Crucial role of iron in epigenetic rewriting during adipocyte differentiation mediated by JMJD1A and TET2 activity.

Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, 　including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.

Development of a homogeneous time-resolved fluorescence assay for detection of viral double-stranded RNA.

The group of positive-sense single-stranded RNA ((+) ssRNA) viruses includes many important human pathogens. However, specific antiviral agents are not currently available for many RNA viruses. For screening of antiviral agents, methods that are simple, rapid, and compatible with high-throughput are required. Here, we describe a novel method for measurement of double-stranded RNA using a homogeneous time-resolved fluorescence assay. This method allowed detection of human rhinovirus (HRV), enterovirus, coxsackievirus, and murine norovirus. Furthermore, this method detected antiviral activity of a HRV 3C protease inhibitor. The assay may be useful for discovery of antiviral agents against (+) ssRNA viruses.

End-to-Side Venous Anastomosis to a Ligated Vein Stump for Free Flap Transfer in Head and Neck Reconstruction.

INTRODUCTION: In head and neck reconstruction, use of a free flap paired with end-to-side anastomosis to a preserved vein is generally performed. However, it is frequently difficult to select the recipient vein after a neck dissection in which there is only a ligated internal jugular vein/external jugular vein (IJV/EJV). Here, a new anastomosis technique using a ligated IJV/EJV stump is described. PATIENTS AND METHODS: End-to-side anastomoses to ligated vein stump surgeries for free flap transfer in head and neck reconstruction were performed at the Department of Plastic and Reconstructive Surgery, University of Tsukuba, from 2009 to 2016. RESULTS: The subject pool comprised 6 patients. All patients received a free flap transfer after head and neck tumor excision. The free flaps used were 1 free radial forearm flap, 1 free tensor fascia lata muscle perforator flap, and 4 free rectus abdominis musculocutaneous flaps. The cervical vessels used were 3 IJVs and 3 EJVs. All veins of the free flaps could be anastomosed end-to-side to ligated vein stumps without vein grafting. All flaps survived completely without complications. CONCLUSIONS: The end-to-side venous anastomosis to a ligated vein stump procedures were easy to perform and not dependent on the vessel diameters of the free flaps. No complications were observed in any patient owing to differences in vessel diameter, ease of anastomosis, and safety. Results suggest that this new technique is a simple and very useful option in head and neck reconstruction where the IJV/EJV cannot be preserved.

Occipital lobe epilepsy was presented in a patient with intracerebral schwannoma: a case report and literature review.

Schwannoma arising within brain parenchyma is a rare scenario. So far, only 70 cases were reported. We reported a case of intracerebral schwannoma presented with occipital lobe epilepsy, which has never been reported before. A 19-year-old man suffered from intermittent blurred vision and headache. Neuroradiological findings showed a left occipital lesion with cystic and solid components. Histological and electron micrograph features confirmed the diagnosis of schwannoma after the tumor was totally removed. The theories and literature related to this case were reviewed and the possible developmental origin was discussed. We found that this kind of schwannoma is more often in adolescent and young adults.

Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants: The PASTA Registry - Study Design and Characteristics.

OBJECTIVES: The management of atrial fibrillation and deep venous thrombosis has evolved with the development of direct oral anticoagulants (DOAC), and oral anticoagulant (OAC) might influence the development or clinical course in both ischemic and hemorrhagic stroke. However, detailed data on the differences between the effects of the prior prescription of warfarin and DOAC on the clinical characteristics, neuroradiologic findings, and outcome of stroke are limited. DESIGN: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke (ischemic stroke, transient ischemic attack, and intracerebral hemorrhage) patients receiving OAC in Japan. This study is designed to collect data on clinical background characteristics, drug adherence, drug dosage, neurological severity at admission and discharge, infarct or hematoma size, acute therapy including recanalization therapy or reverse drug therapy, and timing of OAC re-initiation. Patient enrollment started in April 2016 and the target patient number is 1000 patients. CONCLUSIONS: The PASTA prospective registry should identify the status of stroke patients taking OAC in the current clinical practice in Japan.

[Cooperation between Clinics and Hospitals Using a Critical Path for G-CSF Prophylaxis in Cancer Chemotherapy].

BACKGROUND: Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011. METHODS: We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital. RESULTS: Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%). CONCLUSION: Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

A prospective study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in malignant lymphoma patients following highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a troublesome issue in chemotherapy for cancer patients. A second-generation 5HT3 receptor antagonist (5HT3RA), palonosetron, is effective and safe for the prevention of CINV in breast cancer patients treated with cyclophosphamide and anthracycline, but there is little data for malignant lymphoma. We conducted a prospective phase 2 study at a single institution to clarify the efficacy and safety of palonosetron in lymphoma patients. METHODS: Chemotherapy-naïve lymphoma patients who were treated with highly emetogenic chemotherapy (HEC) received a single intravenous bolus of palonosetron, 0.75 mg/body, before chemotherapy on day 1 during the first course of chemotherapy. The occurrence of CINV was assessed using the Multinational Association for Supportive Care in Cancer (MASCC) antiemesis tool, which was recorded by patients during the first course of chemotherapy. RESULTS: A total of 59 patients were enrolled, and 49 patients were eligible and evaluated. The complete response (CR) rate was 93.9% (95% confidence interval 83.1-98.7%) at 0-120 h post-chemotherapy. The proportion of patients who developed nausea of any grade and vomiting at 0-120 h post-chemotherapy was 34.7 and 6.1%, respectively. Although treatment-related adverse events were observed in 36 (73.5%) patients, these were mild and they recovered by the next cycle of chemotherapy. CONCLUSION: The present study demonstrated that a single dose of palonosetron was highly effective and safe for the prevention of CINV in lymphoma patients.

A simple, novel technique for fixing Penrose drains in minor surgeries, with advantages for remote outpatient clinics: a retrospective comparison with conventional drain fixation in North Ibaraki, Japan.

INTRODUCTON: In rural areas with few doctors, Penrose drains in minor surgeries for soft tissue trauma or small subcutaneous tumors are sometimes avoided, even though the drain would prevent hematoma, because of the limited availability of professional postsurgical care. The authors developed a simple fixation method for Penrose drains that can be used even in remote areas where a doctor is not present to remove the drain. A retrospective study was conducted to compare this new method of fixing Penrose drains with instances in which the Penrose drain was fixed to skin by conventional suturing. METHODS: The medical records of patients who underwent minor surgeries using Penrose drains were reviewed. The surgeries were performed from April 2012 to March 2015 in remote outpatient clinics in Ibaraki Prefecture, Japan. The cases were divided into two groups: those using the new method, in which the Penrose drains were sewn onto the wound dressings and could be automatically removed while changing the dressing, and those in which the Penrose drains were conventionally fixed to the skin and removed one or several days after surgery by another doctor at the outpatient clinic. The rates of drain-related complications and of automatic drain removal (ie removal without a doctor's assistance) between the two groups were compared. RESULTS: A total of 54 Penrose drains used for 48 lesions in 44 patients (25 men, 19 women) in the new-method group, and 36 Penrose drains for 25 lesions in 21 patients (12 men, 9 women) in the conventional-method (control) group were analyzed. All 54 Penrose drains in the new-method group were removed automatically, while none of the 36 drains in the control group were removed automatically. There were no drain-related complications, such as massive hematoma, retrograde infection, seroma, or drain breakage or straying, in any of the new-method or control cases. CONCLUSIONS: This new Penrose-drain fixation method is safe and is particularly suitable for minor surgeries in rural areas where there are no resident doctors. The wide use of this method for appropriate minor surgeries in doctorless rural areas has the potential to reduce surgical complications and the time burden for both patients and surgeons.

Olfactory preservation during anterior interhemispheric approach for anterior skull base lesions: technical note.

Anosmia is not a rare complication of surgeries that employ the anterior interhemispheric approach. Here, we present a fibrin-gelatin fixation method that provides reinforcement and moisture to help preserve the olfactory nerve when using the anterior interhemispheric approach and describe the results and outcomes of this technique. We analyze the outcomes with this technique in 45 patients who undergo surgery for aneurysms, brain tumors, or other pathologies via the anterior interhemispheric approach. Anosmia occurred in 4 patients (8.8%); it was transient in 2 (4.4%) and permanent in the remaining 2 (4.4%). Brain tumors clearly attached to the olfactory nerve were resected in the patients with permanent anosmia. We found a significant difference in the presence of anosmia between patients with or without lesions that were attaching the olfactory nerve (p = 0.011). Our results suggested that fibrin-gelatin fixation method can reduce the reported risk of anosmia. However, the possibility of olfactory nerve damage is relatively high when operating on brain tumors attaching olfactory nerve.

Pathophysiology and management of intracranial arterial stenosis around the circle of Willis associated with hyperthyroidism: case reports and literature review.

Cases of moyamoya disease or intracranial arterial stenosis around the circle of Willis (M/IAS) associated with hyperthyroidism have been reported. However, most of these previous reports were of the ischemic form of M/IAS and primary hyperthyroidism. To the best of our knowledge, no studies have documented therapy for M/IAS associated with hyperthyroidism. We discuss four previously unreported cases, including those involving the intracerebral hemorrhage form and thyroid-stimulating hormone (TSH) secretion from a pituitary adenoma (secondary hyperthyroidism). We analyzed data from 52 previously reported cases, including the 4 cases presented here, and discuss M/IAS associated with hyperthyroidism, treatment options, pathophysiology, the ischemic and hemorrhagic forms, secondary hyperthyroidism, and the relevant literature. Hyperthyroidism results in thyrotoxicosis and the stimulation of the superior cervical ganglion by TSH antibodies and f-T3/f-T4. Consequently, hypercoagulability and stenosis of the cerebral artery can occur. There are many reports of ischemic M/IAS associated with hyperthyroidism. A conservative approach to treatment is important in such cases; for example, antithyroid therapy should be the first choice to treat ischemic M/IAS. There have been only a limited number of reports on hemorrhagic M/IAS. We presume that hemorrhagic M/IAS tears the weakened vasculature in a manner similar to that of normal M/IAS (with no complicating hyperthyroidism). The authors also reported M/IAS associated with secondary hyperthyroidism due to pituitary thyroid secreting hormone secreting adenoma.

Subchronic exposure of titanium dioxide nanoparticles to hairless rat skin.

The evaluation of the biological effects of industrial nanoparticles on the skin is necessary for their risk assessment. To clarify the influence of TiO2 nanoparticles on the skin, we carried out a subchronic exposure study of TiO2 nanoparticles to hairless rat skin. W/O emulsion containing 10 wt% TiO2 nanoparticles and control emulsion was applied to the dorsal skin of Hairless Wistar Yagi rats once a day for a maximum period of 56 consecutive days. After 2, 4 and 8 weeks, skin samples were taken from the exposed skin area. Histopathologically, the particles were only located in the stratum corneum layer of epidermis and follicular epithelium. Focal parakeratosis and spongiosis were observed in the epidermis. Transmission electron microscopy with energy-dispersive X-ray spectrometry (EDX) analysis failed to show TiO2 nanoparticles in the viable skin areas. There was no evidence of TiO2 penetration in the viable skin areas. In addition, titanium contents in several organs were determined using inductively coupled plasma mass spectroscopy. Increased titanium concentration was detected in lung samples of the TiO2 emulsion-treated groups after 8 weeks. It was most likely that the presence of TiO2 in the lungs was not caused by direct absorption of nanoparticles from the skin but was due to rats inhaling the nanoparticle. We did not find any obvious evidences of nano-TiO2 particle skin penetration using several morphological methods after the subchronic exposure. We believe that the influence of subchronic exposure of TiO2 is not significant based on our study.

Presurgical orthopedic treatment ameliorates postoperative nasal deformity after cheiloplasty.

We assessed the postoperative nasal form and symmetry after presurgical use of a Hotz plate (HP) in patients with unilateral complete cleft lip and palate (UCLP). The subjects were 28 infants with UCLP who underwent cheiloplasty. Of these subjects, 14 underwent presurgical orthopedic treatment using the HP (HP group) and 14 underwent the same treatment without the HP (non-HP group). Photographic records were obtained 1 and 6 months after cheiloplasty, and the results of anthropometric analysis were compared between the 2 groups. The nasal inclination and the ratio of the width of the nasal base to the total width of the nose were significantly improved in the HP group compared with the non-HP group at both postoperative time points. Thus, presurgical use of the HP significantly improved the nasal asymmetry and deformity in UCLP patients after primary cheiloplasty and nasal repair.

Preoperative liquid embolization of cerebeller hemangioblastomas using N-butyl cyanoacrylate.

INTRODUCTION: We aim to present and discuss clinical outcomes of preoperative liquid embolization of hemangioblastomas (HB) using N-butyl cyanoacrylate (NBCA). METHODS: From 1999 through 2010, 19 patients presenting with symptoms of vertigo and/or headaches were diagnosed with HB based on preoperative magnetic resonance imaging and cerebral angiographic findings at our institution. Preoperative embolization with NBCA was performed on tumors in 10 of 21 operations for 19 patients. For each of these patients, the lesion was pathologically confirmed as HB. RESULTS: Embolization had a favorable outcome in all patients. No permanent neurological complications were observed after preoperative embolization using NBCA. However, thalamic infarction and minor hemorrhage were observed in two patients with cerebellar HB. CONCLUSION: The authors recommend NBCA as an embolization material for large cerebellar HB.

Effects of memantine, an N-methyl-D-aspartate receptor antagonist, on fatigue and neuronal brain damage in a rat model of combined (physical and mental) fatigue.

Most of the fatigue in everyday life is a combination of physical and mental fatigue. Recently, an animal model of combined fatigue was designed by housing rats in a cage filled with water. We have previously hypothesized that mental fatigue is caused partly by neuronal brain damage through the activation of N-methyl-D-aspartate (NMDA) receptors by quinolinic acid (QUIN), a metabolite of tryptophan (TRP). Therefore, we investigated whether the same mechanism also participates in combined fatigue. Rats were housed for 5 d under water-immersed conditions, and the extent of fatigue was evaluated by a weight-loaded forced swimming test. The swimming time of the water-immersed group was shorter than that of the control group, indicating that rats were fatigued by water-immersion. However, unexpectedly, the blood and brain levels of QUIN in the water-immersed group were lower than those of the control group. QUIN levels in both the blood and brains of a food-restricted nonimmersed group, where body weight was matched with the water-immersed group, were also decreased, suggesting that decreased QUIN in the water-immersed group originated from a reduced intake of TRP-containing food. On the other hand, hippocampal neuronal damage was shown in the water-immersed group, similar to that seen in other fatigue models where QUIN increased. Memantine, an NMDA receptor antagonist, inhibited not only the reduction in swimming times but also the neuronal damage induced by water-immersion. These results suggest that neuronal brain damage by an endogenous NMDA receptor agonist other than QUIN participates in combined fatigue by water immersion.

Presurgical nasoalveolar molding orthopedic treatment improves the outcome of primary cheiloplasty of unilateral complete cleft lip and palate, as assessed by naris morphology and cleft gap.

We evaluated the effects of presurgical nasoalveolar molding (NAM) with an orthopedic appliance and compared them with a passive orthopedic method (Hotz plate, HP), focusing on the naris morphology and width of the alveolar and palate cleft gap. The subjects were 28 unilateral complete cleft lip and palate patients treated with primary cheiloplasty at Tsukuba University Hospital from 2004 to 2011. Thirteen patients were treated preoperatively with NAM (NAM group), and 15 with HP (HP group). The surgical outcome was assessed according to left-right naris symmetry, as measured by the area ratio, perimeter ratio, aspect a/u ratio (aspect ratio of the affected side/aspect ratio of the unaffected side), and Hausdorff distance. In addition, the alveolar and palate cleft width was measured at the times of orthopedic plate setting and primary cheiloplasty. The aspect ratio was significantly smaller in the NAM group than in the HP group before the operation. In both groups, the aspect ratio, perimeter ratio, and Hausdorff distance were significantly smaller after the operation than before. The width of the alveolar and palate cleft gap was significantly narrowed in the NAM group, and the cleft gap at the initiation of NAM correlated significantly with the Hausdorff distance after cheiloplasty. We found that NAM improved the form of the naris after primary cheiloplasty and decreased the palate cleft gap more effectively than HP and that the width of the palate cleft gap was correlated with the surgical outcome of the naris.

Nasal molding prevents relapse of nasal deformity after primary rhinoplasty in patients with unilateral complete cleft lip: An outcomes-based comparative study of palatal plate alone versus nasoalveolar molding.

OBJECTIVES: In recent years, many studies have reported that the presurgical nasoalveolar molding method improves the nose morphology; however, the reason for its effectiveness after surgery has never been understood. We evaluated the effect of nasoalveolar molding by comparing it with a passive orthopedic method without a nasal stent and focusing on the nostril morphology after primary cheiloplasty using various measurement methods. We then analyzed the essential factors. MATERIALS AND METHODS: The patients involved were 31 infants with unilateral complete cleft lip and palate treated with primary cheiloplasty at the University of Tsukuba Hospital from 2004 to 2011. Of the 31 infants, 16 received nasoalveolar molding treatment and 15 received passive orthopedic treatment as controls. Photographic facial measurements were performed for all patients immediately and 7 months after primary cheiloplasty. The esthetics of the nostrils were assessed according to the left-right nostril symmetry, as measured by the Hausdorff distance, area ratio, perimeter ratio, and aspect a/u (the aspect ratio of the affected side)/(the aspect ratio of the unaffected side) ratio. In addition, the inclination of the nasal ridge was assessed using anthropometric measurements (Grc-Grn∠midline and midline∠columellar axis). RESULTS: The area ratio, perimeter ratio, and Grc-Grn∠midline were significantly greater in the nasoalveolar molding group immediately after surgery (p = 0.00062, 0.016, and 0.048, respectively) than in the control group. However, the Hausdorff distance and aspect a/u ratio were more favorable (p = 0.0018 and 0.0039, respectively) in the nasoalveolar molding group after 7 months. CONCLUSIONS: The results of our study suggested that using nasoalveolar molding as a presurgical orthopedic treatment could improve the shape of the nasal cartilage with surgeon's corrections.

Characteristics of Ischemic Versus Hemorrhagic Stroke in Patients Receiving Oral Anticoagulants: Results of the PASTA Study.

Objective Limited data exist regarding the comparative detailed clinical characteristics of patients with ischemic stroke (IS)/transient ischemic attack (TIA) and intracerebral hemorrhage (ICH) receiving oral anticoagulants (OACs). Methods The prospective analysis of stroke patients taking oral anticoagulants (PASTA) registry, a multicenter registry of 1,043 stroke patients receiving OACs [vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulant (NOACs)] across 25 medical institutions throughout Japan, was used. Univariate and multivariable analyses were used to analyze differences in clinical characteristics between IS/TIA and ICH patients with atrial fibrillation (AF) who were registered in the PASTA registry. Results There was no significant differences in cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, smoking, or alcohol consumption (all p>0.05), between IS/TIA and ICH among both NOAC and VKA users. Cerebral microbleeds (CMBs) [odds ratio (OR), 4.77; p<0.0001] were independently associated with ICH, and high brain natriuretic peptide/N-terminal pro B-type natriuretic peptide levels (OR, 1.89; p=0.0390) were independently associated with IS/TIA among NOAC users. A history of ICH (OR, 13.59; p=0.0279) and the high prothrombin time-international normalized ratio (PT-INR) (OR, 1.17; p<0.0001) were independently associated with ICH, and a history of IS/TIA (OR, 3.37; 95% CI, 1.34-8.49; p=0.0101) and high D-dimer levels (OR, 2.47; 95% CI, 1.05-5.82; p=0.0377) were independently associated with IS/TIA among VKA users. Conclusion The presence of CMBs, a history of stroke, natriuretic peptide and D-dimer levels, and PT-INR may be useful for risk stratification of either IS/TIA or ICH development in patients with AF receiving OACs.

Indocyanin green videoangiography study of hemangioblastomas.

OBJECTIVE: We present herein the intraoperative indocyanin green videoangiography (ICGVAG) findings for three cases of cerebellar hemangioblastoma (HB). CASES: Cerebellar HB was detected in three patients presenting with symptoms of vertigo and/or headaches and diagnosed on the basis of preoperative magnetic resonance imaging (MRI) and cerebral angiographic findings. Preoperative embolization of the tumor feeding artery was not performed in any of the patients. None of the patients underwent any procedure prior to ICGVAG that would affect the ICG findings, such as perilesional hemostatic coagulation or ablation. In each patient, it was possible to judge the approximate location of the tumor in relation to the brain surface and to distinguish the feeding and draining vessels. Following resection of the tumor, ICGVAG images confirmed that the mural nodule had been eliminated. None of the patients required blood transfusion, either during or after the surgery. For each patient, the lesion was pathologically confirmed as HB, postoperative contrast-enhanced MRI confirmed the absence of residual tumor, and diffusion-weighted MRI revealed no ischemic changes. RESULTS: Differentiation of feeding and draining vessels in the region of the lesion is particularly important for successful surgical removal of HB. In the present three patients, ICGVAG findings enabled easy vascular differentiation and were also useful for confirming that there was no residual tumor. Indocyanin green videoangiography was concluded to be useful for safe resection of HB.