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Nicotinamide adenine dinucleotide (NAD + ) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD + decreases with age in certain tissues, and age-related NAD + depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD + precursor significantly elevates NAD + levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD + in animal studies, the efficacy of NAD + precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD + precursor treatment efficiently increases NAD + levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD + precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD + intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD + metabolism. Also, the reduced form of NAD + precursor shows their potential to raise NAD + , though preclinical studies have yet to discover their efficacy. This review sheds light on NAD + therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD + metabolism., Competing Interests: Declaration of competing interest No financial and commercial conflict of interest was disclosed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD + biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD + concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD + concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: This study aims to elucidate the trajectory of quality of life (QoL) over a two-year period after radiotherapy and/or chemotherapy for head and neck cancer (HNC), addressing the gap in long-term QoL information., Methods: Employing a prospective longitudinal observational design, we tracked 58 HNC patients who underwent radiotherapy and/or chemotherapy, analyzing their QoL using Short-Form 36-Item Health Survey version 2 (SF36v2), the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30), and the European Organization for Research and Treatment of Cancer quality of life head and neck-35 (EORTC-QLQ-H&N35) questionnaires for two years post-discharge. The data underwent repeated measures analysis of variance., Results: Over the two-year follow-up, 10 patients (17.2%) succumbed, and 8 (13.8%) dropped out. SF36v2 physical and role-social component summary scores declined during treatment, requiring 1-2 years for recovery. The mental component summary score remained stable. EORTC-QLQ-30 revealed global health status recovery within one year post-discharge. EORTC-QLQ-H&N35 items like "swallowing," "senses problems," "trouble with social eating," "dry mouth," "sticky saliva," "coughing," and "felt ill" worsened pre-discharge. "Trouble with social contact" improved within a year, while "pain," "swallowing," "senses problems," "trouble with social eating," and "coughing" improved within two years. "Dry mouth" and "sticky saliva" persisted throughout the two-year follow-up, common symptoms of HNC and treatment side effects., Conclusions: Recovery of specific QoL aspects in HNC patients treated with radiotherapy and/or chemotherapy may require up to two years. Prolonged monitoring and management of oral symptoms could enhance QoL. Future research should extend follow-up beyond two years for comprehensive interventions enhancing patient QoL., (© 2023 The Author(s).)

Malaria is an infectious disease caused by Plasmodium parasites and has high mortality rates, especially among children in African and Southeast Asian countries. Patients with hemolytic anemia are suggested to adapt protective measures against malarial infection. Nicotinamide adenine dinucleotide (NAD + ) is a crucial cofactor associated with numerous biological processes that maintain homeostasis in all living organisms. In a previous study, we had demonstrated that the deficiency of nicotinamide mononucleotide adenylyltransferase 3 (Nmnat3), an enzyme catalyzing NAD + synthesis, causes hemolytic anemia accompanied by a drastic decline in the NAD + levels in the erythrocytes. It is well known that hemolytic anemia is linked to a reduced risk of malarial infections. In the present study, we investigated whether hemolytic anemia caused by Nmnat3 deficiency is beneficial against malarial infections. We found that Nmnat3 deficiency exacerbated malarial infection and subsequently caused death. Moreover, we demonstrated that the NAD +  levels in malaria-infected Nmnat3 red blood cells significantly increased and the glycolytic flow was largely enhanced to support the rapid growth of malarial parasites. Our results revealed that hemolytic anemia induced by the deletion of Nmnat3 was harmful rather than protective against malaria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ), a biological molecule integral to redox reactions involved in multiple cellular processes, has the potential to treat nonalcoholic fatty liver diseases (NAFLDs) and nonalcoholic steatohepatitis (NASH). Nicotinamide mononucleotide adenylyltransferase (Nmnat1), one of the NAD + biosynthesizing enzymes, plays a central role in all NAD + metabolic pathways and it is vital to embryonic development. However, the function of Nmnat1 in metabolic pathology and, specifically, in the development and progression of NAFLD and NASH remains unexplored. First, we generated hepatic Nmnat1 knockout (H-Nmnat1 -/- ) mice to investigate the physiological function of Nmnat1 and found that NAD + levels were significantly lower in H-Nmnat1 -/- mice than control mice. However, H-Nmnat1 -/- mice appeared normal with comparable metabolic activity. Next, we used three different diet-induced NASH models to assess the pathophysiological role of Nmant1 in metabolic disorders and discovered that hepatic loos of Nmnat1 decreased 35%-40% of total NAD + in an obese state. Nevertheless, our analysis of phenotypic variations found comparable body composition, gene expression, and liver histology in all NASH models in H-Nmnat1 -/- mice. We also found that aged H-Nmnat1 -/- mice exhibited comparable liver phenotypes with control mice. These findings suggest that Nmnat1 has a redundancy to the pathophysiology of obesity-induced hepatic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Oropharyngeal swallowing is centrally mediated by a swallowing central pattern generator (Sw-CPG) in the medulla oblongata. The activity of the Sw-CPG depends on the sensory inputs determined by physical and chemical bolus properties. Here we investigate the sensory-motor integration during swallowing arising from different sensory sources. To do so we electrically stimulated the superior laryngeal nerve and we triggered swallowing with oral injections of distilled water or capsaicin solution and extracellularly recorded from swallowing interneurons in arterially perfused brainstem preparations of rats. We recorded the activities of 40 neurons, while monitoring the motor activities of the phrenic, vagal and hypoglossal nerves. Eighteen neurons responded to electrical stimulation of the ipsilateral superior laryngeal nerve, and 6 neurons were excited by oral fluid injection, while 16 non-respiratory neurons did not receive afferent inputs to either electrical or physiological stimuli. The cellular activities displayed by swallowing interneurons during electrical and physiological stimulation of pharyngeal and laryngeal afferent input reveal complex adaptations of the timing of firing patterns and frequencies. The modulation of neuronal activity is likely to contribute to the coordination of efficient bolus transfer during the pharyngeal stage of swallowing., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Impairment of pancreatic β cells is a principal driver of the development of diabetes. Restoring normal insulin release from the β cells depends on the ATP produced by the intracellular mitochondria. In maintaining mitochondrial function, the tumor suppressor p53 has emerged as a novel regulator of metabolic homeostasis and participates in adaptations to nutritional changes. In this study, we used orotic acid, an intermediate in the pathway for de novo synthesis of the pyrimidine nucleotide, to reduce genotoxicity. Administration of orotic acid reduced p53 activation of MIN6 β cells and subsequently reduced β cell death in the db/db mouse. Orotic acid intake helped to maintain the islet size, number of β cells, and protected insulin secretion in the db/db mouse. In conclusion, orotic acid treatment maintained β cell function and reduced cell death, and may therefore, be a future therapeutic strategy for the prevention and treatment of diabetes., Competing Interests: Declaration of competing interest All authors have no conflict of interest about the manuscript., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment., Design: Multi-institutional prospective single-arm observational study., Setting and Participants: Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan., Methods: The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA)., Results: Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement., Conclusions and Implications: HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: We devised a new surgical alternative to the conventional nasoseptal flap, a pedicled posterior septal-nasal floor flap that we named the Kegon flap. We evaluated the effectiveness of this flap for skull base reconstruction in patients with high-flow cerebrospinal fluid (CSF) leakage after sellar/parasellar tumor resection., Methods: The Kegon flap with a novel rescue flap was designed to preserve blood flow and mucosa anterior to the nasal septum and to avoid flap damage during surgery. We retrospectively evaluated postoperative flap perfusion with T1-weighted contrast-enhanced magnetic resonance imaging and characterized complications and wound healing in 5 patients who experienced high-flow CSF leakage after sellar/parasellar tumor resection requiring reconstruction., Results: Postoperative T1-weighted contrast-enhanced magnetic resonance imaging demonstrated good flap perfusion in all patients. The area reconstructed with the Kegon flap healed within the first month following surgery. No postoperative CSF leakage or nasal hemorrhage was observed. There was no perforation of the anterior nasal septum after surgery. The mucosal defect had completely epithelialized in all patients by 3 months after surgery. There were no instances of prolonged nasal crusting or any subjective decrease in olfactory function 3 months after surgery., Conclusions: The use of a Kegon flap with a novel rescue flap was effective and helped preserve nasal structure and function in patients undergoing skull base reconstruction after sellar/parasellar tumor resection associated with high-flow CSF leakage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Drug-induced interstitial lung disease (DI-IP) is one of the most serious adverse reactions associated with the use of anticancer drugs. DI-IP prevalence among molecular-targeting drugs and immune checkpoint inhibitors (ICIs) is relatively high in Japanese patients. To assess the risk of cetuximab and/or nivolumab-related IP is important., Patients and Methods: The medical records of 138 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with cetuximab-containing chemotherapy and/or nivolumab monotherapy were retrospectively reviewed., Results: The incidence of DI-IP with R/M HNSCC was 7.2%. DI-IP occurred more frequently in patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy than in patients with other regimens. However, tumor suppression was detected in all patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy, and two achieved a complete response., Conclusions: Although patients treated with cetuximab-containing chemotherapy following nivolumab showed dramatic efficacy, careful monitoring should be recommended., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: As the base of the tongue (BOT) plays essential roles in speech and swallowing, surgical resection of BOT cancer is typically avoided. Moreover, standard reconstructive procedures for larynx-preserving BOT defects have not yet been established. We performed immediate flap reconstruction after wide resection of BOT cancer with laryngeal preservation. Herein, the functional and oncological results of our strategy were analysed., Methods: We retrospectively evaluated patients who underwent extended BOT resection (including the oral tongue, upper/lateral oropharyngeal wall, epiglottis and false vocal cord) with laryngeal preservation between April 2006 and April 2016. We classified defects involving the oral tongue or upper/lateral oropharyngeal wall as the lateral extension type and those involving the epiglottis or false vocal cord as the laryngeal extension type. Lateral extension-type defects were closed primarily and filled with a deepithelialised skin or muscle flap. Laryngeal extension-type defects were reconstructed using a bulky skin flap plus hyo-thyroid-pexy to create a neo-epiglottis. Postoperative functional and oncologic outcomes were assessed., Results: We enrolled 18 patients with extended BOT defects. Of them, 11 had a history of irradiation. The tracheal cannula was removed in all cases, although laryngeal extension defects were associated with a longer duration to removal. All patients achieved complete oral intake and retained intelligible speech, with preservation of laryngeal function. There was no local recurrence, and the 5-year overall survival was 88.9%., Conclusions: Following wide BOT resection, reconstruction with laryngeal preservation is feasible even in cases involving irradiated tumours with laryngeal extension., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Immune-related adverse events (irAEs) have been shown to be associated with higher antitumor responses and a clinical benefit in non-small cell lung carcinoma, renal cell carcinoma, and melanoma patients. However, little is known regarding the association between irAEs and the clinical effect of nivolumab for recurrent/metastatic head and neck squamous cell carcinoma (R/MHNSCC)., Materials and Methods: We evaluated 108 patients treated with nivolumab for R/MHNSCC at 2 participating institutions. IrAEs were identified and profiled. We analyzed the association of each immune-related adverse effect with the clinical outcome of the patients., Results: Among 108 patients, the objective response rate (ORR) was 29.6% (32/108 patients), and the disease control rate (DCR) was 50.0% (54/108 patients). IrAEs were observed in 41 patients (38.0%). Patients with irAEs had a significantly higher ORR and DCR than those without irAEs (46.3% vs. 19.4%, P = 0.004 and 75.6% vs. 34.3%, P < 0.001, respectively). The median progression-free and overall survival rates in patients with irAEs were significantly longer than in those without irAEs., Conclusions: There was a significant relationship between irAEs and efficacy in R/MHNSCC patients treated with nivolumab. Our results indicate that the development of irAEs may aid in the earlier prediction of anticancer effects in patients with recurrent or metastatic HNSCC during nivolumab monotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial in-terests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: A profound understanding of the relationship between the deep cervical fasciae and the skull base is essential for skull base surgery. To our knowledge, there has been little research on the relationship between the deep cervical fasciae and inferior surface of the skull base; thus, this study aims to examine the fascial network of the skull base., Methods: Two cadaveric heads are dissected to reveal the fascial network of the skull base and 19 sides of cadaveric heads were used to reveal an anatomical variant of the pterygospinous and pterygoalar ligaments/muscles., Results: The interpterygoid fascia is attached to the skull base along the sphenopetrosal fissure and tympanosquamous suture. The tensor vascular styloid fascia extends from the inferior border of the tensor veli palatini and covers the tympanic bone and styloid apparatus laterally. The pharyngobasilar fascia attaches to the pharyngeal tubercle on the inferior surface of the basilar part of the occipital bone and petro-occipital synchondrosis. In the middle of the clivus, we found thick fibrocartilaginous tissue and the prevertebral fascia fused to this area. Fascia of the longus capitis, the tensor-vascular styloid fascia, and stylopharyngeal fascia extend laterally and form the complex fascial network around the internal jugular vein and the internal carotid artery. The carotid sheath attaches anteriorly to the vaginal process and posteriorly to the fibrocartilaginous tissue around the jugular foramen and carotid canal., Conclusions: This study comprehensively exposes the fascial network of the skull base. Our cadaveric dissection findings support those from previous imaging-anatomical studies. Precise knowledge of these fascial layers is essential for accurate diagnosis and understanding the spread of disease, as well as helping skull base surgeons safely perform challenging procedures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In many cases in which bifrontal craniotomy is performed, the frontal sinus is opened, and postoperative complications occur. Various methods to close the frontal sinus have been reported. However, all these methods require skill to perform and take time. The aim of this study was to report results obtained with closure of the frontal sinus using polymethyl methacrylate, which is a simpler method., Methods: From December 2008 to June 2018, 122 patients with a ruptured anterior communicating aneurysm were transported to the authors' facility, and 52 patients consecutively underwent bifrontal craniotomy with opening of the frontal sinuses, which were then filled with polymethyl methacrylate., Results: Mean follow-up period was 21.8 months; the longest follow-up was 116 months. No cerebrospinal fluid leakage or other complications were observed., Conclusions: The method of filling the frontal sinus with polymethyl methacrylate reported in this study was safe and had no complications. This method should be considered as a method of frontal sinus closure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Serine is a nonessential amino acid and plays an important role in cellular metabolism. In mammalian serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH) is considered a rate-limiting enzyme and is required for normal development. Although the biological functions of PHGHD in the nervous system have been intensively studied, its function in adipose tissue is unknown. In this study, we found that PHGDH is abundantly expressed in mature adipocytes of white adipose tissue. We generated an adipocyte-specific PHGDH knockout mouse (PHGDH FKO) and used it to investigate the role of serine biosynthesis in adipose tissues. Although PHGDH FKO mice had no apparent defects in adipose tissue development, these mice ameliorated glucose intolerance upon diet-induced obesity. Additionally, we found that the serine levels increase drastically in the adipose tissues of obese wild type mice, whereas no significant rise was observed in PHGDH FKO mice. Furthermore, wild type mice fed a serine-deficient diet also exhibited better glucose tolerance. These results suggest that PHGDH-mediated serine biosynthesis has important roles in adipose tissue glucose metabolism and could be a therapeutic target for diabetes in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia-thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The endoscopic endonasal approach to the anatomically complex lateral skull base presents technical challenges. The use of the eustachian tube as a landmark to identify the petrous internal carotid artery has recently been reported, and this study aims to define the anatomic relationship between the eustachian tube and its surrounding structures using cadaveric dissection and radiologic analysis., Methods: To clarify the relationship of the eustachian tube with its surrounding structures, we performed endoscopic and microscopic dissection of 4 adult cadaveric heads and analyzed computed topography scans from 20 patients., Results: The eustachian tube is divided into the osseous and cartilaginous parts. The cartilaginous part can be further subdivided into the posterolateral, middle, and anteromedial parts, based on its relationship to the skull base. The eustachian tube is closely related to the pterygoid process of the sphenoid bone, the foramen lacerum, and the petrosal apex and is directed away from the oblique sagittal plane almost parallel to the vidian canal at 12.2° ± 6.2° (mean ± standard deviation). The relationship between the course of the vidian canal and the eustachian tube can aid the estimation of the anatomic course of the horizontal segment of the petrous carotid artery., Conclusions: The eustachian tube is a useful landmark for predicting the course of the internal carotid artery when accessing the lateral skull base regions via an endonasal route. A profound understanding of the relationship between the eustachian tube and the surrounding skull base structures is important for endoscopic endonasal skull base surgeries., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Spinal intradural arachnoid cysts are rare in the pediatric population. We present a rare case of intradural spinal arachnoid cysts that spontaneously and repeatedly disappeared and reoccurred., Case Description: A 2-year-and-8-months-old boy presenting with lower extremity weakness was found to have spinal intradural arachnoid cysts in cervical and thoracolumbar regions at separate times. Although spontaneous disappearance of both lesions was observed, surgical treatment was finally performed for the symptomatic recurrent thoracolumbar lesion., Conclusions: To the best of our knowledge, this is the first report of spontaneously disappearing and recurring spinal arachnoid cysts., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of 1 in every 3000 births. Numerous studies have focused on the main function of NF1 as a tumor suppressor, whereas few have examined the cerebrovascular abnormalities observed in patients with NF1. It is worth noting that intracranial aneurysms are uncommon in this condition., Case Description: We report a case of NF1 with a dissection of the distal segment of the superior cerebellar artery. A 36-year-old woman presented with a distal superior cerebellar artery (SCA) dissection causing subarachnoid hemorrhage. Subsequently, because of the rich collateral blood flow distal to the dissection, N-butyl cyanoacrylate (NBCA) glue embolization was unsuccessful. Therefore, direct trapping of the artery was necessary. The patient was discharged after an uneventful postoperative period, and has remained without complications., Conclusions: In the treatment of subarachnoid hemorrhage because of a distal SCA dissection in patients with NF1, NBCA glue embolization may be a safer option than microsurgery or coil embolization, in the acute phase, considering the possible vulnerability of the vessel wall, accessibility, morphology of the lesions, and the risk of developing unpredictable infarcts in the case of parent artery occlusion. However, regular reevaluation of the blood flow is necessary to monitor recurrence, given the rich collateral circulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Ventriculostomy from Paine's point is an effective technique to ensure that the brain is relaxed for aneurysm surgery. This study aimed to use Paine's point for other neurosurgical procedures (except for those that require a pterional approach) by delineation of surface landmarks for identification of Paine's point on the cranium and scalp., Methods: Based on the anatomical knowledge and examination of 3-dimensional computed tomography images of skull, we determined novel surface landmarks to identify Paine's point on the cranium and scalp. The new method was used in patients with intraventricular hemorrhage and aneurysmal subarachnoid hemorrhage caused by ruptured aneurysm of the anterior communicating artery., Results: The puncture point was determined at a point located 2.5 cm superior to the supraorbital margin on linea temporalis on the skull and 2.5 cm superior to the eyebrow along the anterior edge of temporal muscle on the skin. Ventriculostomy was performed from Paine's point in patients with intraventricular hemorrhage or aneurysmal subarachnoid hemorrhage who underwent aneurysm surgery via an interhemispheric approach. No adverse events were observed in any of the patients., Conclusions: By accurate surface marking on skull and skin, the use of Paine's point for ventriculostomy performed via an interhemispheric approach or for simple burr-hole surgery was found to be safe and reliable., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: To improve prognosis of pancreatic cancer (PC) patients, the discovery of more reliable biomarkers for the early detection is desired., Methods: Blood samples were collected by 2 independent groups. The 1st set was included 55 early PC and 58 healthy volunteers (HV), and the 2nd set was included 16 PC and 16HV. The 16 targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry together with their corresponding stable isotopes. In the 1st set, the levels of these metabolites were evaluated, and diagnostic models were constructed via multivariate logistic regression analysis, leading to validation using the 2nd set., Results: In the 1st set, model X consisting of 4 candidates based on our previous report possessed higher sensitivity (74.1%) than carbohydrate antigen 19-9 (CA19-9). Model Y, consisting of 2 metabolites newly selected from 16 metabolites via stepwise method possessed higher sensitivity (70.4%) than CA19-9. Furthermore, combining model Y with CA19-9 increased its sensitivity (90.7%) and specificity (89.5%). In the 2nd set, combining model Y with CA19-9 displayed high sensitivity (81.3%) and specificity (93.8%). In particular, it displayed very high sensitivity (100%) for resectable PC., Conclusions: Quantitative analysis confirmed that metabolomics-based diagnostic methods are useful for detecting PC early., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Serine racemase (SR) catalyzes the production of d-serine, a co-agonist of the N-methyl-d-aspartate receptor (NMDAR). A previous report shows the contribution of SR in the NMDAR-mediated neuronal cell death process., Methods and Results: To analyze the intrinsic role of SR in the cell death process, we established the epithelial human embryonic kidney 293T (HEK293T) cell lines expressing wild-type SR (SR-WT), catalytically inactive mutant SR (SR-K56G), and catalytically hyperactive mutant SR (SR-Q155D). To these cell lines, staurosporine (STS), which induces apoptosis, was introduced. The cells expressing SR-WT and SR-Q155D showed resistance to STS-induced apoptosis, compared with nontransfected HEK293T cells and cells expressing SR-K56G. The SR-WT cells also showed a significant higher viability than the SR-QD cells. Furthermore, we detected elevated phosphorylation levels of Bcl-2 at serine-70 and Akt at serine-473 and threonine-308, which are related to cell survival, in the cells expressing SR-WT and SR-Q155D. From the results of metabolite analysis, we found elevated levels of acetyl CoA and ATP in cells expressing SR-WT., Conclusion: Because SR has two enzymatic activities, namely, racemization and α, β-elimination, and SR-Q155D shows enhanced racemization and reduced α, β-elimination activities, we concluded that the racemization reaction catalyzed by SR may have a more protective role against apoptosis than the α, β-elimination reaction. Moreover, both of these activities are important for maximal survival and elevated levels of acetyl CoA and ATP., General Significance: Our findings reveal the NMDAR-independent roles of SR in metabolism and cell survival., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Upon initial evaluation in the emergency department (ED), it is often difficult to differentiate between comatose patients resuscitated following acute coronary syndrome (ACS)-associated and subarachnoid hemorrhage (SAH)-associated out-of-hospital cardiac arrest (OHCA). We assessed the clinical differences between resuscitated comatose ACS-OHCA and SAH-OHCA patients during initial evaluation in the ED., Methods: Data of 1259 consecutive OHCA patients were analyzed retrospectively. Of these, 23 resuscitated comatose ACS-OHCA patients and 20 resuscitated comatose SAH-OHCA patients were included in the final analysis. Clinical data obtained during initial evaluation in the ED were compared between groups., Results: Pulseless electrical activity (PEA) or asystole as the initial cardiac rhythm, female gender, and preserved left ventricular ejection fraction (≥50%) on the echocardiogram were significantly more common in the SAH-OHCA group (p<0.05 each). Although ST-T abnormalities suggesting myocardial damage (ST elevation and/or ST depression) were noted in most patients in both groups via 12-lead electrocardiogram (95%, ACS-OHCA group; 85%, SAH-OHCA group, p=0.50), reciprocal ST depression was significantly more often absent in the SAH-OHCA group (p=0.025). Initial PEA/asystole and presence of 1 other factor was sufficient to differentiate SAH-OHCA patients from ACS-OHCA patients (100% sensitivity, 91% specificity, 95% accuracy)., Conclusions: Initial ED evaluation is sufficient to differentiate between comatose ACS-OHCA and SAH-OHCA patients prior to further diagnostic work-up (e.g. emergent coronary angiography and head computed tomography)., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR)., Methods: We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence., Results: Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan., Conclusion: ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The long-term survival of vasospastic angina (VSA) patients is generally good, so long as they remain on calcium channel blockers (CCBs) and avoid smoking. However, the pathogenesis, appropriate treatments, and prognosis of VSA associated with cardiac arrest remain unclear. This study aimed to elucidate the clinical features and long-term outcomes of patients with VSA associated with cardiac arrest., Methods and Results: Eighteen consecutive patients with VSA associated with cardiac arrest [13 patients resuscitated after out-of-hospital cardiac arrest (OHCA) and 5 resuscitated after in-hospital-cardiac arrest] were retrospectively analyzed. Sixteen of the eighteen patients were smokers. None had other cardiac diseases possibly causing cardiac arrest. Although 1 patient resuscitated after OHCA later died of cerebral hypoxia, the remaining 17 were discharged without complications. One patient died of cancer 50 months after resuscitation. The other 16 patients are still alive and none have shown ventricular arrhythmias, syncope, or cardiac arrest during a mean follow-up of 67 months. All are treated with long-acting CCBs/nitrates and successfully quit smoking. Six patients received implantable cardioverter defibrillators (ICD). However, none demonstrated any ventricular arrhythmias and appropriate ICD actuation was achieved., Conclusion: Appropriate medical treatment can achieve favorable long-term outcomes even for patients with VSA associated with cardiac arrest., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We have developed a new methodology that determines protein structures using small-angle X-ray scattering (SAXS) data. The current bottlenecks in determining the protein structures require a new strategy using the simple design of an experiment, and SAXS is suitable for this purpose in spite of its low information content. First we demonstrated that SAXS constraints work additively to NMR-derived information in calculating structures. Next, structure calculations for nine proteins taking different folds were performed using the SAXS constraints combined with the NMR-derived distance restraints for local geometry such as secondary structures or those for tertiary structure. The results show that the SAXS constraints complemented the tertiary-structural information for all the proteins, and that accuracy of the structures thus obtained with SAXS constraints and local geometrical restraints ranged from 1.85 to 4.33Å. Based on these results, we were able to construct a coarse-grained protein model at amino acid residue resolution., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Cilostazol is a phosphodiesterase (PDE)3 inhibitor used to treat peripheral arterial disease with intermittent claudication, as there is clinical evidence that it improves treadmill exercise capacity. However, details of the mechanism underlying this enhanced walking capacity remain to be elucidated., Methods: Based on the hypothesis that PDE3 inhibitors improve peripheral microcirculation in the hindlimbs via vascular smooth muscle relaxation and antiplatelet effects, we examined the effects of a more potent and selective PDE3 inhibitor, K-134, in rat models of peripheral arterial disease (PAD)., Results: In a hindlimb ischemia model established by bilateral femoral artery occlusion, oral administration of K-134 for 27 days significantly increased blood flow in hindlimb skeletal muscle after exercise induced by electrical stimulation of the sciatic nerve. Moreover, K-134 enlarged the luminal area of intramuscular arteries and prevented rarefaction of capillary density in the gastrocnemius muscle. These effects were observed without pre-administration on the day following the last administration, suggesting that vasodilatory, antiplatelet and angiogenic activities of K-134 were indirectly responsible for the long-term beneficial effects. In fact, K-134 dose-dependently induced relaxation of rat femoral arteries in vitro, and inhibited rat platelet aggregation ex vivo. Interestingly, in a laurate-induced peripheral vascular injury model, oral administration of K-134 for 6 days prevented progression of hindlimb necrosis., Conclusion: These findings suggest that the beneficial effects of PDE3 inhibitors on walking capacity are due to increased hindlimb skeletal muscle blood flow via intramuscular artery enlargement, and that K-134 is a promising drug for PAD associated with platelet hyperaggregability., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Protein tyrosine kinase plays a central role in the proliferation and differentiation of various types of cells. One of these protein kinases, Tyk2, a member of the Jak family kinases, is known to play important roles in receptor signal transduction by interferons, interleukins, growth factors, and other hormones. In the present study, we investigated Tyk2 expression and its role in the growth and invasiveness of human prostate cancer cells. We used a small interfering RNA targeting Tyk2 and an inhibitor of Tyk2, tyrphostin A1, to suppress the expression and signaling of Tyk2 in prostate cancer cells. We detected mRNAs for Jak family kinases in prostate cancer cell lines by RT-PCR and Tyk2 protein in human prostate cancer specimens by immunohistochemistry. Inhibition of Tyk2 signaling resulted in attenuation of the urokinase-type plasminogen activator-enhanced invasiveness of prostate cancer cells in vitro without affecting the cellular growth rate. These results suggest that Tyk2 signaling in prostate cancer cells facilitate invasion of these cells, and interference with this signaling may be a potential therapeutic pathway.

Bilirubin is a well-known neurotoxin that can result in multiple neurologic deficits. Previous studies have suggested that bilirubin affects aspects of synaptic transmission; however the acute effects of bilirubin on synaptic transmission have not been examined in real-time. In this study, using whole-cell voltage-clamp recordings, we observed the effect of bilirubin on inhibitory postsynaptic currents (IPSC) in postnatal 13-15-day-old neurons dissociated from lateral superior olive nuclei (LSO), one of the brainstem auditory nucleus that are highly vulnerable to bilirubin. The results showed that 10(-5)M bilirubin increased the frequency of spontaneous IPSC without causing change in their amplitudes or in the response to bath applied glycine, suggesting a presynaptic locus for the action. In the presence of tetrodotoxin, the frequency of miniature IPSC was also potentiated by 10(-5)M bilirubin. The facilitation by bilirubin was concentration dependent and increased with an increase in exposure time. Bicuculline only partially reduced the action of bilirubin. The action of bilirubin was observed in extracellular Ca(2+)-free ([Ca(2+)](o) free) solution but was fully occluded by pretreatment with BAPTA-AM in [Ca(2+)](o) free solution. Thus, in LSO neurons, bilirubin facilitates inhibitory synaptic transmission, in a manner independent of voltage-activated Na(+) and Ca(2+) channels but dependent on presynaptic [Ca(2+)](i). The increase of inhibitory synaptic transmission in response to acute bilirubin is a novel effect of bilirubin on the central nervous system and may have implications for neurotoxicity and the impairment of auditory transduction seen in hyperbilirubinemia.

The physiological and pharmacological properties of gamma-aminobutyric acid (GABA)-induced responses were investigated in acutely isolated spiral ganglion cells (SGCs) of guinea pig by using either a nystatin-perforated patch recording configuration or a conventional whole-cell patch recording mode combined with rapid drug application. GABA and GABA(A) subtype receptor agonist, muscimol, induced inward currents in a concentration-dependent manner in 74% of all cells. The current-voltage relationship for the GABA response indicated the GABA-induced current in SGCs is carried by Cl-. Bicuculline (BIC), strychnine (STR), and picrotoxin (PTX) suppressed the GABA response in a concentration-dependent manner. BIC and STR, and PTX blocked the GABA response in a competitive manner and in a non-competitive manner, respectively. For inorganic antagonists, Cd2+ and Ni2+ also inhibited the GABA response. On the other hand, Zn2+ failed to suppress the GABA response in SGCs. An antibiotic, benzylpenicillin, suppressed the GABA response. The GABA response was augmented by both a barbiturate derivative, pentobarbital (PB), and a benzodiazepine derivative, diazepam. The results suggest clearly that the physiological and pharmacological characteristics of GABA(A) receptor on acutely isolated guinea pig SGCs are quite similar to the common GABA(A) receptor found in other sensory ganglion cells.

Study Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. The incidence of IPF increases with age. Aging contributes to lifestyle-related diseases, including diabetes mellitus (DM); therefore, it is possible that lifestyle-related diseases may affect either the initiation or progression of IPF., Design: Case-control study., Setting: Nippon Medical School and Omiya City Clinic., Patients and Participants: Sixty-five consecutive patients with IPF who were admitted to Nippon Medical School Hospital from 1995 to 2000, and 184 control subjects selected from 15,798 subjects who were admitted to Omiya City Clinic for routine medical examination between September 1999 and August 2000., Measurements: Age, sex, smoking history, and results of physical examinations, blood examinations, and lung function testing were extracted from medical records and were compared with the diagnostic criteria for lifestyle-related diseases., Results: The adjusted odds ratios for cigarette smoking were 5.40 (95% confidence interval [CI], 2.30 to 12.66) and 4.06 (95% CI, 1.80 to 9.15) for diabetes. There were no differences in clinical characteristics of patients with IPF that could be related to the presence of DM., Conclusion: DM may be a risk factor for IPF.

The identification of the in vitro metabolites of dehydroepiandrosterone formed from human prostate homogenate was investigated by hyphenated techniques using the stable-isotope dilution method. A mixture of dehydroepiandrosterone and [2H4]dehydroepiandrosterone was incubated with hypertrophied human prostate tissue homogenate in the presence of NAD, NADH and NADPH. The metabolites were extracted with AcOEt-hexane, purified by solid-phase extraction, and then analyzed by LC-atmospheric pressure chemical ionization MS and/or GC-MS. Androst-5-ene-3beta,17beta-diol (major product), androst-4-ene-3,17-dione, testosterone, 5alpha-dihydrotestosterone, androsterone, and 7alpha-hydroxydehydroepiandrosterone were identified in comparison with authentic samples based on their chromatographic behavior and mass spectra.