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Objective: To study obstructive sleep apnea syndrome (OSAS) in epilepsy patients using Epworth questionnaire and overnight polysomnography test. Patients & Method: All epilepsy patients, both male and female who attended the neurology clinic in Universiti Sains Malaysia Hospital (HUSM) and who agree to participate in this study were included. This protocol involved the assessment of sleepiness in epilepsy patients by using the Epworth questionnaire. All of the subjects underwent an overnight polysomnography test in HUSM sleep laboratory. Result: Our preliminary survey of epilepsy patients showed the majority of them were sleepy as compared to the general population. Further data will correlate the sleepiness with the obstructive sleep apnea syndrome. Discussion & Conclusion: The effect of antiepileptic medication in epileptic patients may be associated with OSAS. The mechanism of the association is still unknown. Perhaps treating OSAS may reduce the frequency of epileptic attack and improve compliance of epileptic patients. [ABSTRACT FROM AUTHOR]

PURPOSE: To study the prevalence of OSAS in children with Adenotonsillar enlargement in HUSM and the association of adenoid and tonsillar pharyngeal ratio with severity of OSAS in HUSM. METHODS: This pilot study is a cross sectional study done from October 2003 to October 2004 in children age 1 to 17 years old in HUSM, Kubang Kerian. . History of symptoms of OSAS were obtained from the parents and all subjects are subjected to a ENT physical examination, lateral soft tissue x-ray of nasopharynx and oropharynx and an overnight polysomnography. The Adenoids size was determine by measuring the adenoid to nasopharyngeal ratio and the tonsil size was determined by the tonsillar to pharyngeal ratio (T-P ratio) on the radiograph. The severity of OSAS was assessed using Apnea Index (AI) in the Polysomnography. RESULTS: A total of 12 males and 4 females with median age is 7 years were involved. The commonest symptoms are snoring, restless sleep and mouth breathing. 87.5% subjects had tonsillar enlargement. The median for TP ratio was 0.83. The median Adenoid ratio was 0.58 and the median for Apnea Index was 12.05. The clinical tonsil size did not associate with AI. The TP and Adenoid ratio also did not correlate with AI. CONCLUSION: The prevalence of OSAS among children with Adenotonsillar pathology is high. Symptoms of OSAS should be asked regularly to those children with Adenotonsillar pathology because certain symptoms of OSAS are under detected. It is important to recognized and treat the disease early. [ABSTRACT FROM AUTHOR]

Background: Japanese dietary patterns have traditionally focused on vegetables, legumes, and fish; however, in the last few quarters of the century, the consumption of meat, processed food, and ultra-processed food has become popular. It is anticipated that these changes in the Japanese dietary environment will increase the risk of developing psychosomatic disorders., Methods: In this study, we examined the relationship between dietary habits, psychosomatic disorders, and a sense of achievement. For men and women aged 20-80 years ( n = 851) living in and around Ebetsu City, Hokkaido, Japan, a questionnaire on dietary habits over the past year, including mental and physical stress and a sense of achievement, was administered. The associations between dietary habits and psychosomatic disorders or a sense of achievement were analyzed using logistic regression ( n = 654)., Results: The associations between dietary habits and psychosomatic disorders differ depending on sex and age. We found that subjects who consumed more processed meat and ultra-processed food reported more psychosomatic disorders. On the other hand, those who perceived a sense of achievement consumed higher amounts of vegetables, albeit with a lower fish intake., Conclusions: In this study, we demonstrated that dietary habits and food ingredients are associated with mental and physical stress and a sense of achievement. Fish, which is considered to be good for the body, was mostly consumed by subjects who experienced mental and physical stress. These data indicate that highly stressful conditions may encourage fish consumption, as the body needs to mitigate psychosomatic disorders.

Background: Aggressive lipid-lowering therapy is important for secondary prevention of acute myocardial infarction (AMI). The recommended target for low-density lipoprotein cholesterol (LDL-C) of <70 mg/dL is often not achieved. To address this gap, we implemented a clinical pathway in all hospitals that perform percutaneous coronary interventions (PCI) with primary care physicians in Nagasaki and aimed to validate the effectiveness of this pathway in an acute setting., Methods and Results: This retrospective cohort study included medical records extracted from 8 hospitals in Nagasaki, Japan, where PCI was performed for patients with AMI. The index date was defined as the date of hospitalization for AMI between July 1, 2021, and February 28, 2023. The primary outcome was the rate of achieving LDL-C <70 mg/dL at discharge. The median baseline LDL-C level at admission was 121 mg/dL (n=226) in the pre-implementation group and 116 mg/dL (n=163) in the post-implementation group. In the post-implementation group, 131 patients were treated using the clinical pathway. The rate of achieving LDL-C <70 mg/dL at discharge increased significantly from 37.2% before implementation to 54.6% after implementation. Logistic regression analysis revealed a positive correlation between the implementation of the clinical pathway and achieving LDL-C <70 mg/dL., Conclusions: Implementation of a region-wide clinical pathway for LDL-C management significantly improved the rate of intensive lipid-lowering therapy and the achievement of LDL-C targets.

Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against polyomavirus infection in vitro and in vivo using mouse polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although in vitro BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection in vivo , supporting further investigation into the use of BCV to treat clinical polyomavirus infections., Importance: Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic., Competing Interests: K.F. and M.H. are employees of Symbio, which owns the license to BCV.

Although promoting healthy eating is a policy objective, the manageability of dietary habits remains uncertain. Personal dietary patterns reflect many factors, some of which are relatively manageable for individuals whilst others are not. In this article, assuming that some sort of information about the manageability of dietary habits is contained in the observed patterns of food consumption, we focused on dietary patterns on their own. We introduced a statistical descriptive model for data from a food frequency questionnaire, estimated the strength of pairwise linkage between foodstuffs, and grouped foodstuffs by applying community detection to the networks of the estimated inter-food linkages. Those linkages represent the co-movement of pairs of food in consumption. Furthermore, we demonstrated an analysis of the relationship between mental health and dietary habits, considering the aspect of the manageability of dietary habits. Using an observational study in Japan, we obtained the following results: 115 foodstuffs were divided into three groups for both genders, but the compositions were different by gender; in the analysis of mental and physical health, some stress response items were associated with a dependence on some of those food groupings (e.g., "extremely tired" was negatively associated with a group containing tomatoes, cucumber, mandarin, etc., for female subjects). As the grouping of foodstuffs based on our estimation depicted an internal structure of dietary habit that a healthy eating policy could regard as a constraint, it follows that we should design such a policy along the same lines as that grouping.

Background: Electroconvulsive therapy is effectively used for treatment-resistant depression; however, its neural mechanism is largely unknown. Resting-state functional magnetic resonance imaging is promising for monitoring outcomes of electroconvulsive therapy for depression. This study aimed to explore the imaging correlates of the electroconvulsive therapy effects on depression using Granger causality analysis and dynamic functional connectivity analyses., Methods: We performed advanced analyses of resting-state functional magnetic resonance imaging data at the beginning and intermediate stages and end of the therapeutic course to identify neural markers that reflect or predict the therapeutic effects of electroconvulsive therapy on depression., Results: We demonstrated that information flow between the functional networks analyzed by Granger causality changes during electroconvulsive therapy, and this change was correlated with the therapeutic outcome. Information flow and the dwell time (an index reflecting the temporal stability of functional connectivity) before electroconvulsive therapy are correlated with depressive symptoms during and after treatment., Limitations: First, the sample size was small. A larger group is needed to confirm our findings. Second, the influence of concomitant pharmacotherapy on our results was not fully addressed, although we expected it to be minimal because only minor changes in pharmacotherapy occurred during electroconvulsive therapy. Third, different scanners were used the groups, although the acquisition parameters were the same; a direct comparison between patient and healthy participant data was not possible. Thus, we presented the data of the healthy participants separately from that of the patients as a reference., Conclusions: These results show the specific properties of functional brain connectivity., Competing Interests: Conflict of interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is one of the most effective treatments for depression and schizophrenia, particularly in urgent or treatment-resistant cases. After ECT, regional gray matter volume (GMV) increases have been repeatedly reported both in depression and schizophrenia. However, the interpretation of these findings remains entangled because GMV changes do not necessarily correlate with treatment effects and may be influenced by the intervention itself. We hypothesized that the comparison of longitudinal magnetic resonance imaging data between the two diagnostic groups will provide clues to distinguish diagnosis-specific and transdiagnostic changes., Method: Twenty-nine Japanese participants, including 18 inpatients with major depressive disorder and 11 with schizophrenia, underwent longitudinal voxel-based morphometry before and after ECT. We investigated GMV changes common to both diagnostic groups and those specific to each group. Moreover, we also evaluated potential associations between GMV changes and clinical improvement for each group., Results: In both diagnostic groups, GMV increased in widespread areas after ECT, sharing common regions including: anterior temporal cortex; medial frontal and anterior cingulate cortex; insula; and caudate nucleus. In addition, we found a schizophrenia-specific GMV increase in a region including the left pregenual anterior cingulate cortex, with volume increase significantly correlating with clinical improvement., Conclusions: Transdiagnostic volume changes may represent the effects of the intervention itself and pathophysiological changes common to both groups. Conversely, diagnosis-specific volume changes are associated with treatment effects and may represent pathophysiology-specific impacts of ECT., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human mastadenovirus (HAdV), a linear double-stranded DNA (dsDNA) virus, is the causal agent of several diseases, including pharyngoconjunctival fever, epidemic keratoconjunctivitis, and hemorrhagic cystitis, in immunocompromised individuals. There are more than 100 reported types of adenoviruses, but the pathogenicity of many HAdVs remains unknown. Brincidofovir (BCV) is a hexadecyloxypropyl lipid conjugate of cidofovir (CDV) that is active against dsDNA viruses. Clinical effectiveness of BCV against certain HAdV species has been reported; however, its activity against novel HAdV types remains unknown. We investigated the half-maximal inhibitory concentration (IC 50 ) values of BCV for novel HAdV types and found that the epidemic keratoconjunctivitis-associated HAdV-D54 prevalent in the Asian region was the most susceptible. The mean overall IC 50 value of BCV was lower than that of CDV, indicating that BCV is effective against HAdVs, including the novel types. IMPORTANCE We investigated the IC 50 values of BCV for novel HAdV types and found that the epidemic keratoconjunctivitis-associated HAdV-D54 prevalent in the Asian region was the most susceptible. In addition, the mean overall IC 50 value of BCV was lower than that of CDV, indicating that BCV is effective against HAdVs.

Introduction: Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE) which contributes to significant morbidity and mortality. It is unclear whether the timing of LN onset influences renal outcome. This study aimed to investigate differences in clinical features-particularly the relapse-free rate-in remission duration from induction therapies for LN and the onset timing of LN after the development of SLE., Methods: We enrolled 66 LN patients from January 2004 to March 2020. We collected the following: demographic data, laboratory data, renal histology data, and LN induction therapy data. Renal remission and relapse-free rates were calculated for each group., Results: Patients were first divided into early remission group (achieved renal remission in <12 months [n = 44]) and others (n = 22). There were no significant differences in clinical data, treatments, and relapse-free rate of LN. Patients were then divided into initial-onset LN (<12 months after development of SLE [n = 49]) and delayed-onset LN (≥12 months after development of SLE [n = 17]). Kaplan-Meier analysis showed that the relapse-free rate was significantly higher in all patients with initial-onset LN than those with delayed-onset LN (P = .0094)., Conclusion: The relapse-free rate was significantly higher in the initial-onset LN group than the delayed-onset LN group of patients with LN of various histopathological backgrounds. These data suggest that delayed-onset LN is a risk factor for the relapse of LN., (© 2021 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Luc's abscess is an exceedingly rare complication of otitis media, where the middle ear infection spreads extratemporally causing a subperiosteal collection under the temporalis muscle. It is known as a benign complication of otitis media as it is thought not to involve the mastoid bone in comparison to other types of extratemporal abscesses related to otitis media. We describe a challenging case of a 19-year-old male with Down syndrome diagnosed with Luc's abscess involving the mastoid bone. A high-resolution computed tomography scan is important to determine the extent of the abscess, with or without mastoid involvement, and the presence of complications. These findings will then help to determine the surgical options. Drainage of abscesses is a simple, initial, and conservative approach but less effective compared to mastoidectomy. 'Mastoidsparing' approach should only be considered if there is complete resolution after a simple drainage and antibiotic treatment.

Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP (cAMP), a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and profibrotic responses. Clinical benefits of pentoxifylline, a non-selective PDE inhibitor, have been reported in patients with kidney disease. Here, we identified compound A as a potent and selective PDE4 inhibitor and evaluated its potential as a novel therapeutic agent for diabetic nephropathy (DN). To determine its in vivo efficacy on DN, uninephrectomized (UNx-) db/db mice and KKA y mice were used as DN mice models. Eight-week repeated dosing with compound A (1-10 mg/kg, QD, p.o.) showed dose-dependent and significant suppressive effects on glycosylated hemoglobin (GHb) and urinary albumin/creatinine ratio (UACR) in UNx-db/db mice. These effects are more potent than irbesartan, a clinically approved angiotensin II receptor blocker of DN. Moreover, compound A suppressed pro-fibrotic and pro-inflammatory marker mRNAs and increased anti-reactive oxygen species marker mRNAs in the kidneys of UNx-db/db mice. The similar effect of compound A on UACR was also demonstrated by 8-week repeated dose in KKA y mice, another model for DN with intact leptin axis. Taken together, these data suggest that the PDE4-selective inhibitor compound A has potential as a new therapeutic agent for DN with multiple mechanisms of action including anti-diabetic, anti-fibrotic, and anti-reactive oxygen species effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKA y mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-β). Moreover, compound A significantly suppressed TGF-β-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms., (© 2020 Federation of American Societies for Experimental Biology.)

Recent studies examining electroconvulsive therapy (ECT) have reported that early sessions can induce rapid antidepressant and antipsychotic effects, and the early termination of ECT was reported to increase the risk of relapse. We hypothesized that different neural mechanisms associated with the therapeutic effects of ECT may be involved in the different responses observed during the early and late periods of ECT treatment. We investigated whether these antidepressant and antipsychotic effects were associated with temporally and spatially different regional gray matter volume (GMV) changes during ECT. Fourteen patients with major depressive disorder, with or without psychotic features, underwent 3-Tesla structural magnetic resonance imaging scans before (time point [Tp] 1), after the fifth or sixth ECT session (Tp2), and after ECT completion (Tp3). We investigated the regions in which GMV changed between Tp1 and Tp2, Tp2 and Tp3, and Tp1 and Tp3 using voxel-based morphometry. In addition, we investigated the association between regional GMV changes and improvement in depressive or psychotic symptoms. GMV increase in the left superior and inferior temporal gyrus during Tp1-Tp2 was associated with improvement in psychotic symptoms (P < 0.025). GMV increase in the left hippocampus was associated with improvement of depressive symptoms in Tp2-Tp3 (P < 0.05). Our findings suggest that different temporal lobe structures are associated with early antipsychotic and late antidepressant effects of ECT.

Autoantibodies have been implicated in schizophrenia aetiology. Here, novel autoantibodies were isolated from patients with schizophrenia. Autoantibody candidates were searched using two-dimensional gel electrophoresis and western blotting with rat brain proteins as antigens and two sera pools (25 schizophrenia patients versus 25 controls) as antibodies. Immunoreactive antigens were identified by mass spectrometry. Antibody prevalence were evaluated by western blotting using human recombinant proteins. Furthermore, brain magnetic resonance imaging data (regional brain volumes and diffusion tensor imaging measures) were compared. Two proteins of the mitochondrial respiration pathway were identified as candidate antigens. Three patients with schizophrenia, but no controls, expressed antibodies targeting one of the candidate antigens, i.e., pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial (PDHA1, EC 1.2.4.1), which is related to mitochondrial energy production. Anti-PDHA1 antibody-positive patients (n = 3) had increased volumes in the left occipital fusiform gyrus compared to both controls (n = 23, p = 0.017) and antibody-negative patients (n = 16, p = 0.009), as well as in the left cuneus compared to antibody-negative patients (n = 16, p = 0.018). This is the first report of an anti-PDHA1 antibody in patients with schizophrenia. Compatible with recent findings of mitochondrial dysfunction in schizophrenia, this antibody may be involved in the pathogenesis of a specific subgroup of schizophrenia.

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.

Introduction: Multicentric reticulohistiocytosis (MRH) is a rare histiocytic disorder that involves the skin, joints, and visceral organs., Case Presentation: We report a 67-year-old woman with MRH who presented with a 2-years history of polyarthralgia and skin nodules. Her symptoms were an inflammatory polyarthropathy with punched-out lesions of the distal interphalangeal (DIP) joints of both hands. Doppler ultrasonography of the hands showed large bone erosions with power Doppler signals in the DIP joints. F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated increased FDG uptake in cutaneous papules surrounding the affected joints, suggesting an inflammatory process. There was no evidence of malignancy. Biopsy samples of skin nodules exhibited dermal infiltration with CD68-positive histiocytes and multinucleated giant cells. The patient was diagnosed with MRH and treated with combination therapy comprising a steroid (prednisolone), tacrolimus, methotrexate, and infliximab, which resulted in clinical improvement. Following infliximab treatment, there was a significant decrease in a bone resorption marker (tartrate-resistant acid phosphatase 5b: TRACP-5b), suggesting that tumor necrosis factor-α targeting therapy may inhibit osteoclast formation and resorption activity in patients with MRH., Conclusion: MRH is a progressive destructive arthritic condition, and early diagnostic and therapeutic strategies are necessary to improve the outcome. FDG-PET/CT and joint ultrasonography might be noninvasive imaging modalities that could help diagnose MRH.

Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy., (© FASEB.)

The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC 50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED 50 =1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pneumatosis cystoides intestinalis (PCI) is a rare disease that involves the presence of gas in the intestinal wall. Connective tissue disease (CTD) is a major cause of secondary PCI. In addition to the nature of CTDs, the use of prednisolone and some immunosuppressants, and the presence of complicating diseases such as diabetes mellitus, constipation and pulmonary diseases are involved in the development of PCI. This report describes four cases of PCI with different CTDs (granulomatosis with polyangiitis, rheumatoid arthritis, dermatomyositis, and overlap syndrome) and discusses the background of each patient and common risk factors for the occurrence of PCI.

Background: Despite lifestyle interventions and various types of anti-hypertension agents, hypertension remains difficult to control in some patients with type 2 diabetes. As a noninvasive device-based approach for the treatment of clinic hypertension, we examined the effects of low-frequency and low-intensity ultrasound (500 or 800kHz, 25mW/cm(2)) applied to the forearm on blood pressure (BP) and pulse rate in Japanese subjects with type 2 diabetes and hypertension., Methods: We examined the effects of low-frequency and low-intensity ultrasound (500 or 800kHz, 25mW/cm(2)) applied to the forearm on BP, pulse rate, and pulse pressure in 212 Japanese subjects (82 men and 130 women; mean age±SE, 65±1years) with type 2 diabetes and hypertension (systolic BP>140mmHg). The subjects were treated with anti-hypertension agents., Results: Systolic and diastolic BP, pulse rate, pulse pressure in the 800-kHz ultrasound treatment group were significantly lower than the baseline values in hypertensive subjects with type 2 diabetes, and lower than those of placebo controls. In addition, systolic and diastolic BP, pulse rate, and pulse pressure in the 500-kHz ultrasound treatment group were significantly lower than the baseline values in hypertensive subjects with type 2 diabetes, and systolic BP, pulse rate, and pulse pressure were significantly lower than those of placebo controls., Conclusions: Low-frequency (800kHz or 500kHz) and low-intensity (25mW/cm(2)) ultrasound irradiation to the forearm might have potential usefulness as a therapeutic application for clinic hypertension in subjects with type 2 diabetes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Visualizing the detailed brain anatomy of individuals with schizophrenia has been made possible by recent advances in magnetic resonance imaging (MRI). Although structural MRI cannot be currently used to diagnose schizophrenia, multimodal MRI can reveal insightful information on key clinical aspects of the pathological physiology of schizophrenia. However, in this regard, the number of multimodal MRI studies is still limited and definitely required. In this review, we discuss how classical and popular theories on the pathological physiology of schizophrenia can be re-examined using neuroimaging studies, and also discuss how multimodal MRI studies may provide additional findings. The pathological hypotheses examined include the "progressive brain disease hypothesis" and "disconnection hypothesis". This article is discussed mainly based on recent findings published by our research group., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

The human Nogo-66 receptor 1 (NgR1) gene, also termed Nogo receptor 1 or reticulon 4 receptor (RTN4R) and located within 22q11.2, inhibits axonal growth and synaptic plasticity. Patients with the 22q11.2 deletion syndrome show multiple changes in brain morphology, with corpus callosum (CC) abnormalities being among the most prominent and frequently reported. Thus, we hypothesized that, in humans, NgR1 may be involved in CC formation. We focused on rs701428, a single nucleotide polymorphism of NgR1, which is associated with schizophrenia. We investigated the effects of the rs701428 genotype on CC structure in 50 healthy participants using magnetic resonance imaging. Polymorphism of rs701428 was associated with CC structural variation in healthy participants; specifically, minor A allele carriers had larger whole CC volumes and lower radial diffusivity in the central CC region compared with major G allele homozygous participants. Furthermore, we showed that the NgR1 3' region, which contains rs701428, is a neuronal activity-dependent enhancer, and that the minor A allele of rs701428 is susceptible to regulation of enhancer activity by MYBL2. Our results suggest that NgR1 can influence the macro- and microstructure of the white matter of the human brain.

Photoactive molecules that reversibly switch upon visible light irradiation are one of the most attractive targets for biological as well as imaging applications. One possible approach to prepare such photoswitches is to extend π-conjugation length of molecules and shift the absorption bands to longer wavelengths. Although several attempts have been demonstrated based on this approach for diarylethene (DAE) photoswitches, photoreactivity of the DAE derivatives is dramatically suppressed when the conjugation length is extended by connecting aromatic dyes at the side positions of aryl groups in the DAE unit. In this study, we successfully prepared a visible-light reactive DAE derivative by introducing an aromatic dye at the reactive carbon atom of the DAE unit, optimizing orbital level of each component, and controlling the mutual orientation of the aromatic dye and the DAE unit. The DAE derivative (3) undergoes a photocyclization reaction upon irradiation with 560 nm light and the closed-isomer converts to the open-ring isomer upon irradiation with 405 nm light. The high photoconversion yields (>90%) were achieved for both photocyclization and photocycloreversion reactions. The photoreactivity induced by visible light irradiation and the molecular design strategy were discussed based on theoretical calculations.

Previous neuroimaging studies have revealed that both gray matter (GM) and white matter (WM) are altered in several morphological aspects in schizophrenia patients. Although several studies reported associations between GM and WM alterations in restricted regions, the existence of a global association between GM and WM pathologies is unknown. Considering the wide distribution of GM morphological changes and the profound genetic background of WM abnormalities, it would be natural to postulate a global association between pathologies of GM and WM in schizophrenia. In this investigation, we studied 35 schizophrenia patients and 35 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) and investigated the association between GM thickness and WM fractional anisotropy (FA) as a proxy of pathology in each tissue. To investigate cortical thickness, surface-based analysis was used. The mean cortical thickness for the whole brain was computed for each hemisphere, and group comparisons were performed. For DTI data, mean FA for the whole brain was calculated, and group comparisons were performed. Subsequently, the correlation between mean cortical thickness and mean FA was investigated. Results showed that the mean cortical thickness was significantly thinner, and the mean FA was significantly lower in schizophrenia patients. Only in the patient group the mean cortical thickness and mean FA showed significant positive correlations in both hemispheres. This correlation remained significant even after controlling for demographic and clinical variables. Thus, our results indicate that the GM and WM pathologies of schizophrenia are intertwined at the global level.

Social isolation contributes to the development of obesity and insulin-independent diabetes in KKA(y) mice. Here we show that systemic administration of liraglutide, a long-acting human glucagon-like peptide-1 (GLP-1) analog, significantly decreased food intake, body weight, and blood glucose levels at 24 h after its administration while having no significant effects on plasma insulin and glucagon levels in individually housed KKA(y) mice. In addition, the systemic administration of liraglutide significantly increased plasma fibroblast growth factor (Fgf) 21 levels (1.8-fold increase) associated with increases in the expression of hepatic Fgf21 (1.9-fold increase) and Pparγ (1.8-fold increase), while having no effects on the expression of hepatic Pparα and Fgf21 in white adipose tissue. Moreover, systemic administration of liraglutide over 3 days significantly suppressed food intake, body weight gain, and hyperglycemia in KKA(y) mice. On the other hand, despite remarkably increased plasma active GLP-1 levels (4.2-fold increase), the ingestion of alogliptin, a selective dipeptidyl peptidase-4 inhibitor, over 3 days had no effects on food intake, body weight, blood glucose levels, and plasma Fgf21 levels in KKA(y) mice. These findings suggest that systemic administration of liraglutide induces hepatic Fgf21 production and suppresses the social isolation-induced obesity and diabetes independently of insulin, glucagon, and active GLP-1 in KKA(y) mice.

The atomic and electronic structures of NiO(001)∕Au(001) interfaces were analyzed by high-resolution medium energy ion scattering (MEIS) and photoelectron spectroscopy using synchrotron-radiation-light. The MEIS analysis clearly showed that O atoms were located above Au atoms at the interface and the inter-planar distance of NiO(001)∕Au(001) was derived to be 2.30 ± 0.05 Å, which was consistent with the calculations based on the density functional theory (DFT). We measured the valence band spectra and found metallic features for the NiO thickness up to 3 monolayer (ML). Relevant to the metallic features, electron energy loss analysis revealed that the bandgap for NiO(001)∕Au(001) reduced with decreasing the NiO thickness from 10 down to 5 ML. We also observed Au 4f lines consisting of surface, bulk, and interface components and found a significant electronic charge transfer from Au(001) to NiO(001). The present DFT calculations demonstrated the presence of an image charge beneath Ni atoms at the interface just like alkali-halide∕metal interface, which may be a key issue to explain the core level shift and band structure.

G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein-coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca²⁺ concentration ([Ca²⁺](i)) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca²⁺](i) was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of β-cell [Ca²⁺](i). TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The β-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia.

Background: Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy., Methods: Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned., Discussion: We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials., Trial Registration: This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm).

Aim: Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and voglibose, an alpha-glucosidase inhibitor, have different but complementary mechanisms of action on glucagon-like peptide-1 (GLP-1) regulation and glucose-lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice., Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice., Results: After 3 weeks, voglibose treatment increased GLP-1 secretion (voglibose alone, 1.6-fold; alogliptin plus voglibose, 1.5-fold), while it decreased plasma glucose-dependent insulinotropic polypeptide (GIP) (voglibose alone, -30%; alogliptin plus voglibose, -29%). Alogliptin, voglibose and combination treatment decreased plasma DPP-4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP-1 levels by 4.5-, 1.8- and synergistically by 9.1-fold respectively. Combination treatment increased plasma insulin by 3.6-fold (alogliptin alone, 1.3-fold; voglibose alone, 1.8-fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6-, 3.4- and synergistically by 8.5-fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha-cell distribution in the pancreatic islet., Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP-1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta-cells and islet structure in prediabetic db/db mice.

Background: Hypersensitivity reaction (HSR) and sensory neuropathy are major complications of oxaliplatin-based chemotherapy. Preplanned withdrawal of oxaliplatin after the first six cycles and reintroduction at the time of disease progression (stop-and-go strategy) may reduce neurotoxicity. However, the effect of an oxaliplatin-free interval on HSR occurrence remains poorly understood., Patients and Methods: Data on patients with colorectal cancer who received FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) treatment between June 2005 and June 2009 were retrieved from the prospective cohort database of the Outpatient Oncology Unit of the Kyoto University Hospital. Factor analysis was performed., Results: Among patients who received six or fewer cycles of FOLFOX, the incidence of HSR was low (7/99, 7.1%). For patients who received more than six cycles, the incidence of HSR was higher among patients treated with stop-and-go FOLFOX than among patients treated with continuous FOLFOX (25/61, 41.0% vs. 13/63, 20.6%; p = 0.019). Interestingly, most cases of HSR during stop-and-go FOLFOX occurred during the second or third cycle of the reintroduction phase (21/25, 84%). Multivariate analysis identified undergoing an oxaliplatin-free interval as an independent risk factor (p = 0.016)., Conclusions: An oxaliplatin-free interval may increase the risk of HSR. Special vigilance is needed during the second and third cycles after reintroduction of oxaliplatin., (Copyright © 2010 S. Karger AG, Basel.)

Administration of an alpha-glucosidase inhibitor, voglibose, increases the secretion of glucagon-like peptide (GLP)-1, a key modulator of pancreatic islet hormone secretion and glucose homeostasis. In the present study, novel mechanisms by which voglibose increases active GLP-1 circulation were evaluated. Voglibose (0.001 and 0.005%) was administered in the diet to ob/ob mice for 1 day or 3 to 4 weeks to determine effects on incretin profiles and plasma activity of dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for GLP-1 degradation. Voglibose showed no direct inhibitory effect against DPP-4 in vitro (DPP-4 inhibitor alogliptin, IC(50) < 10 nM). Likewise, 1-day treatment with voglibose did not change plasma DPP-4 activity; however, it increased plasma active GLP-1 by 1.6- to 3.4-fold. After chronic treatment, voglibose stimulated GLP-1 secretion, as evidenced by the 1.3- to 1.5-fold increase in plasma active plus inactive amidated GLP-1 levels. Plasma DPP-4 activity was decreased unexpectedly by 40 to 51%, resulting from reduced plasma DPP-4 concentrations in voglibose-treated mice. Voglibose increased GLP-1 content by 1.5- to 1.6-fold and 1.4- to 1.6-fold in the lower intestine and colon, respectively. The increased GLP-1 content in the colon was associated with elevated expression of gut glucagon gene. Chronic treatment with voglibose resulted in 1.9- to 4.1-fold increase in active GLP-1 circulation, which was higher than 1-day treatment. A similar treatment with pioglitazone (0.03%), an insulin sensitizer, did not affect plasma DPP-4 activity or GLP-1 levels. These results suggest that increased GLP-1 secretion, decreased DPP-4 activity, and increased gut GLP-1 content may have contributed to increased active GLP-1 circulation after chronic treatment with voglibose in a glucose control-independent manner in ob/ob mice.

We have described a new DNA sequencing platform based on the Sanger chemistry, in which the large-scale microfabricated channel plates and electrophoretic system result in higher-throughput DNA sequencing. Three hundred and eighty-four channels are arranged in a fan-like shape on a 25x47 cm glass plate, on which 384 oval sample holes are connected to each channel coupled to the opposite anode access holes. Two microfabricated plates are set on the sequencing apparatus, in which sequencing electrophoresis is conducted on one plate and the preparation process is on another plate. Each sample hole is loaded with 2.3 microL volume of sample and injected into separation channels electrokinetically. High-quality sequencing data were acquired using the pUC18 template, achieving an average read-length of 1001 bases with 99% accuracy and a throughput of 5 Mbases per day per instrument. To assess the performance in actual sequencing field, the bacterial artificial chromosome shotgun library of the Pseudorca crassidens genome was sequenced, using 1/80 of the quantity of Sanger reagent (0.1 microL). We believe that this is the first demonstration of the useful performance of DNA sequencing using monolithic microfabricated devices with walk-away operation.

Photochromism of a symmetric diarylmaleimide derivative, having two thiophene rings (1), and a non-symmetric derivative having a S,S-dioxide thiophene ring and a thiophene ring (2) as the aryl moieties, was studied in various solvents. The photocyclization quantum yield of gradually decreased with increasing the solvent polarity and the reaction was not observed in polar solvents, such as ethanol and acetonitrile; on the other hand, such a strong solvent dependence of the photocyclization reaction was not observed for ; the different behavior is attributed to the weaker electron donating ability of the S,S-dioxide thiophene ring.

Epiglottic cyst is usually asymptomatic and the commonest presentation is foreign body sensation in the throat. Treatment of epiglottic cysts depends on their size and on the clinical symptoms. Surgery is necessary for large ones. Various modalities of therapy include endoscopic excision, marsupialization and deroofing with or without a carbon dioxide laser. We report our experience of managing a case of a large epiglottic cyst with a carbon dioxide laser.

Our aim was to examine the effects of gender, ear asymmetry, and age of infants on various parameters of transient evoked otoacoustic emissions (TEOAEs). Three hundred thirty-two infants (181 males, 151 females) were tested using the ILO292 Otodynamics Analyzer (Otodynamics Ltd, England) as a screening procedure. The subjects were divided into two age groups: group 1, newborn infants prior to hospital discharge (mean age of 4 days), and group 2, infants at the 1-month-old health checkup (mean age of 35 days). Responses to TEOAE stimuli were recorded at 1.0, 1.5, 2.0, 3.0, and 4.0 kHz. There were significant effects of gender and ear (left/right) on the signal-to-noise ratio, response level, and whole-wave and band reproducibility values in TEOAEs. The right ear had higher values of whole-wave reproducibility, response level, signal-to-noise ratio, and band reproducibility than the left ear. Females displayed higher whole-wave reproducibility, response level, band reproducibility, and signal-to-noise ratio values than males. There was no significant difference in response level, signal-to-noise ratio, and band reproducibility between the two age groups. The findings of the present investigation may contribute toward future improvements in neonatal hearing screening based on the community.

Transgenesis using large DNA such as YAC or BAC has extended the range of applications in functional genomics. Here we describe an efficient BAC transgenesis protocol using a simple BAC DNA preparation method adopted from YAC DNA purification methods. This method allowed us to isolate BAC DNA from small scale culture of BAC-containing cells in sufficient quantity and purity for microinjection. More than 40 founders have been produced with linearized BAC DNA prepared by this method, and 85% of them contained intact BAC transgenes. In contrast, when circular BAC DNA was injected, an approximately three-fold reduction of transgene integration rate was observed and fewer intact transgene integrations were obtained. A line of transgenic mice carrying a 170-kb BAC clone generated in this way successfully rescued tail and embryonic lethality phenotypes of the mouse Brachyury (T) mutants, further demonstrating the utility of this method in functional analysis of the mouse genome.

Corticothalamic projections from cortical auditory field to the medial geniculate body (MG) in the rat were systematically examined by making small injections of biocytin in cortical area Te1. All injections, confined to 400 microm in diameter, resulted in two projections terminating in the ventral (MGV) and dorsal divisions (MGD) of the MG. The projections to the MGV were evidently topographic. The rostral and caudal portions of area Te1 projected to the ventromedial and dorsolateral parts of the MGV, respectively, forming narrow bands of terminal axons that extended in the mediolateral direction in the coronal plane of the MGV. The minimum dorsoventral width of the bands ranged approximately from 100 to 300 microm. Besides, the more rostral portion of area Te1 tended to project to the more rostral side of the MGV. The projections to the MGD consistently arborized in its ventral margin made up of the deep dorsal nucleus of the MGD. A similar weak topography along the rostrocaudal direction was observed in the projections to the MGD. Large terminals were occasionally found in the MGD after the injections involving cortical layer V. The distribution of large terminals also appeared topographic along with small terminals that were the major component of labeling. Collaterals of labeled axons produced slabs of terminal field in the thalamic reticular nucleus, which also exhibited a weak topography of distribution. These results provide insights into the structural basis of corticofugal modulations related to the tonotopic organizations in the cortex and MG.

A novel series of 5-(omega-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neurotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were performed by construction of an oxazole ring as a key reaction. Most of the 5-(omega-aryloxyalkyl)oxazole derivatives markedly increased BDNF production in SK-N-SH cells. 4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-[3-(2-methoxyphenoxy)propyl]-1, 3-oxazole, one of the most promising compounds, showed potent activity (EC(50)=7.9 microM) and the improvement of the motor nerve conduction velocity and the tail-flick response accompanied by a recovery of the brain-derived neurotrophic factor level in the sciatic nerve of streptozotocin (STZ)-diabetic rats.

Thalamocortical projections from the auditory thalamic nuclei were examined systematically in the rat, including those from the dorsal division (MGD) of the medial geniculate body (MG), which were less clearly determined in previous studies. Injections of biocytin confined in each thalamic nucleus revealed characteristic features of projections in terms of cortical areas and layers of termination. In contrast to exclusively selective projections to cortical area Te1 from the ventral division (MGV) of the MG, diffuse and selective terminations were observed in the projections from the dorsal (MGD) and medial divisions (MGM) of the MG and the suprageniculate nucleus (SG). Diffuse termination was continuous in layer I or VI of the temporal cortex, while selective termination was in layers III and IV of discrete cortical areas. In addition to diffuse termination in the upper half of layer I of cortical areas Te1, Te2d and Te3v, the MGD and SG projections formed plexuses of axons selectively in lower layer III and layer IV of Te2d and Te3v. The SG projections targeted further the dorsal bank of the perirhinal cortex (PRh), while the MGD projections targeted in part the ventral fringe of Te1. The MGM projections terminated diffusely in layer VI of Te1 and Te3v, and selectively in lower layer III and layer IV of the rostral part of Te3v. Diffuse projections to layers I and VI from the SG and MGM extended in cortical regions over the dorsal fringe of Te1. Selective dense projections to middle cortical layers of Te2d and Te3v (especially its rostral part) indicate the existence of auditory areas, which could be involved in cross-modal interaction with visual and somatosensory system, respectively. Diffuse projections are supposed to bind information processings in these areas and the primary auditory area (Te1).

A 69-year-old man with a history of transient chest pain was diagnosed takotsubo cardiomyopathy. In I-123-beta-metyl-iodophenyl pentadecanoic acid myocardial scintigraphy, decreased uptake of apex was seen in the acute phase, and it recovered in 3 months. In I-123-meta-iodobenzyl-guanidine myocardial scintigraphy, decreased uptake of apex persisted for 6 months, and there was a discrepancy between apical and total washout rate in the acute phase and after 3 months, which disappeared after 6 months. We speculate that the discrepancy of sympathetic innervation between the apical and basal region is the cause of the characteristic left ventricular apical akinesia of takotsubo cardiomyopathy.

Parvalbumin (PV) is expressed in fast-twitch fibers in skeletal muscles and a subpopulation of inhibitory neurons in the CNS. We generated transgenic mice that expressed the human interleukin-2 receptor alpha-subunit-green fluorescent fusion protein (hIL-2R-GFP) using two types of PV transgene. One contained the hIL-2R-GFP gene downstream of a 16.5-kb 5'-upstream PV genomic sequence (PV line). The other comprised the hIL-2R-GFP gene in bacterial artificial chromosome (BAC) with either a 180-kb (PA line) or 155-kb (PB line) insert encompassing the PV gene. Independent lines of all transgenic mice showed a faithful hIL-2R-GFP expression in fast-twitch muscle fibers. However, appreciable hIL-2R-GFP expression in the CNS occurred only in the PA transgenic lines. In one line of PA transgenic mice, hIL-2R-GFP was properly expressed in PV-containing neurons in the cerebellum, thalamic reticular nucleus, globus pallidus and cerebral cortex, though ectopic expression was observed in a particular subset of cerebellar astrocytes. Another line of PA transgenic mice showed a selective and mosaic expression of hIL-2R-GFP in PV-containing Purkinje, basket and stellate cells in the cerebellum. These results indicate that the 16.5-kb PV genomic sequence is sufficient for fiber-type-selective transcription but additional regulatory sequences comprised in BAC DNA are required for proper expression in PV-containing neurons.

Monoamine compartmentalization in monoaminergic neurons uses serial action of the plasma membrane and vesicular monoamine (VAMT2) transporters. We can now define the sequences of the genes encoding these transporters in mice and humans, examine influences of deletions of this gene and alteration in its expression levels in transgenic mice, and identify sequence polymorphisms in the human VMAT2 gene. Examination of VMAT2 variants can provide potential insights into roles for allelic variants at these loci in variant drug responses and in diseases linked to monoaminergic systems, including substance abuse and Parkinson's disease.

The RIKEN high-throughput 384-format sequencing pipeline (RISA system) including a 384-multicapillary sequencer (the so-called RISA sequencer) was developed for the RIKEN mouse encyclopedia project. The RISA system consists of colony picking, template preparation, sequencing reaction, and the sequencing process. A novel high-throughput 384-format capillary sequencer system (RISA sequencer system) was developed for the sequencing process. This system consists of a 384-multicapillary auto sequencer (RISA sequencer), a 384-multicapillary array assembler (CAS), and a 384-multicapillary casting device. The RISA sequencer can simultaneously analyze 384 independent sequencing products. The optical system is a scanning system chosen after careful comparison with an image detection system for the simultaneous detection of the 384-capillary array. This scanning system can be used with any fluorescent-labeled sequencing reaction (chain termination reaction), including transcriptional sequencing based on RNA polymerase, which was originally developed by us, and cycle sequencing based on thermostable DNA polymerase. For long-read sequencing, 380 out of 384 sequences (99.2%) were successfully analyzed and the average read length, with more than 99% accuracy, was 654.4 bp. A single RISA sequencer can analyze 216 kb with >99% accuracy in 2.7 h (90 kb/h). For short-read sequencing to cluster the 3' end and 5' end sequencing by reading 350 bp, 384 samples can be analyzed in 1.5 h. We have also developed a RISA inoculator, RISA filtrator and densitometer, RISA plasmid preparator which can handle throughput of 40,000 samples in 17.5 h, and a high-throughput RISA thermal cycler which has four 384-well sites. The combination of these technologies allowed us to construct the RISA system consisting of 16 RISA sequencers, which can process 50,000 DNA samples per day. One haploid genome shotgun sequence of a higher organism, such as human, mouse, rat, domestic animals, and plants, can be revealed by seven RISA systems within one month.

A 4-year-old girl with congenital profound deafness underwent cochlear implant surgery. Preoperative CT and MRI revealed that her inner ears had common-cavity or aplasia-type malformation. The bilateral internal auditory meatus were markedly narrowed. Audiometric examination demonstrated that only slight residual hearing remained in the low-frequency range and that a hearing aid would be of no benefit. Cochlear implantation was performed in her left ear. Because of the abnormal position of the facial nerve, the routine facial recess approach could not be performed. A canal-wall-down mastoidectomy was performed, and multichannel cochlear implant electrodes were inserted by careful drilling of the bony wall of the semicircular canal area. All 22 electrodes were completely inserted into the cavity. The patient can perceive sounds and her hearing ability is progressively improving.

The clinical features of patients with Klinefelter's syndrome attending a male infertility clinic have been investigated in order to consider their assisted reproduction treatment options. Over 12 years, a total of 148 patients with sterility due to azoospermia had Klinefelter's syndrome. Eight patients were shown by fluorescence in-situ hybridization (FISH) on metaphase spreads to be mosaic (46,XY/47,XXY), and 140 patients showed only 47,XXY. Small testes were observed in 95% of patients and gynaecomastia was seen in 12.4%. Half of the patients showed hypergonadotrophic hypogonadism, while others showed normogonadism (usually hypergonadotrophic). Spermatozoa were observed in semen from one patient with mosaicism and one without. Three-colour FISH revealed hyperploidy in 2.7% and 2.3% of these spermatozoa respectively. Multiple-site testicular biopsies in five recent patients were performed and yielded a specimen with round and elongated spermatids in one patient with 47,XXY karyotype. This sample was cryopreserved for future intracytoplasmic sperm injection. At follow-up, 46% of couples had chosen artificial insemination with donor sperm, and none had chosen adoption. Two patients developed testicular tumours, one a mature teratoma and the other a Leydig cell tumour. Two patients required androgen replacement therapy.

Impairment of endothelial cells by oxidized low density lipoprotein (OxLDL) is believed to be the first step in atherogenesis. It is also believed that oxidative stress/antioxidant imbalance is involved in the cell damage by OxLDL. However, little is known about the interaction between OxLDL and antioxidants. In this study, we show that treatment of human vascular endothelial cells with OxLDL caused a gradual increase of glutathione (gamma-glutamylcysteinyl glycine, GSH) levels in 24 h. OxLDL increased the intracellular levels of reactive oxygen species (ROS) and stimulated the expression of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for the GSH synthesis, the mitogen-activated protein kinase (MAPK) activity, and the AP-1-DNA binding activity. The luciferase activity of gamma-GCS promoter containing AP-1 site was activated by OxLDL. Collectively, OxLDL induces gamma-GCS expression mediated by AP-1 resulting in an increase of GSH levels. The MAPK activity stimulated by ROS may be involved in the activation of AP-1. The increase in GSH by OxLDL may afford cellular protection against OxLDL-induced oxidative stress.