.

Thermostability and catechol-O-methyltransferase inhibitory activity of acylated anthocyanins from purple yam.

The thermostability of purple yam was investigated to be used as natural colorants. In addition, the inhibitory properties of purple yam and its isolated anthocyanins toward human catechol-O-methyltransferase (COMT), a key neurotransmitter involved in Parkinson's disease and depression, were also investigated. The thermostability of purple yam was higher than that of the reference samples (purple sweet potato and purple potato). Quantitative HPLC analysis revealed that alatanin A (2) contributed to the thermostability of purple yam. Methanol extracts of purple yam exhibited the highest COMT inhibitory activity of the tested samples. Alatanin D (1) showed the highest inhibitory activity of the anthocyanins in purple yam (IC50 19 µM). This study revealed the thermostability and COMT inhibitory activity of purple yam and may lead to its use not only as a thermostable natural source of colorants, but also for the prevention and treatment of Parkinson's disease and depression.

Seven-day services in surgery and the "weekend effect" at a Japanese teaching hospital: a retrospective cohort study.

BACKGROUND: Hospitals deliver 24-h, 7-day care on a 5-day workweek model, as fewer resources are available on weekends. In prior studies, poorer outcomes have been observed with weekend admission or surgery. The purpose of this study was to investigate the effect of 7-day service at a hospital, including outpatient consultations, diagnostic examinations and elective surgeries, on the likelihood of the "weekend effect" in surgery. METHODS: This was a retrospective cohort study of patients who underwent surgery between April 2014 and October 2016 at an academic medical centre in Tokyo, Japan. The main outcome measure was 30-day in-hospital mortality from the index surgery. The characteristics of the participants were compared using the Mann-Whitney U test or the chi-squared test as appropriate. Logistic regression was used to test for differences in the mortality rate between the two groups, and propensity score adjustments were made. RESULTS: A total of 7442 surgeries were identified, of which, 1386 (19%) took place on the weekend. Of the 947 emergency surgeries, 25% (235) were performed on the weekend. The mortality following emergency weekday surgery was 21‰ (15/712), compared with 55‰ (13/235) following weekend surgery. Of the 6495 elective surgeries, 18% (1151) were performed on the weekend. The mortality following elective weekday surgery was 2.3‰ (12/5344), compared with 0.87‰ (1/1151) following weekend surgery. After adjustment, weekend surgeries were associated with an increased risk of death, especially in the emergency setting (emergency odds ratio: 2.7, 95% confidence interval: 1.2-6.5 vs. elective odds ratio: 0.4, 95% confidence interval: 0.05-3.2). CONCLUSIONS: Patients undergoing emergency surgery on the weekend had higher 30-day mortality, but showed no difference in elective surgery mortality. These findings have potential implications for health administrators and policy makers who may try to restructure the hospital workweek or consider weekend elective surgery.

Efficacy of sodium-glucose cotransporter 2 inhibitor with glucagon-like peptide-1 receptor agonist for the glycemic control of a patient with Prader-Willi syndrome: a case report.

Prader-Willi syndrome (PWS) is often related to severe obesity and diabetes mellitus (DM). Clinical findings suggesting the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists for glycemic control of DM in PWS have been recently increasing. However, there are only a few reports describing the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors for PWS. We present a diabetic female with PWS, whose glycemic control was deteriorated at the age of 19 but improved to a certain extent by introducing the GLP-1 analog liraglutide. At the age of 20, the SGLT2 inhibitor empagliflozin was administered. Subsequently, her HbA1c level and body weight markedly decreased. Improvement in both insulin resistance and secretion was observed during the subsequent six months. In addition to GLP-1 receptor agonists, SGLT2 inhibitors may be a potential approach for the management of DM in PWS, especially in young patients whose pancreatic insulin secretion capabilities are still preserved.

Noncontact Phased-Array Ultrasound Facilitates Acute Wound Healing in Mice.

BACKGROUND: The authors developed a noncontact low-frequency ultrasound device that delivers high-intensity mechanical force based on phased-array technology. It may aid wound healing because it is likely to be associated with lower risks of infection and heat-induced pain compared with conventional ultrasound methods. The authors hypothesized that the microdeformation it induces accelerates wound epithelialization. Its effects on key wound-healing processes (angiogenesis, collagen accumulation, and angiogenesis-related gene transcription) were also examined. METHODS: Immediately after wounding, bilateral acute wounds in C57BL/6J mice were noncontact low-frequency ultrasound- and sham-stimulated for 1 hour/day for 3 consecutive days (10 Hz/90.6 Pa). Wound closure (epithelialization) was recorded every 2 days as the percentage change in wound area relative to baseline. Wound tissue was procured on days 2, 5, 7, and 14 (five to six per time point) and subjected to histopathology with hematoxylin and eosin and Masson trichrome staining, CD31 immunohistochemistry, and quantitative polymerase-chain reaction analysis. RESULTS: Compared to sham-treated wounds, ultrasound/phased-array-treated wounds exhibited significantly accelerated epithelialization (65 ± 27 percent versus 30 ± 33 percent closure), angiogenesis (4.6 ± 1.7 percent versus 2.2 ± 1.0 percent CD31 area), and collagen deposition (44 ± 14 percent versus 28 ± 13 percent collagen density) on days 5, 2, and 5, respectively (all p < 0.05). The expression of Notch ligand delta-like 1 protein (Dll1) and Notch1, which participate in angiogenesis, was transiently enhanced by treatment on days 2 and 5, respectively. CONCLUSIONS: The authors' noncontact low-frequency ultrasound phased-array device improved the wound-healing rate. It was associated with increased early neovascularization that was followed by high levels of collagen-matrix production and epithelialization. The device may expand the mechanotherapeutic proangiogenesis field, thereby helping stimulate a revolution in infected wound care.

Distensibility and Gross Elasticity of the Skin at Various Body Sites and Association with Pathological Scarring: A Case Study.

Objective: Pathological scars, including hypertrophic scars and keloids, have a strong predilection for specific regions of the body. Such site specificity might reflect regional differences in skin properties. Greater knowledge about the characteristics of the skin at various body regions can promote the development of clinical approaches to skin incision and flap design and reduce the formation of cutaneous scars. It could also help elucidate the etiology of pathological scar development and progression. Thus, we measured the distensibility and gross elasticity of the skin at various body sites. Methods: Five healthy adult volunteers were enrolled. In each, the cutaneous viscoelasticity at 16 sites (forehead, superior eyelid, lower jaw, earlobe, deltoid, outside and medial side of the upper arm, palm, scapular region, anterior chest, upper abdomen, lateral abdomen, lower abdomen, lateral thigh, anterior lower leg, and planta) was examined using a Cutometer MPA 580® (Courage Khazaka electronic GmbH, Cologne, Germany). Results: The skin was particularly distensible at the medial side of the upper arm, followed by the earlobe, lower jaw, upper abdomen, lateral abdomen, lower abdomen, and superior eyelid. It was poorly distensible at the planta, followed by the anterior lower leg, palm, and forehead. The skin was poorly elastic at the earlobe, superior eyelid, planta, and palm and highly elastic at the lateral and upper abdomen, scapular region, and deltoid. Conclusions: Except for the earlobe, all regions with poorly distensible and hard skin are not prone to pathological scarring. This association between these skin properties and abnormal scarring could be useful for skin surgeons.

Developmental changes in the balance of glycolytic ATP production and oxidative phosphorylation in ventricular cells: A simulation study.

The developmental program of the heart requires accurate regulation to ensure continuous circulation and simultaneous cardiac morphogenesis, because any functional abnormalities may progress to congenital heart malformation. Notably, energy metabolism in fetal ventricular cells is regulated in a manner that differs from adult ventricular cells: fetal cardiomyocytes generally have immature mitochondria and fetal ventricular cells show greater dependence on glycolytic ATP production. However, although various characteristics of energy metabolism in fetal ventricular cells have been reported, to our knowledge, a quantitative description of the contributions of these factors to fetal ventricular cell functions has not yet been established. Here, we constructed a mathematical model to integrate various characteristics of fetal ventricular cells and predicted the contribution of each characteristic to the maintenance of intracellular ATP concentration and sarcomere contraction under anoxic conditions. Our simulation results demonstrated that higher glycogen content, higher hexokinase activity, and lower creatine concentration helped prolong the time for which ventricular cell contraction was maintained under anoxic conditions. The integrated model also enabled us to quantitatively assess the contributions of factors related to energy metabolism in ventricular cells. Because fetal cardiomyocytes exhibit similar energy metabolic profiles to stem cell-derived cardiomyocytes and those in the failing heart, an improved understanding of these fetal ventricular cells will contribute to a better comprehension of the processes in stem cell-derived cardiomyocytes or under pathological conditions.

Platelet-derived Factor Concentrates with Hyaluronic Acid Scaffolds for Treatment of Deep Burn Wounds.

A deep burn wound is a critical condition that generally necessitates vascularized tissue coverage. We performed the injection of platelet-derived factor concentrates combined with non-cross-linked hyaluronic acid scaffolds for 2 patients with critical burn wounds with bone and tendon exposure and achieved successful healing. Hyaluronic acid was considered to have served as a controlled-release carrier of platelet-derived factors, being clinically effective for the treatment of deep burn wounds.

The Stainless Steel Wire-based Method of Sogawa Effectively Corrects Severe Ingrown Nails.

Ingrown nails are defined as inflammation of the lateral nail fold that is caused by penetration by the nail plate and associates with pain and/or infection. The pain associated with ingrown nail hampers walking, raises the risk of falls, and decreases the quality of life. The Sogawa method is a novel conservative medical treatment for ingrown nails that is based on stainless steel wire. It was first reported in 2012 by Sogawa, and we have found that it is very effective for ingrown nails, especially in difficult cases. Here, we show the beneficial effects of the Sogawa method in 2 extremely difficult cases where ingrown nails had recurred after partial nail ablation. We found the Sogawa method to be a quick and easy technique that rapidly improves the pain associated with ingrown nails and later produces properly configured nails. Our experience suggests that it is suitable for severe ingrown nails, such as too short ingrown nails and ingrown nails that have strong inflammation and granulation tissue formation. This is significant because it is difficult to treat such cases with conventional conservative methods, which means that the only remaining therapeutic option is surgery. Thus, the Sogawa method is a novel and highly effective ingrown nail treatment that obviates the need for invasive surgical treatment.

Foot loading is different in people with and without pincer nails: a case control study.

BACKGROUND: Recent studies suggest that pincer nails are caused by lack of upward mechanical forces on the toe pad. However, clinically significant pincer nails are also often observed among healthy walkers. It was hypothesized that in these cases, the affected toes do not receive adequate physical stimulation from walking and loading. To test this, the gait characteristics of pincer nail cases were assessed by measuring plantar pressure during walking. METHODS: In total, 12 bilateral pincer nail cases (24 affected feet) and 12 age- and sex-controlled healthy control subjects (24 ft) were enrolled in this prospective case-control study. Plantar pressure during free ambulation in both the barefoot and shod state was assessed using a digital pressure-plate system named S-Plate platform (Medicapteurs Co. France). First toe pressure and the frequencies of peak pressure in the first toe, metatarsal head, or other foot areas were calculated. RESULTS: In both the barefoot and shod state, the pincer nail group had significantly lower pressure on the first toe than the control group. In both the barefoot and shod state, the peak pressure area was mostly the metatarsal head area in the pincer nail group, whereas it was mostly the first toe area in the control group. Binomial logistic regression analysis revealed that peak pressure area was a significant risk factor for pincer nail development. CONCLUSION: Walking behavior appears to contribute to pincer nail development. Pincer nails of walkers could be treated by correcting the walking behaviour so that more pressure is placed on the toe pad.

A novel nonsurgical treatment for pincer nail that involves mechanical force control.

We hypothesize that nails have an automatic curvature feature and that their flat shape is maintained by the daily upward mechanical forces from the finger/toe pad. Thus, nail deformities, such as pincer nail, spoon nail, and koilonychias, may be caused by an imbalance between these forces and can be treated by controlling these forces. Here, we report the case of a 55-year-old man whose severe pincer nail was effectively treated by thinning the nail, which reduced the automatic curvature force. This is the first report to show that pincer nail can be treated by a nonsurgical method that reduces the automatic curvature force, thus obviating the need for surgery. This supports the notion that mechanical stimulus-based treatments have high therapeutic potential for nail deformities.

Influence of oxygen on wound healing dynamics in healing-impaired diabetic mice.

A previous experiment using an in vivo mouse model has proved that hypoxia increased angiogenesis during wound healing. It was hypothesised that one of the mechanisms for wound healing impairment in diabetes includes insufficient angiogenic ability in response to hypoxia. The current study aims to investigate the influence of hypoxia on wound healing in diabetic mice. Oxygen-impermeable (hypoxic group) and -permeable membranes (normoxic group) were used to control topical oxygen tension. Membranes were applied to symmetrical excisional wounds on diabetic mice. Wound area, granulated tissue thickness, and vascular density were analyzed. As results, a decrease in wound size on day 7 was observed in the normoxic group (20.7 ± 3.64%) compared with the hypoxic group (34.1 ± 4.98%). The normoxic group also showed significantly thicker granulated tissue than the hypoxic group (225.7 ± 54.7 vs 128.7 ± 42.4 µm). There was no significant difference in mean vascular density between normoxic and hypoxic groups (0.046 ± 0.022 vs 0.038 ± 0.017 mm(2)/mm(2), p = 0.80). Contrary to healthy mice, diabetic mice have shown no enhancement of angiogenesis in hypoxic condition. The findings illustrate that neovascularisation in response to hypoxia is diminished in diabetic wounds.

Involvement of nitric oxide in the wound bed microcirculatory change during negative pressure wound therapy.

This study investigated the role of nitric oxide (NO) in the mechanism of blood flow increase in the wound bed during negative pressure wound therapy (NPWT). We developed an improved experimental model that allowed visualisation of the wound bed microcirculation under NPWT. Wounds were created on the mouse ear, taking care to preserve the subdermal vascular plexus, because the wound bed microcirculation was visualised using an intravital microscope system. We investigated whether application of a NO synthase inhibitor (N(G) -nitro-l-arginine methyl ester: L-NAME) might diminish the effect of the NPWT in increasing the wound blood flow. The experimental animals were divided into a negative pressure group (negative pressure of -125 mmHg applied to the wound for 5 minutes; n = 8), and a negative pressure plus L-NAME group (administration of L-NAME prior to application of the negative pressure; n = 8). In the negative pressure group, significant increase of blood flow was observed at 1 minute after the negative pressure application, which was sustained until 5 minutes. On the contrary, in the negative pressure plus L-NAME group, no significant changes were observed throughout the period of observation. These findings suggest that NO synthesis is involved in the wound bed microcirculatory change induced by NPWT.