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.

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.

Severe Aneurysmal Subarachnoid Hemorrhage after Warning Headache during Pregnancy: A Case Report.

BACKGROUND: Aneurysmal subarachnoid hemorrhage is a rare but important cause of maternal death during pregnancy. CASE DESCRIPTION: A 34-year-old primigravida (31 weeks of pregnancy) with acute headache but no neurological deficits or neck stiffness was prescribed medication and returned home. Four weeks later she presented with severe headache and consciousness disturbance. She was admitted to our hospital, where she fell into a deep coma. Brain CT and three-dimensional CT angiography showed subarachnoid hemorrhage and a 5-mm right internal carotid-posterior communicating artery aneurysm. Fetal heart rate was 60 beats per minute. Emergent cesarean section and surgical clipping were performed. Intraoperative examination revealed that the aneurysm originated at the right posterior communicating artery. There were no postoperative neurological focal deficits. On postoperative day 13 she developed delayed cerebral ischemia of the right temporo-parieto-occipital lobe. She was discharged home 36 days after surgery with left hemianopsia. The infant was free of complications and was discharged at age 17 days. CONCLUSIONS: A pregnant woman with severe headache should undergo brain CT or magnetic resonance imaging to rule out subarachnoid hemorrhage.

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.

Hydrocephalus Secondary to Intradural Extramedullary Malignant Melanoma of Spinal Cord.

BACKGROUND: Hydrocephalus secondary to spinal cord tumors is rare. CASE DESCRIPTION: We present a 39-year-old male with gradual-onset headache whose initial diagnosis was cerebral aneurysm and communicating hydrocephalus. The correct diagnosis was primary intradural extramedullary malignant melanoma of the spinal cord. Initial brain magnetic resonance imaging demonstrated slight dilation of cerebral ventricles and a 3-mm unruptured anterior communicating artery aneurysm. He was placed under observation therapy. Two months later he was seen again due to severe headache. There was no intracranial hemorrhage on brain computed tomography scans. As we suspected rupture of the aneurysm, we operated on him for surgical clipping; however, there was no aneurysmal rupture. We found no lesions responsible for hydrocephalus, so we placed a ventriculoperitoneal shunt. His headache subsequently resolved. Nine months later he developed gait disturbance; a large volume of ascites was observed. Gadolinium-enhanced lumbar magnetic resonance imaging revealed an intradural extramedullary mass at the L-1 to S-5 level. Cytology and immunohistochemistry of the cerebrospinal fluid and ascites identified a few atypical cells positive for HMB-45, S-100 protein, and Melan-A. Whole-body examinations detected no primary lesions outside the central nervous system. Our final diagnosis was primary intradural extramedullary malignant melanoma of the spinal cord with cerebrospinal fluid dissemination. CONCLUSIONS: Our findings indicate that communicating hydrocephalus may be due to primary malignant melanoma of the spinal cord.

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.

[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.

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.

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.

Pedicle Galeo-pericranial Flap Augmentation in Salvage Frontotemporal Cranioplasty: Additional 'Neurosurgeon-friendly' Reconstruction Technique of Aesthetic Neurosurgery in Superficial Temporal Artery Branch Compromised Host.

This technical note aims to demonstrate the usefulness, indications and its limitations of augmentation technique by bipedicle galeo-pericranial rotation flap and by monopedicle galeo-pericranial flap, both in STA (superficial temporal artery) branch compromised hosts in salvage frontotemporal cranioplasty. Although these flaps are not always idealistically vascularized owing to accidental injuries to the STA branches during previous surgeries, they are properly augmenting after salvage frontotemporal craniotomy when infection is not active. The procedure is indicated for salvage frontotemporal craniotomy when vasculature is needed at the surgical site, such as beneath the skin incision line in a thin injured scalp, onto the titanium plates or beneath the fragile fibrous scar. We do not apply this technique by neurosurgeons alone where infection is active or if the host is irradiated. This technique is recommended as a reconstructive aesthetic neurosurgical procedure. It is a 'neurosurgeon-friendly' simple procedure, as it does not require any special tools or complicated techniques.

Characteristics of multiple basal cell carcinomas: The first study on Japanese patients.

Basal cell carcinoma (BCC), the most frequent skin cancer, has been increasing in incidence. However, the characteristics of multiple BCC have not been clarified in Japan. Therefore, we conducted a retrospective study to elucidate the features of multiple BCC compared with solitary BCC. The study population consisted of 327 patients with histopathologically proven BCC who were referred to the Department of Dermatology in Tottori University Hospital between November 2006 and April 2016. Of the 327 patients, 304 (93.0%) had solitary BCC and 23 (7.0%) had multiple BCC. The mean age of the patients with solitary BCC was 74.7 years (range, 31-102) and that of patients with multiple BCC was 79.3 years (range, 63-91). There was a significant difference in mean age between the two groups (P = 0.01). Approximately four-fifths of the BCC were located on the head or neck in the total study population. In the group of patients with multiple BCC, the incidence of lesions on the head and neck was lower and that on the trunk was higher than those in patients with solitary BCC. There was a significant difference in the tumor site between the two groups (P < 0.0001). With respect to tumor histopathology, the ratio of superficial BCC was significantly higher in the group of patients with multiple BCC than in the group of patients with solitary BCC (P < 0.0001). In conclusion, we demonstrated that older age, truncal location and superficial histopathological type of tumor are features of multiple BCC in Japanese subjects.

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.

An intraoperative motor tract positioning method in brain tumor surgery: technical note.

Intraoperative 3D recognition of the motor tract is indispensable to avoiding neural fiber injury in brain tumor surgery. However, precise localization of the tracts is sometimes difficult with conventional mapping methods. Thus, the authors developed a novel brain mapping method that enables the 3D recognition of the motor tract for intrinsic brain tumor surgeries. This technique was performed in 40 consecutive patients with gliomas adjacent to motor tracts that have a risk of intraoperative pyramidal tract damage. Motor tracts were electrically stimulated and identified by a handheld brain-mapping probe, the NY Tract Finder (NYTF). Sixteen-gauge plastic tubes were mounted onto the NYTF and inserted in the estimated direction of the motor tract with reference to navigational information. Only the NYTF was removed, leaving the plastic tubes in their places, immediately after muscle motor evoked potentials were recorded at the minimum stimulation current. Motor tracts were electrically identified in all cases. Three-dimensional information on the position of motor tracts was given by plastic tubes that were neurophysiologically placed. Tips of tubes showed the resection limit during tumor removal. Safe tumor resection with an arbitrary safety margin can be performed by adjusting the length of the plastic tubes. The motor tract positioning method enabled the 3D recognition of the motor tract by surgeons and provided for safe resection of tumors. Tumor resections were performed safely before damaging motor tracts, without any postoperative neurological deterioration.

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.

Intracerebral Hemorrhage Caused by Cerebral Hyperperfusion after Superficial Temporal Artery to Middle Cerebral Artery Bypass for Atherosclerotic Occlusive Cerebrovascular Disease.

Few papers have reported detailed accounts of intracerebral hemorrhage caused by cerebral hyperperfusion after superficial temporal artery to middle cerebral artery bypass (STA-MCA) bypass for atherosclerotic occlusive cerebrovascular disease. We report a case of vasogenic edema and subsequent intracerebral hemorrhage caused by the cerebral hyperperfusion syndrome (CHS) after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease disease without intense postoperative blood pressure control. A 63-year-old man with repeating left hemiparesis underwent magnetic resonance angiography (MRA), which revealed right internal carotid artery (ICA) occlusion. We performed a double bypass superficial temporal artery (STA)-middle cerebral artery (MCA) bypass surgery for the M2 and M3 branches. While the patient's postoperative course was relatively uneventful, he suffered generalized convulsions, and computed tomography revealed a low area in the right frontal lobe on Day 4 after surgery. We considered this lesion to be pure vasogenic edema caused by cerebral hyperperfusion after revascularization. Intravenous drip infusion of a free radical scavenger (edaravone) and efforts to reduce systolic blood pressure to <120 mmHg were continued. The patient experienced severe left hemiparesis and disturbance of consciousness on Day 8 after surgery, due to intracerebral hemorrhage in the right frontal lobe at the site of the earlier vasogenic edema. Brain edema associated with cerebral hyperperfusion after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease should be recognized as a risk factor for intracerebral hemorrhage. The development of brain edema associated with CHS after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease requires not only intensive control of blood pressure, but also consideration of sedation therapy with propofol.