iNKT cells prevent obesity-induced hepatic steatosis in mice in a C-C chemokine receptor 7-dependent manner.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7-/- mice than in the wild-type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7-/- mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7-/- mice. Moreover, liver inflammation was detected in obese CCR7-/- mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d-/- or interleukin-10-deficient (IL-10-/-) mice. Overall, these results suggest that CCR7+ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells.

A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer.

The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor. Mechanistically, CP prevented nuclear accumulation and promoted ß-TrCP-dependent degradation of NRF2 in a glucocorticoid receptor- and a glycogen synthase kinase 3 (GSK3)-dependent manner. As a result, CP induced oxidative stress and strongly suppressed the anchorage-independent growth of tumors with KEAP1 mutation, but not with the wild-type KEAP1. Further, CP alone or in combination with rapamycin strongly inhibited the in vitro and in vivo growth of tumors harboring mutations in KEAP1 or both KEAP1 and LKB1 that are frequently observed in lung cancer. Thus, CP could be a repurposed therapeutic agent for cancers with high NRF2 activity. We also proposed that the use CP and rapamycin in combination could be a potential therapeutic strategy for tumors harboring both KEAP1 and LKB1 mutations.

Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.

In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7ΔCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARα) was consistently increased in the adipose tissues of Atg7ΔCD11c mice, B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity.

The impact of depression and somatic symptoms on treatment outcomes in patients with chronic prostatitis/chronic pelvic pain syndrome: a preliminary study in a naturalistic treatment setting.

AIM: The aim of this study was to evaluate the impact of depression and somatic symptoms on treatment outcomes in Korean male patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) attending a routine clinical practice. METHODS: This was a 12-week prospective observational study (n = 80). The Korean version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) to measure the severity of CP/CPPS, the Korean version of the Patient Health Questionnaire-9 (PHQ-9) to assess depression, the Korean version of the Patient Health Questionnaire-15 (PHQ-15) to evaluate somatisation and the Korean version of the EuroQol Questionnaire-5 Dimensions (EQ-5D), specifically the EQ-5D utility index and the EQ-5D visual analogue scale (EQ-5D VAS), to assess quality of life, were utilised and given at baseline and week 12. The primary and secondary end-points in this study were changes in the NIH-CPSI total score from baseline to week 12 according to depression and somatisation. RESULTS: The change in NIH-CPSI total score was significantly higher in those without depression than in those with depression (p = 0.003), with a magnitude of difference of 2.8. The responder rate (a ≥ 4 point decrease in NIH-CPSI total score from baseline) was significantly higher in those without depression (42.9%) than in those with depression (17.2%, p = 0.023). However, significant differences were not observed between the two groups in the other outcome measures or in all study outcomes between subjects with or without somatisation. A logistic regression analysis revealed that the presence or absence of depression may be a principal predictor of response to treatment. CONCLUSION: These preliminary results indicate that depression may have a negative impact on treatment outcome and is a likely predictor of response to treatment in patients with CP/CPPS. However, additional studies with adequate power and improved design are necessary to further support the present findings.

Greater osteoporosis educational outreach is desirable among Chinese immigrants in Chinatown, Chicago.

UNLABELLED: Osteoporosis beliefs were assessed in immigrant Chinese women in Chinatown, Chicago. Results from a survey utilizing the Osteoporosis Health Belief Scale showed that women expressed concern about osteoporosis but lacked both knowledge of preventive care and health motivation. INTRODUCTION: The objective of this study was to assess osteoporosis beliefs in immigrant Chinese women in Chinatown, Chicago. METHODS: In a community-based health fair, osteoporosis knowledge and self-efficacy among postmenopausal Chinese immigrants were assessed using the translated Osteoporosis Health Belief Scale. Bone mineral density (BMD) was assessed with calcaneal ultrasound. RESULTS: The study population included 94 women with mean age of 51 +/- 9 years, mean length of residence in the United States of 9 +/- 7 years, and 73% (n = 76) of whom were recent immigrants. Women expressed concern about the seriousness of osteoporosis and their relative susceptibility to osteoporosis. In particular, women with a prior fracture reported higher seriousness to osteoporosis. Nonetheless, women exhibited low health motivation and low awareness of the benefits of calcium and exercise. Bone densitometry results corresponded to a T score of -1.2 +/- 1.5. Multiple regression analysis revealed that a younger age and longer length of residence in the USA were associated with higher BMD. CONCLUSION: Chinese immigrant women in Chicago exhibit concern regarding osteoporosis, but are unaware of the benefits of calcium and exercise, and exhibit low health motivation. Chinese women in Chinatown lack necessary knowledge about osteoporosis to develop adequate self-efficacy. Public health initiatives should be undertaken among recent immigrant Chinese women.

Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys.

Her-2/neu is a well-characterized tumor-associated antigen, the overexpression of which in human carcinomas correlates with a poor prognosis. Here, we evaluated Her-2/neu-specific humoral and cellular immune responses in immunized monkeys after immunization with nonreplicating adenovirus (AdHM) expressing the extracellular and transmembrane domain of human Her-2/neu (HM) and/or naked DNA vaccine (pHM-hGM-CSF) expressing human granulocyte-macrophage colony-stimulating factor together with HM. Priming of monkeys with AdHM generated Her-2/neu-specific long-lasting antibody production. Furthermore, these Her-2/neu-specific antibodies produced by AdHM immunization, some of which shared epitope specificity with Herceptin, were able to induce antibody-dependent cellular cytotoxicity against Her-2-expressing target cells. Cellular immune responses were elicited in all monkeys immunized with Her-2/neu-expressing vaccine; interferon-gamma was secreted when these splenocytes were restimulated with Her-2/neu-expressing autologous cells, and immunization with AdHM induced Her-2/neu-specific lymphoproliferative responses. Further, immunization with pHM-hGM-CSF before AdHM immunization noticeably enhanced cytotoxic T-lymphocyte activity. In addition, we observed no abnormalities that would indicate that the genetic vaccines had toxic effects in the immunized monkeys. Thus, we can conclude that our genetic vaccines efficiently elicited Her-2/neu-specific humoral and cellular immune responses without causing severe adverse effects in nonhuman primates and that as such they warrant further clinical investigation.

Targeting and immobilization of bioactive peptides on dentin matrix.

The regeneration of structurally/functionally competent tooth root cementum is a critical step for the successful restoration of periodontal attachment. In this study, we tested whether a poly-glutamic acid-rich domain and glutamine-containing transglutaminase substrate can be used to target biologically active peptides to the mineralized root matrix and to bind such peptides covalently to the organic matrix. As a biologically active model molecule, the integrin-binding motif, RGD, was used. The effects of immobilization of such synthetic peptides to the dentin matrix on cementoblastic adhesion in vitro and cementogenesis in vivo were studied. In vitro, cementoblastic adhesion improved significantly when the dentin surface contained covalently bound peptides. In vivo, this bound peptide significantly increased cementum formation compared with that attained in control conditions. Transglutaminase-catalyzed covalent binding of bioactive peptides targeted to mineralized collagenous dentin matrix via the poly-glutamate domain can be readily achieved. This approach offers potential for clinical use in periodontal regeneration.

Growth of well-aligned ZnO nanorods using auge catalyst by vapor phase transportation.

Well-aligned ZnO nanorods have been achieved using new alloy (AuGe) catalyst. Zn powder was used as a source material and it was transported in a horizontal tube furnace onto an AuGe deposited Si substrates. The structural and optical properties of ZnO nanorods were characterized by scanning electron microscopy, high resolution X-ray diffraction, and photoluminescence. ZnO nanorods grown at 650 degrees C on 53 nm thick AuGe layer show uniform shape with the length of 8 +/- 0.5 microm and the diameter of 150 +/- 5 nm. Also, the tilting angle of ZnO nanorods (+/- 5.5 degrees) is confirmed by HRXRD. High structural quality of the nanorods is conformed by the photoluminescence measurement. All samples show strong UV emission without considerable deep level emission. However, weak deep level emission appears at high (700 degrees C) temperature due to the increase of oxygen desertion.

The shape control of ZnO based nanostructures.

Tetrapod-shape ZnO nanostructures are formed on Si substrates by vapor phase transportation method. The effects of two important growth parameters, growth temperature and VI/II ratio, are investigated. The growth temperature is varied in the range from 600 degrees C to 900 degrees C to control the vapor pressure of group II-element and the formation process of nanostructures. VI/II ratio was changed by adjusting the flux of carrier gas which affects indirectly the supplying rate of group VI-element. From the scanning electron microscopy (SEM), systematic variation of shape including cluster, rod, wire and tetrapod was observed. ZnO tetrapods, formed at 800 degrees C under the carrier gas flux of 0.5 cc/mm2 min, show considerably uniform shape with 100 nm thick and 1-1.5 microm long legs. Also stoichiometric composition (O/Zn - 1) was observed without any second phase structures. While, the decrease of growth temperature and the increase of carrier gas flux, results in the irregular shaped nanostructures with non-stoichiometric composition. The excellent luminescence properties, strong excitonic UV emission at 3.25 eV without deep level emission, indicate that the high crystalline quality tetrapod structures can be formed at the optimized growth conditions.

Consumo voluntário e digestibilidade aparente da matéria seca, matéria orgânica, energia e parede celular das silagens de quatro genótipos de girassol (Helianthus annus) / Voluntary intake and apparent digestibility of dry matter, organic matter, energy and cell wall components of silages of four sunflower (Helianthus annus) genotypes

O valor nutricional de silagens de quatro genótipos de girassol (Rumbosol 91, M734, C11 e S430) foi avaliado a partir do consumo voluntário e da digestibilidade aparente da matéria seca, da matéria orgânica, da energia e dos componentes da parede celular. Vinte carneiros adultos foram alojados em gaiolas metabólicas, em delineamento inteiramente ao acaso, com quatro tratamentos e cinco repeticões. Não foram observadas diferencas para consumo de matéria seca, matéria orgânica, energia digestível e metabolizável e dos componentes fibrosos entre os genótipos de girassol. A digestibilidade aparente da matéria orgânica foi superior para os genótipos R91, M734 e S430, no entanto não influenciou o consumo de matéria orgânica digestível. As silagens de girassol foram classificadas como alimento volumoso de boa qualidade, uma vez que o consumo de matéria seca foi acima dos requisitos recomendados para mantenca animal, 63,6; 69,6; 50,2 e 74,5g MS/kg0,75/dia para R91, M734, C11 e S430, respectivamente. O baixo coeficiente de digestibilidade aparente médio da FDN (32,3 por cento) e da FDA (28,7 por cento) foi conseqüência da baixa qualidade dos constituintes da parede celular das silagens de girassol utilizadas.

Magnetic resonance imaging and proton magnetic resonance spectroscopy in neuro-Behçet's disease.

OBJECTIVE: Neuro-Behcet's disease (NBD) is one of the most serious complications of Behcet's disease (BD). Proton magnetic resonance spectroscopy (1H MRS) has been proved to be useful in detecting neuro-metabolic abnormalities in various diseases affecting the brain. In this study, we attempted to characterize the magnetic resonance imaging (MRI) findings in Korean patients with NBD and then examined the usefulness of 1HMRS in evaluating the MRI-negative brain area of NBD patients. METHODS: We performed brain MRI in 18 BD patients with neurologic symptoms and signs. Seven NBD patients without thalamic lesions and 8 healthy controls underwent brain 1H MRS, in which an 8 ml voxel was placed in the left thalamus and the N-acetylaspartate (NAA)/creatine (Cr) ratio was measured. RESULTS: Fourteen of 18 BD patients were diagnosed as having NBD and 12 NBD patients (86%) had brain lesions on MRI. Most lesions were of high signal intensity on T2-weighted images and located in the midbrain, pons, basal ganglia, and white matter. On 1H MRS, the thalamic area without gross abnormalities on MRI showed a significantly lower NAA/Cr ratio in NBD patients compared to healthy controls (1.07 +/- 0.08 versus 1.54 +/- 0.27, P < 0.01). In 2 NBD patients, the NAA/Cr ratios, monitored serially, were normalized along with clinical improvement 6 months after treatment with prednisolone and immune suppressive agents. CONCLUSION: MRI is a very sensitive diagnostic method for NBD, and 1H MRS may be useful for the early detection and follow-up of MRI-negative NBD.

Nonlinear analysis of the EEG of schizophrenics with optimal embedding dimension.

We estimated the correlation dimensions of EEGs in patients with schizophrenia to investigate the dynamical properties underlying the EEG. We employed a new method, proposed by Kennel et al. (Kennel MB, Brown R, Abarbanel HDI. Determining embedding dimension for phase-space reconstruction using a geometrical construction. Phys Rev A 1992;45:3403-11), to calculate the correlation dimension D2. That method determined the proper minimum embedding dimension by looking at the behaviour of nearest neighbours under a change in the embedding dimension d from d to d + 1. We demonstrated that for limited noisy data, our algorithm was strikingly faster and more accurate than previous ones. We estimated the D2 of EEGs from 16 channels in patients with schizophrenia according to DSM-IV whereas previous studies, which estimated chaoticity of EEG in schizophrenia, recorded EEG only in a limited number of channels. Schizophrenic patients had a lower correlation dimension in the left inferior frontal and anterior temporal regions compared with controls. Our finding of decreased left frontal and temporal chaotic activity in schizophrenics is in line with the findings of a hypofrontality and hypotemporality reported in previous clinical studies such as EEG, blood flow, brain MRI and positron emission tomography studies in schizophrenia. This result suggests that chaos analysis may be a useful tool in analysing EEG data to explore the brain mechanism of schizophrenia.

Reliability and validity of the cognitive impairment diagnosing instrument (CIDI) in the elderly.

The reliability and validity of the Cognitive Impairment Diagnosing Instrument (CIDI) were studied in 67 nursing home elderly subjects and 251 elderly psychiatric patients. Its possible highest score is 77 and covers 10 subscales: short-term memory, long-term memory, concentration/calculation, abstract thinking, judgement, memory registration, higher cortical functions, orientation in time, orientation in place and object naming. Test-retest correlations were between 0.827 and 0.990 for the subscale scores and 0.984 for the total score. Inter-tester kappas for each item ranged from 0.200 to 1.000 with a mean of 0.698. Concordance rates were between 50.0 and 100.0% with a mean of 87.2%. Cronbach's alphas for the items of the individual subscales ranged from 0.702 to 0.915. Inter-subscale and subscale-total correlations ranged from 0.503 to 0.820 with a mean of 0.684 and from 0.721 to 0.883, respectively. Cronbach's alpha of the subscales was 0.934. Sensitivity and specificity were 93.3% and 93.8% at the cut-off point of 57.0/57.5 for dementia. Subscale and total scores were significantly different between the demented and non-demented. The total CIDI score was significantly correlated with scores of the Blessed Dementia Rating Scale and the Korean version of the Mini-Mental State Examination.

Dementia among the elderly in a rural Korean community.

The age-specific prevalence of dementia, its sex difference, and the relative prevalence of important types of dementia were studied in the elderly people in a Korean rural community. A two-stage approach was employed, involving screening and clinical assessment. The prevalence among individuals aged 65 and over was found to be 10.8%, with rates of 7.2% in men and 14.5% in women. The dementia was of the Alzheimer type in 60.0% of cases, multi-infarct dementia in 12.0%, mixed dementia of Alzheimer type and multi-infarct in 10.7%, alcoholic dementia in 8.0%, and others and unclassifiable in 9.3%. The prevalence of dementia of the Alzheimer type was significantly higher in women and rapidly increased with age in both sexes. The prevalence of multi-infarct dementia was not related to sex or age. Alcoholic dementia was identified only in men. These findings indicate that the prevalence of dementia in rural Korea is similar to that reported in Western countries and that the prevalence of dementia of the Alzheimer type in rural Korea is greater than that of multi-infarct dementia.

Psychological maladjustment and academic achievement: a cross-cultural study of Japanese, Chinese, and American high school students.

Psychological maladjustment and its relation to academic achievement, parental expectations, and parental satisfaction were studied in a cross-national sample of 1,386 American, 1,633 Chinese, and 1,247 Japanese eleventh-grade students. 5 indices of maladjustment included measures of stress, depressed mood, academic anxiety, aggression, and somatic complaints. Asian students reported higher levels of parental expectation and lower levels of parental satisfaction concerning academic achievement than their American peers. Nevertheless, Japanese students reported less stress, depressed mood, aggression, academic anxiety, and fewer somatic complaints than did American students. Chinese students reported less stress, academic anxiety, and aggressive feelings than their American counterparts, but did report higher frequencies of depressed mood and somatic complaints. High academic achievement as assessed by a test of mathematics was generally not associated with psychological maladjustment. The only exception was in the United States, where high achievers indicated more frequent feelings of stress than did low achievers.

Possible superoxide radical-induced alteration of vascular reactivity in aortas from streptozotocin-treated rats.

We investigated the possible involvement of the superoxide (.O2-) radical in alterations of vascular reactivity and phosphoinositide (PI) turnover in aortas from streptozotocin (STZ)-induced diabetic (4 week) rats. STZ treatment increased the maximal contractile response of the aorta to norepinephrine (NE), phenylephrine (PE) and high K+, whereas the sensitivity remained unaltered. Ca(++)-induced contractions in the presence of maximally effective concentrations of PE and K+ were also augmented after STZ treatment. The increased maximal response was associated with both decreased endothelium-dependent relaxation and increased NE-induced PI turnover. Pyrogallol (PYR), a potent .O2- generating agent, did not affect basal tone or PI turnover but, depending on concentrations, it significantly increased or decreased both the contractile response to PE and NE-induced PI turnover in control aorta. In contrast, PYR decreased NE-induced PI turnover in diabetic aorta. The malondialdehyde content of liver, serum and aorta, and of .O2- from aorta of diabetic rats, were increased significantly. Copper catalyzed oxidation of ascorbic acid resulted in contraction followed by relaxation, depending upon the ascorbic acid concentration in both control and diabetic aorta. Pretreatment with superoxide dismutase (300 U/ml) prevented the PYR-induced potentiation of the PE contraction, but not of NE+PYR-induced PI turnover in control aorta and decreased further NE+PYR-induced PI turnover in diabetic aorta. The present findings indicate that .O2- may be responsible, at least in part, for the impaired endothelial integrity, enhanced alpha adrenergic receptor-mediated PI turnover and augmented contractility, possibly through modification of calcium channels in STZ-induced short-term (4 week) diabetic rat aorta.

Pharmacological characterization of effects of verapamil and GS 283 on isolated guinea pig and rat trachealis.

The pharmacological effects of verapamil and GS 283, 1-(4'-methoxybenzyl)-6,7-dihydroxy-3,4-dihydroxyisoquinoline, were investigated using isolated rat and guinea pig trachealis. Both verapamil and GS 283 inhibited carbachol-, histamine (only guinea pig)-, and high-K(+)-induced contraction in a dose-dependent manner. GS 283 acted as a weak histamine H1 and muscarinic receptor antagonist in guinea pig and rat trachealis with respective pKB values in the range of 5.60 approximately 6.12 and 5.17 approximately 5.83. On the other hand, pyrilamine and atropine showed a typical competitive antagonism on histamine (guinea pig) and on muscarinic receptors (rat trachea) with pKB values of 9.25 +/- 0.21 and 9.37 +/- 0.32, respectively. GS 283 inhibited Ca(2+)-induced contraction on guinea pig trachealis in Ca(2+)-free media. Furthermore, very high concentrations of GS 283 and verapamil completely abolished a phasic contraction induced by carbachol in Ca(2+)-free media, suggesting that verapamil and GS 283 can enter into the cytoplasm, where they may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum. It is concluded that GS 283 has a Ca2+ antagonistic action along with weak histamine and muscarinic receptor blocking activity in isolated rat and guinea pig tracheal smooth muscle and its mode of action is likely inhibition of Ca2+ influx from plasma membrane and also release from the sarcoplasmic reticulum.

The nature of clotting and fibrinolytic activities of Bacteroids melaninogenicus.

From the supernatant of B. melaninogenicus ss. asaccharolyticus culture, a protein fraction was isolated by ethanol precipitation. The fraction was tested for the presence of clotting and fibrinolytic activities by application of quantitative techniques and specific substrates for measurement of prothrombin and plasminogen activation, and collagenase and elastase activity. It is postulated that ability of Bacteroides melaninogenicus ss. asaccharolyticus extracellular factors to clot fibrinogen and activate plasminogen, are due to a limited proteolysis by the proteolytic enzymes produced by this microorganism and not to the existence of specific B. melaninogenicus coagulase of plasminogen activator.