The impact of omalizumab on paid and unpaid work productivity among severe Japanese cedar pollinosis (JCP) patients.

AIMS: Japanese cedar pollinosis (JCP) is a form of seasonal allergic rhinitis that affects 38.8% of the Japanese population. Particularly severe and most severe symptoms among JCP patients can lead to impairments of paid work productivity and unpaid work activities. Indeed, the current standard of care (SoC) is not always able to relieve these symptoms. Omalizumab, a novel JCP treatment recently approved in Japan, provides an effective add-on therapy to the SoC. This study estimates the effect of omalizumab on paid and unpaid work activities (i.e. its social impact) in patients with severe and most severe JCP symptoms in Japan. METHODS: The impact of omalizumab was estimated through a one-year static cohort model using the Work Productivity and Activity Impairment Allergy Specific (WPAI-AS) questionnaire derived from a clinical trial on omalizumab enrolling patients with severe and most severe JCP symptoms, which had been conducted in Japan. This effect was quantified using Japanese official statistics on employment and time use. The human capital approach and the proxy good approach were employed to monetize paid and unpaid work activities, respectively. A sensitivity analysis was implemented to account for modeling structural uncertainties. RESULTS: Our results show that the use of omalizumab might reduce the paid and unpaid work productivity losses due to severe and most severe JCP by nearly one-third. In the severe symptom period of three weeks, 36.6 million hours of lost paid and unpaid work hours could be avoided, which sums up to a monetized productivity loss of 728.3 million USD. CONCLUSIONS: Omalizumab could provide substantial benefits in terms of paid and unpaid work activities in patients with severe and most severe JCP. Our results also highlight the importance of considering unpaid work in estimating productivity costs due to poor health.

Emotion regulation processes and middle-aged Japanese women's health.

OBJECTIVES: Emotion regulation processes, such as mindfulness, self-compassion, and acceptance, have been discussed as modifiable psychological factors related to middle-aged women's psychological distress and adjustment. Although these emotion regulation factors have been discussed separately, the question remains of which factors reflect the most variance in middle-aged women's health. Therefore, this study aimed to reveal the most relevant explanatory variable for middle-aged women's health: mindfulness, self-compassion, or acceptance. METHOD: A total of 200 middle-aged women completed self-reported measures of depressive symptoms, menopausal symptoms, physical quality of life, mental quality of life, and well-being. RESULTS: Correlation analysis showed that mindfulness, self-compassion, and acceptance were significantly associated with all variables of psychological distress and adjustment. Hierarchical multiple regression analysis revealed that acceptance significantly explained the most variance of depressive symptoms, menopausal symptoms, and mental quality of life. On the other hand, self-compassion significantly explained the greatest variance in well-being. CONCLUSIONS: These findings suggest that, for middle-aged women, 'acceptance' is an important explanatory variable of psychological distress and 'self-compassion' is an important variable of psychological adjustment.

A randomized controlled phase II clinical trial comparing ONO-4053, a novel DP1 antagonist, with a leukotriene receptor antagonist pranlukast in patients with seasonal allergic rhinitis.

BACKGROUND: Prostaglandin D2 (PGD2 ) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea. OBJECTIVE: This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR). METHODS: This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. A total of 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated. RESULTS: Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study. CONCLUSIONS: We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).

Communicating Radiation Risk to the Population of Fukushima.

Radiological specialists from Nagasaki University have served on the medical relief team organized at Fukushima Medical University Hospital (Fukushima City) ever since the accident at the Fukushima Dai-ichi nuclear power plant. Furthermore, we have conducted the radiation crisis communication efforts by spreading correct information on the health effects of radiation as 'advisors on radiation health risk control'. Nagasaki University has been assisting the reconstruction efforts of Kawauchi Village in Fukushima Prefecture, which was the first village to declare that residents could safely return to their homes because radiation doses were found to be at comparatively low levels. In April 2013, Nagasaki University and the Kawauchi government office concluded an agreement concerning comprehensive cooperation toward reconstruction of the village. As a result, we established a satellite facility of the university in the village. In conclusion, training of specialists who can take responsibility for long-term risk communication regarding the health effects of radiation as well as crisis communication in the initial phase of the accident is an essential component of all such recovery efforts. Establishment of a training system for such specialists will be very important both for Japan and other countries worldwide.

Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: role of hepatocyte growth factor.

OBJECTIVE AND DESIGN: Since rebamipide is effective for the treatment of ulcerative colitis (UC), we examined the involvement of hepatocyte growth factor (HGF) in the action of rebamipide. MATERIALS: Fifty-five and forty female Balb/c mice, respectively, were used in Exp. 1 and 2. TREATMENT: 50 mg/kg/day rebamipide (Exp. 1) and 1 x 10(7) pfu pAxCAHGF (the CAG promoter-driving HGF gene in adenovirus vector) (Exp. 2) were intrarectally introduced after induction of colitis by 4 % dextran sulfate sodium (DSS). METHODS: Therapeutic effects were assessed by cell proliferation and apoptosis. RESULTS: Rebamipide caused proliferation of epithelial cells at 10 days after treatment, and decreased apoptosis at 10, 14 and 21 days, compared with controls. Expression of HGF was greatly increased in rebamipide-treated mice. pAxCAHGF caused cell proliferation and apoptosis, which showed the same pattern as with rebamipide treatment. CONCLUSIONS: Rectal administration of rebamipide is effective for DSS-induced colitis in association with induction of HGF.

Display of the epileptogenic zone on the frontal cortical surface using dynamic voltage topography of ictal electrocorticographic discharges.

To evaluate the usefulness of computerized brain-surface dynamic voltage topography (DVT) of ictal electrocorticographic (ECoG) discharges to localize and identify epileptogenic areas, 3 patients with intractable frontal lobe epilepsy who underwent epilepsy surgery after chronic subdural electrode recording were assessed. Cortical surfaces and subdural electrodes were photographed during initial surgery to create an electrode map that could be superimposed onto a picture of the brain surface. DVT was performed by calculating sequential amplitudes of ictal ECoG discharges, which were then superimposed onto the cortical and electrode maps. In all cases, DVT clearly identified the ictal onset zone and the early propagation area on the operative field. DVT allowed recognition of spatial relationships between the epileptogenic area and structural abnormalities, functional cortex, and cortical veins; and was useful to decide on the resection area.

Localization of mitochondrial DNA base excision repair to an inner membrane-associated particulate fraction.

Mitochondrial DNA (mtDNA) contains high levels of oxidative damage relative to nuclear DNA. A full, functional DNA base excision repair (BER) pathway is present in mitochondria, to repair oxidative DNA lesions. However, little is known about the organization of this pathway within mitochondria. Here, we provide evidence that the mitochondrial BER proteins are not freely soluble, but strongly associated with an inner membrane-containing particulate fraction. Uracil DNA glycosylase, oxoguanine DNA glycosylase and DNA polymerase gamma activities all co-sedimented with this particulate fraction and were not dissociated from it by detergent (0.1% or 1.0% NP40) treatment. The particulate associations of these activities were not due to their binding mtDNA, which is itself associated with the inner membrane, as they also localized to the particulate fraction of mitochondria from 143B (TK-) rho(0) cells, which lack mtDNA. However, all of the BER activities were at least partially solubilized from the particulate fraction by treatment with 150-300 mM NaCl, suggesting that electrostatic interactions are involved in the association. The biological implications of the apparent immobilization of BER proteins are discussed.

Spatio-temporal analysis by voltage topography of ictal electroencephalogram on MR surface anatomy scan for the localization of epileptogenic areas.

A 15-year-old girl developed intractable epilepsy following a right transcallosal resection of the intraventricular teratoma. Magnetic resonance (MR) imaging showed a T (2)-prolonged subcortical lesion in the right frontal lobe as well as a residual intraventricular tumor. The integration of the voltage topography of ictal onset activities of the scalp-recorded electroencephalogram (EEG) and a surface anatomy scan of MR images clearly revealed the epileptogenic area on the cortex above the subcortical lesion, with the propagation pattern towards the frontopolar area. Excision of the epileptogenic cortex and underlying gliosis resulted in a successful cessation of the epilepsy. This non-invasive EEG technique provided useful information that accurately localized the epileptogenic area on a large structural abnormality without invasive intracranial electrocorticographic monitoring.

The C-terminal alphaO helix of human Ogg1 is essential for 8-oxoguanine DNA glycosylase activity: the mitochondrial beta-Ogg1 lacks this domain and does not have glycosylase activity.

The human Ogg1 glycosylase is responsible for repairing 8-oxo-7,8-dihydroguanine (8-oxoG) in both nuclear and mitochondrial DNA. Two distinct Ogg1 isoforms are present; alpha-Ogg1, which mainly localizes to the nucleus and beta-Ogg1, which localizes only to mitochondria. We recently showed that mitochondria from rho(0) cells, which lack mitochondrial DNA, have similar 8-oxoG DNA glycosylase activity to that of wild-type cells. Here, we show that beta-Ogg1 protein levels are approximately 80% reduced in rho(0) cells, suggesting beta-Ogg1 is not responsible for 8-oxoG incision in mitochondria. Thus, we characterized the biochemical properties of recombinant beta-Ogg1. Surprisingly, recombinant beta-Ogg1 did not show any significant 8-oxoG DNA glycosylase activity in vitro. Since beta-Ogg1 lacks the C-terminal alphaO helix present in alpha-Ogg1, we generated mutant proteins with various amino acid substitutions in this domain. Of the seven amino acid positions substituted (317-323), we identified Val-317 as a novel critical residue for 8-oxoG binding and incision. Our results suggest that the alphaO helix is absolutely necessary for 8-oxoG DNA glycosylase activity, and thus its absence may explain why beta-Ogg1 does not catalyze 8-oxoG incision in vitro. Western blot analysis revealed the presence of significant amounts of alpha-Ogg1 in human mitochondria. Together with previous localization studies in vivo, this suggests that alpha-Ogg1 protein may provide the 8-oxoG DNA glycosylase activity for the repair of these lesions in human mitochondrial DNA. beta-Ogg1 may play a novel role in human mitochondria.

DNA base excision repair activities and pathway function in mitochondrial and cellular lysates from cells lacking mitochondrial DNA.

Mitochondrial DNA (mtDNA) contains higher steady-state levels of oxidative damage and mutates at rates significantly greater than nuclear DNA. Oxidative lesions in mtDNA are removed by a base excision repair (BER) pathway. All mtDNA repair proteins are nuclear encoded and imported. Most mtDNA repair proteins so far discovered are either identical to nuclear DNA repair proteins or isoforms of nuclear proteins arising from differential splicing. Regulation of mitochondrial BER is therefore not expected to be independent of nuclear BER, though the extent to which mitochondrial BER is regulated with respect to mtDNA amount or damage is largely unknown. Here we have measured DNA BER activities in lysates of mitochondria isolated from human 143B TK(-) osteosarcoma cells that had been depleted of mtDNA (rho(0)) or not (wt). Despite the total absence of mtDNA in the rho(0) cells, a complete mitochondrial BER pathway was present, as demonstrated using an in vitro assay with synthetic oligonucleotides. Measurement of individual BER protein activities in mitochondrial lysates indicated that some BER activities are insensitive to the lack of mtDNA. Uracil and 8-oxoguanine DNA glycosylase activities were relatively insensitive to the absence of mtDNA, only about 25% reduced in rho(0) relative to wt cells. Apurinic/apyrimidinic (AP) endonuclease and polymerase gamma activities were more affected, 65 and 45% lower, respectively, in rho(0) mitochondria. Overall BER activity in lysates was also about 65% reduced in rho(0) mitochondria. To identify the limiting deficiencies in BER of rho(0) mitochondria we supplemented the BER assay of mitochondrial lysates with pure uracil DNA glycosylase, AP endonuclease and/or the catalytic subunit of polymerase gamma. BER activity was stimulated by addition of uracil DNA glycosylase and polymerase gamma. However, no addition or combination of additions stimulated BER activity to wt levels. This suggests that an unknown activity, factor or interaction important in BER is deficient in rho(0) mitochondria. While nuclear BER protein levels and activities were generally not altered in rho(0) cells, AP endonuclease activity was substantially reduced in nuclear and in whole cell extracts. This appeared to be due to reduced endogenous reactive oxygen species (ROS) production in rho(0) cells, and not a general dysfunction of rho(0) cells, as exposure of cells to ROS rapidly stimulated increases in AP endonuclease activities and APE1 protein levels.

Ntg1 and Ntg2 proteins as 5-formyluracil-DNA glycosylases/AP lyases in Saccharomyces cerevisiae.

PURPOSE: 5-Formyluracil (5-foU) is a potentially mutagenic lesion of thymine produced in DNA by ionizing radiation and various chemical oxidants. The present authors reported previously that MutM, Nth and Nei in Escherichia coli removed 5-foU from DNA. The present study identified 5-foU DNA glycosylases in Saccharomyces cerevisiae in order to clarify the repair mechanisms of 5-foU in eukaryotic cells. MATERIALS AND METHODS: The borohydride-trapping assay and DNA-nicking assay were carried out to detect and characterize the repair activities for 5-foU in extracts from S. cerevisiae with oligonucleotides containing 5-foU at specific sites. RESULTS: Two proteins in crude extracts from S. cerevisiae formed covalent complexes with oligonucleotides containing site-specific 5-foU in the presence of NaBH4. Extracts from S. cerevisiae strains defective in either the NTG1 or the NTG2 gene lacked either one or the other of these two proteins. Purified Ntg1 and Ntg2 were trapped in such complexes by the 5-foU-containing oligonucleotides in the presence of NaBH4. Furthermore, purified Ntg1 and Ntg2 efficiently cleaved the oligonucleotide at the 5-foU site. CONCLUSIONS: The results indicate that both Ntg1 and Ntg2 are involved in the repair of 5-foU in DNA, and thereby serve to reduce mutations in S. cerevisiae.

Human placental trophoblast cells express alpha-tocopherol transfer protein.

Alpha-tocopherol transfer protein (alpha-TTP), a 30 kDa cytosolic protein first described to be present in the liver and important for alpha-tocopherol trafficking, plays a major role in maintaining alpha-tocopherol levels in plasma, while alpha-tocopherol is known as the major lipid-soluble antioxidant. Expression of alpha-TTP has not only been described in animal model liver, but also in diverse other tissues such as rat brain or pregnant mouse uterus, the latter finding stressing the importance of alpha-TTP for embryogenesis and foetal development. In this study, we report the identification of alpha-TTP in human liver by anti-human alpha-TTP monoclonal antibodies made in rat and the cellular localization of alpha-TTP in term human placenta. By immunohistochemistry, intense staining of alpha-TTP was seen in syncytiotrophoblast as well as in villous and invading extravillous cytotrophoblast, while basal decidual cells showed slighter, but present staining of alpha-TTP. Foetal vessel endothelium remained unstained. It is therefore suggested that alpha-TTP may play a major role in supplying alpha-tocopherol to the foetus prior to delivery and is likely involved in maintaining adequate alpha-tocopherol levels in the foetus.

Characterization of 2-hydroxyadenine DNA glycosylase activity of Escherichia coli MutY protein.

PURPOSE: 2-Hydroxyadenine (2-ohA) is an oxidation product of adenine generated in DNA by ionizing radiation and various chemical oxidants. 2-ohA has mutational potential comparable to that of 8-oxoguanine in bacteria and mammalian cells. Recent studies have shown that 2-ohA is removed from DNA by a human MutY homolog, MYH protein, in vitro. On the other hand, the repair mechanisms for 2-ohA in Escherichia coli are not yet understood. MATERIALS AND METHODS: Gel shift assays were used to assess the binding activity of E. coli full-length MutY protein and its N-terminal (residues 1-226) domain (M25) to 2-ohA/G-, 2-ohA/A-, 2-ohA/C- and 2-ohA/T-containing 24-mer oligonucleotides. Furthermore, whether these proteins specifically cleave 2-ohA-containing duplex oligonucleotides was examined. RESULTS: The purified MutY and M25 proteins had similar binding affinities to 2-ohA/G-, 2-ohA/A- and 2-ohA/C-containing oligonucleotides. MutY protein removed 2-ohA preferentially from 2-ohA/G mispairs. M25 protein showed the reduced catalytic activity for 2-ohA/G-containing oligonucleotides. CONCLUSIONS: E. coli MutY protein has a DNA glycosylase activity that removes 2-ohA from 2-ohA/G mispairs in DNA. The C-terminal domain is required for the removal of 2-ohA from DNA, but is not crucial for binding to 2-ohA-containing oligonucleotides.

Mobile intracranial oily substances from a ruptured teratoma.

A patient with a ruptured intracranial teratoma is presented. The distinctive imaging and neuroendoscopic findings of mobile fatty or oily globules in the subarachnoid or ventricular space are described. Fat suppression magnetic resonance imaging (MRI) and MRI performed with the patient prone was helpful in distinguishing tumour tissue from floating oil.

Morphological character of crystalline components present in saiga horn.

The purpose of this study was to investigate the ultrastructure of saiga-antelope (Saiga tatarica) horn for proposing the mechanism of the initial mineralization. Horn is derived from horny tooth of Cyclostomata. The minerals in saiga horn were identified crystallographically using electron microscopy and X-ray diffraction techniques. Soft X-ray photographs revealed the degree of the mineralization pattern. However, the number of rings did not indicate the age of saiga. Mineral deposites were observed among well banded keratin fibers and composed of powder like crystals. This deposited crystals were found by the X-ray diffraction method to be octacalcium phospate (OCP) by comparing these periodic lattice fringes to JCPDS card data. The chemical formula of OCP is Ca8H2(PO4)6.5H2O. Evidences for the presence of OCP in mature hard tissues have never been obtained. This phenomenon described here may be characteristic of saiga horn because we have found no reports on this type of OCP mineralization in any other animal species. It is possible that OCP is the precursor in the initial mineralization step, indicating in a nucleation of mineral on the keratin fibers.

Clinical study of venous thromboembolism during pregnancy and puerperium.

We encountered 16 cases of venous thromboembolism (VTE) in women during pregnancy and/or puerperium over the past 15 years at our perinatal center, representing 0.14% of all patients who delivered babies. The present study was undertaken to analyze the risk factors, clinical course and outcomes in these 16 cases. The ages of the patients varied from 29 to 39 years. Four women had pulmonary embolism (PE), 3 of which after caesarean section (C/S) at 35 to 40 weeks, and one case after ovarian cystectomy at 13 weeks of gestation. Twelve cases had deep venous thrombosis (DVT), 4 of which during pregnancy, and the remaining 8 cases after C/S. Four patients who had DVT during a normal course of pregnancy had severe thrombophilia: antiphospholipid antibody syndrome, a history of thrombosis and antithrombin (AT) deficiency. They were treated with heparin with or without AT and had healthy babies via successful vaginal deliveries. The common risk factors in 3 cases of PE with C/S was prolonged bed rest due to threatened premature delivery with total placenta previa, uterine myoma and Ehlers-Danlos syndrome. Other risk factors were massive bleeding, and positive lupus anticoagulant. However, the case of the ovarian cystectomy had only one risk factor, which was obesity. This patient died but the remaining patients recovered with treatment. Because of the low incidence of thrombosis in the Japanese population, prophylactic anticoagulant therapy has not routinely been given to patients undergoing obstetrical operations. However, proper management including prophylactic anticoagulant therapy might be considered for risk patients, depending on the risk factors.

Late occurrence of diffuse cerebral swelling after intracerebral hemorrhage in a patient with the HELLP syndrome--Case report.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome can occur at any time in the course of pregnancy and is associated with many complications including fatal stroke. A 37-year-old female presented with HELLP syndrome causing an intracerebral hematoma, which was treated by evacuation and mild hypothermia. Unexpected diffuse cerebral swelling occurred on the 15th day of the initially favorable postoperative course. Considerable impairment of consciousness persisted despite conservative therapy. Serial computed tomographic findings indicated delayed cerebral vasospasm as the cause of the swelling. Particularly careful management is required even beyond the first 2 weeks for patients with stroke as a complication of HELLP syndrome.

[Increased intracranial pressure caused by obstruction of torcular herophili with hemangiopericytoma: a case report].

A 49-year-old male had experienced diplopia for half a year. The intracranial pressure was markedly elevated (450 mmH2O). Neuroimaging revealed a tumor incompletely occluding the torcular herophili and the bilateral transverse sinuses without cerebral or cerebellar compression by the tumor. Both cortical veins and cervical veins were enlarged, and the Sylvian vein and Rabbe's vein and the tentorial sinus were collateral vessels. Biopsy was performed and histologic examination proved hemangiopericytoma. The patient underwent Gamma-knife treatment and the tumor decreased in size 3 months after the treatment.