The plasma membrane of mammalian cochlear outer hair cells contains prestin, a unique motor protein. Prestin is the fifth member of the solute carrier protein 26A family. Orthologs of prestin are also found in the ear of non-mammalian vertebrates such as zebrafish and chicken. However, these orthologs are electrogenic anion exchangers/transporters with no motor function. Amphibian and reptilian lineages represent phylogenic branches in the evolution of tetrapods and subsequent amniotes. Comparison of the peptide sequences and functional properties of these prestin orthologs offer new insights into prestin evolution. With the recent availability of the lizard and frog genome sequences, we examined amino acid sequence and function of lizard and frog prestins to determine how they are functionally and structurally different from prestins of mammals and other non-mammals. Somatic motility, voltage-dependent nonlinear capacitance (NLC), the two hallmarks of prestin function, and transport capability were measured in transfected human embryonic kidney cells using voltage-clamp and radioisotope techniques. We demonstrated that while the transport capability of lizard and frog prestin was compatible to that of chicken prestin, the NLC of lizard prestin was more robust than that of chicken’s and was close to that of platypus. However, unlike platypus prestin which has acquired motor capability, lizard or frog prestin did not demonstrate motor capability. Lizard and frog prestins do not possess the same 11-amino-acid motif that is likely the structural adaptation for motor function in mammals. Thus, lizard and frog prestins appear to be functionally more advanced than that of chicken prestin, although motor capability is not yet acquired.

Microevolution and origins of Bradyrhizobium populations associated with soybeans at two field sites (A and B, 280 km apart in Canada) with contrasting histories of inoculation was investigated using probabilistic analyses of six core (housekeeping) gene sequences. These analyses supported division of 220 isolates in five lineages corresponding either to B. japonicum groups 1 and 1a or to one of three novel lineages within the genus Bradyrhizobium. None of the isolates from site A and about 20% from site B (the only site with a recent inoculation history) were attributed to inoculation sources. The data suggest that most isolates were of indigenous origin based on sequence analysis of 148 isolates of soybean-nodulating bacteria from native legumes (Amphicarpaea bracteata and Desmodium canadense). Isolates from D. canadense clustered with B. japonicum group 1, whereas those from A. bracteata were placed in two novel lineages encountered at soybean field sites. One of these novel lineages predominated at soybean sites and exhibited a significant clonal expansion likely reflecting selection by the plant host. Homologous recombination events detected in the 35 sequence types from soybean sites had an effect on genetic diversification that was approximately equal to mutation. Interlineage transfer of core genes was infrequent and mostly attributable to gyrB that had a history of frequent recombination. Symbiotic gene sequences (nodC and nifH) of isolates from soybean sites and native legumes clustered in two lineages corresponding to B. japonicum and B. elkani with the inheritance of these genes appearing predominantly by vertical transmission. The data suggest that soybean-nodulating bacteria associated with native legumes represent a novel source of ecologically adapted bacteria for soybean inoculation.

Background

Mutations in SLC26A4, which encodes pendrin, are a common cause of deafness. SLC26A4 mutations are responsible for Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA). The mutation spectrum of SLC26A4 varies widely among ethnic groups. To investigate the incidence of EVA in Chinese population and to provide appropriate genetic testing and counseling to patients with SLC26A4 variants, we conducted a large-scale molecular epidemiological survey of SLC26A4.

Methods

A total of 2352 unrelated non-syndromic hearing loss patients from 27 different regions of China were included. Hot spot regions of SLC26A4, exons 8, 10 and 19 were sequenced. For patients with one allelic variant in the hot spot regions, the other exons were sequenced one by one until two mutant alleles had been identified. Patients with SLC26A4 variants were then examined by temporal bone computed tomography scan for radiological diagnosis of EVA. Ten SLC26A4 variants were cloned for functional study. Confocal microscopy and radioisotope techniques were used to examine the membrane expression of pendrin and transporter function.

Results

Of the 86 types of variants found, 47 have never been reported. The ratio of EVA in the Chinese deaf population was at least 11%, and that in patients of Han ethnicity reached at least 13%. The mutational spectrum and mutation detection rate of SLC26A4 are distinct among both ethnicities and regions of Mainland China. Most of the variants caused retention of pendrin in the intracellular region. All the mutant pendrins showed significantly reduced transport capability.

Conclusion

An overall description of the molecular epidemiological findings of SLC26A4 in China is provided. The functional assessment procedure can be applied to identification of pathogenicity of variants. These findings are valuable for genetic diagnosis, genetic counseling, prenatal testing and pre-implantation diagnosis in EVA families.

Objective

We studied the clinical and laboratory features and outcomes of multiple myeloma (MM) with extramedullary plasmocytoma (EP) disease both at diagnosis and during the course of MM.

Patients and methods

Forty-two patients of 467 patients with MM were retrospectively analyzed from both the 100th Hospital of the People’s Liberation Army and Shanghai Changzheng Hospitals. The clinical characteristics, laboratory parameters, responses, risk factors, and outcomes were analyzed.

Results

The median age was 53 years with a male/female sex ratio of 34:8. Twenty-six patients had EP disease at the time of diagnosis, and 16 patients developed EP during the course of the disease. We found that the Durie–Salmon stage, serum lactate dehydrogenase level, beta-2-microglobulin, complete blood counts, albumin, and the type of immunoglobulin (Ig) were not associated with the development of EP disease. Patients who developed EP during the course of MM had a higher ratio of plasmocytes and premature plasmocytes in the bone marrow with lower C-reactive protein level and earlier stage of International Staging System for Lung Cancer at the diagnosis of MM compared with patients who presented with EP at diagnosis. Once the patients developed EP disease, they frequently showed resistance to chemotherapy. With a median follow-up of 30 months, 19 patients were alive. Log-rank univariate analysis showed that patients with EP who had normal C-reactive protein, higher hemoglobin, lower serum lactate dehydrogenase, and stage I of International Staging System for Lung Cancer had longer survival. However, cyclooxygenase multivariate analysis failed to show statistical significance for any factor.

Conclusions

EP disease is the MM end-phase and is not a rare manifestation of MM with a cumulative incidence of 9% of MM. The prognosis is very poor once the diagnosis of EP disease is concurrent with MM.

Influenza vaccines are less effective in older people than younger people. This impaired ability to protect older people from influenza viral lung infection has important implications as older people suffer a higher morbidity and mortality from influenza viral lung infection than younger people. Therefore, the development of novel effective vaccines that induce protection from influenza viral infections in older people are urgently needed. We had previously shown that direct linking the TLR5 activator, flagellin, to viral peptides induces effective immunity to viral antigens in young mice and people, respectively. In this study, we tested the efficacy of this vaccine platform with the hemagglutinin peptide of the influenza A strain virus (vaccine denoted as STF2.HA1-2) in protecting aged mice from subsequent influenza viral lung infection. We found that a 3.0μg dose of the vaccine was effective in reducing mortality and increasing clinical well-being during influenza viral lung infection in aged mice. However, this effect was inferior to the response induced in young mice. Defects in the adaptive immune system but not the innate immune system were associated with this reduced effectiveness of the vaccine with aging. Our results indicate that the STF2.HA1-2 vaccine is effective in protecting aged hosts from influenza lung infection, although defects in the adaptive immune system with aging may limit the effectiveness of this vaccine in older people.

Background

Human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) are among the most complex health problems in the world. Young people are at high risk of HIV and AIDS infections and are, therefore, in need of targeted prevention. School-based HIV/AIDS health education may be an effective way to prevent the spread of AIDS among adolescents.

Methods

The study was a school-based intervention conducted in three middle schools and two high schools in Wuhan, China, which included 702 boys and 766 girls, with ages from 11 to 18 years old. The intervention was a one-class education program about HIV/AIDS for participants. HIV/AIDS knowledge, attitude, and high-risk behaviors were investigated using an anonymous self-administered questionnaire before and after the education intervention. Chi-square test was used to compare differences before and after the intervention. Non-conditional logistic regression analysis was used to identify the factors that affect HIV/AIDS knowledge.

Results

Misconceptions about basic medical knowledge and non-transmission modes of HIV/AIDS among all the students prevail. Approximately 10% to 40% of students had negative attitudes about HIV/AIDS before the intervention. After the intervention, all of the students had significant improvements in knowledge and attitude about HIV/AIDS (P<.05), indicating that educational intervention increased the students’ knowledge significantly and changed their attitudes positively. Logistic regression analyses indicated that before the intervention the students’ level of knowledge about HIV/AIDS was significantly associated with grade, economic status of the family, and attitudes toward participation in HIV/AIDS health information campaigns.

Conclusions

HIV/AIDS education programs were welcomed by secondary students and positively influenced HIV/AIDS-related knowledge and attitudes. A systematic and long-term intervention among secondary school students must be conducted for the prevention of HIV.

The aim of the present study was to establish a canine model of delayed splenic rupture (DSR). A total of 15 mongrel dogs were anesthetized and laparotomized. The hematomas were observed following an injection of heparin. The hematomas were ruptured. The severity of the spleen rupture was evaluated and the intra-abdominal free liquid was measured. The splenic hematomas in the dogs continued to form and the hematoma area gradually increased. The hematomas were ruptured after impacting the abdominal wall. The spleens were damaged, and conventional ultrasonography showed intra-abdominal free liquid. These conditions were demonstrated via computed tomography scanning. A DSR canine model was established successfully.

Time-resolved cardiac imaging is particularly interesting in the interventional setting since it would provide both image guidance for accurate procedural planning and cardiac functional evaluations directly in the operating room. Imaging the heart in vivo using a slowly rotating C-arm system is extremely challenging due to the limitations of the data acquisition system and the high temporal resolution required to avoid motion artifacts. In this paper, a data acquisition scheme and an image reconstruction method are proposed to achieve time-resolved cardiac cone-beam computed tomography imaging with isotropic spatial resolution and high temporal resolution using a slowly rotating C-arm system. The data are acquired within 14 s using a single gantry rotation with a short scan angular range. The enabling image reconstruction method is the prior image constrained compressed sensing (PICCS) algorithm. The prior image is reconstructed from data acquired over all cardiac phases. Each cardiac phase is then reconstructed from the retrospectively gated cardiac data using the PICCS algorithm. To validate the method, several studies were performed. Both numerical simulations using a hybrid motion phantom with static background anatomy as well as physical phantom studies have been used to demonstrate that the proposed method enables accurate reconstruction of image objects with a high isotropic spatial resolution. A canine animal model scanned in vivo was used to further validate the method.

Of all available reconstruction methods, statistical iterative reconstruction algorithms appear particularly promising since they enable accurate physical noise modeling. The newly developed compressive sampling/compressed sensing (CS) algorithm has shown the potential to accurately reconstruct images from highly undersampled data. The CS algorithm can be implemented in the statistical reconstruction framework as well. In this study, we compared the performance of two standard statistical reconstruction algorithms (penalized weighted least squares and q-GGMRF) to the CS algorithm. In assessing the image quality using these iterative reconstructions, it is critical to utilize realistic background anatomy as the reconstruction results are object dependent. A cadaver head was scanned on a Varian Trilogy system at different dose levels. Several figures of merit including the relative root mean square error and a quality factor which accounts for the noise performance and the spatial resolution were introduced to objectively evaluate reconstruction performance. A comparison is presented between the three algorithms for a constant undersampling factor comparing different algorithms at several dose levels. To facilitate this comparison, the original CS method was formulated in the framework of the statistical image reconstruction algorithms. Important conclusions of the measurements from our studies are that (1) for realistic neuro-anatomy, over 100 projections are required to avoid streak artifacts in the reconstructed images even with CS reconstruction, (2) regardless of the algorithm employed, it is beneficial to distribute the total dose to more views as long as each view remains quantum noise limited and (3) the total variation-based CS method is not appropriate for very low dose levels because while it can mitigate streaking artifacts, the images exhibit patchy behavior, which is potentially harmful for medical diagnosis.

The potential capabilities and analytical performance of lab-on-valve (LOV) manifold as a front end to amperometry have been explored for the on-line determination of morin. Meanwhile, the electrochemical behaviors of morin were investigated based on polyvinylpyrrolidone- (PVP-) doped carbon paste electrode (CPE), which found that PVP can significantly improve its oxidation peak current. The excellent amperometric current response was achieved when the potential difference (ΔE) of 0.6 V was implemented in pH 6.5 phosphate buffer solution (PBS) that served as the supporting electrolyte. A well-defined oxidation peak has been obtained in studies using PVP as a modifier of CPE based on the oxidation of morin. The present work introduces the LOV technique as a useful tool for amperometric measurement, documents advantages of using programmable flow, and outlines means for miniaturization of assays on the basis of PVP modified CPE. The proposed method was applied successfully to the determination of morin in real samples, and the spiked recoveries were satisfactory.

Purpose

This study explored the extent to which trait aggression is associated with suicidal behavior in a nationwide school-based sample of adolescents.

Methods

A nationwide sample of 14,537 high school students in urban areas of China was recruited. Information concerning suicide ideation, plans, attempts, trait aggression and other risk factors was collected by a self-reported questionnaire. Multivariate regression analyses were employed to predict suicidal behavior.

Results

Approximately 18.5% of students reported suicide ideation, 8.7% reported suicide plans, and 4.1% reported attempts during the past one year. Hostility and trait anger had a significant positive association with suicidal ideation. Hostility and physical aggression were positively related to suicide plans. Hostility had a positive correlation with suicide attempts, while trait anger was inversely associated with suicide attempts.

Conclusions

This study suggests that hostility, physical aggression and trait anger may be able to be used to predict suicidal behavior among adolescents. Suicide prevention programs should target at attenuating the severity of hostility, anger and physical aggression. But teachers and parents should also give close attention to students with low trait anger.

There are two independent mol­ecules in the asymmetric unit of the title compound, C20H17ClO3, each having an E configuration about the –C=C– bond. The dihedral angles between the two benzene rings in the two mol­ecules are 7.17 (11) and 9.82 (11)°. In both mol­ecules, the hy­droxy group is involved in an intra­molecular O—H⋯O hydrogen bond.

Background

An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood–brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system.

Methods

Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography.

Results

Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP (P < 0.05) and were significantly higher than that of the conventional liposome (P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups (P < 0.01 versus LIP).

Conclusion

The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.

Background

In recent years, many studies have focused on adolescent's sex-related issues in China. However, there have been few studies of unmarried migrant females' sexual knowledge, attitudes and behaviors, which is important for sexual health education and promotion.

Methods

A sample of 5156 unmarried migrant female workers was selected from three manufacturing factories, two located in Shenzhen and one in Guangzhou, China. Demographic data, sexual knowledge, attitudes and behaviors were assessed by self-administered questionnaires. Multivariate logistic regression analysis was conducted to examine the factors associated with premarital sexual intercourse.

Results

The average age of the unmarried female workers included in the sample was 20.2 years, and majority of them showed a low level of sex-related knowledge. Females from the west of China demonstrated a significant lower level of sex-related knowledge than those from the eastern or central provinces (p < 0.05). Approximately 13% of participants held a favorable attitude towards premarital sexual intercourse, and youths from the east/central were more likely to have favorable attitudes compared with those from the west (p < 0.05). About 17.0% of the unmarried female workers reported having engaged in premarital sexual intercourse, and females from the east/central were more likely to have experienced premarital sexual intercourse than those from the west (p < 0.05). Multivariate analysis revealed that age, education, current residential type, dating, sexual knowledge, attitudes, and pattern of communication were significantly associated with premarital sexual intercourse.

Conclusion

The unmarried migrant female workers lack sexual knowledge and a substantial proportion of them are engaged in premarital sexual behaviors. Interventions aimed at improving their sexual knowledge and related skills are needed.

Much life science and biology research requires an understanding of complex relationships between biological entities (genes, compounds, pathways, diseases, and so on). There is a wealth of data on such relationships in publicly available datasets and publications, but these sources are overlapped and distributed so that finding pertinent relational data is increasingly difficult. Whilst most public datasets have associated tools for searching, there is a lack of searching methods that can cross data sources and that in particular search not only based on the biological entities themselves but also on the relationships between them. In this paper, we demonstrate how graph-theoretic algorithms for mining relational paths can be used together with a previous integrative data resource we developed called Chem2Bio2RDF to extract new biological insights about the relationships between such entities. In particular, we use these methods to investigate the genetic basis of side-effects of thiazolinedione drugs, and in particular make a hypothesis for the recently discovered cardiac side-effects of Rosiglitazone (Avandia) and a prediction for Pioglitazone which is backed up by recent clinical studies.

Autophagy is an evolutionarily conserved catabolic process that allows recycling of cytoplasmic organelles, such as mitochondria, to offer a bioenergetically efficient pathway for cell survival. Considerable progress has been made in characterizing mitochondrial autophagy. However, the dedicated ubiquitin E3 ligases targeting mitochondria for autophagy have not been revealed. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells. The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane. RNF185 stimulates LC3II accumulation and the formation of autophagolysosomes in human cell lines. We further identified the Bcl-2 family protein BNIP1 as one of the substrates for RNF185. Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. Our study might reveal a novel RNF185-mediated mechanism for modulating mitochondrial homeostasis through autophagy.

SUMMARY

Anti-HER2/neu antibody therapy is reported to mediate tumor regression by interrupting oncogenic signals and/or inducing FcR-mediated cytotoxicity. Here, we demonstrate that the mechanisms of tumor regression by this therapy also require the adaptive immune response. Activation of innate immunity and T cells, initiated by antibody treatment, was necessary. Intriguingly, the addition of chemotherapeutic drugs, while capable of enhancing the reduction of tumor burden, could abrogate antibody-initiated immunity leading to decreased resistance to re-challenge or earlier relapse. Increased influx of both innate and adaptive immune cells into the tumor microenvironment by a selected immunotherapy further enhanced subsequent antibody-induced immunity, leading to increased tumor eradication and resistance to re-challenge. Therefore, this study proposes a model and strategy for anti-HER2/neu antibody-mediated tumor clearance.

The trafficking protein particle complex 4 (TRAPPC4) is implicated in vesicle-mediated transport, but its association with disease has rarely been reported. We explored its potential interaction with ERK2, part of the ERK1/2 complex in the Extracellular Signal-regulated Kinase/ Mitogen-activated Protein Kinase (ERK-MAPK) pathway, by a yeast two-hybrid screen and confirmed by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down. Further investigation found that when TRAPPC4 was depleted, activated ERK1/2 specifically decreased in the nucleus, which was accompanied with cell growth suppression and apoptosis in colorectal cancer (CRC) cells. Overexpression of TRAPPC4 promoted cell viability and caused activated ERK1/2 to increase overall, but especially in the nucleus. TRAPPC4 was expressed more highly in the nucleus of CRC cells than in normal colonic epithelium or adenoma which corresponded with nuclear staining of pERK1/2. We demonstrate here that TRAPPC4 may regulate cell proliferation and apoptosis in CRC by interaction with ERK2 and subsequently phosphorylating ERK1/2 as well as modulating the subcellular location of pERK1/2 to activate the relevant signaling pathway.

Purpose

This study examined the association between non-suicidal self-injury (NSSI) and suicide attempts among Chinese adolescents and college students.

Methods

A total sample of 2013 Chinese students were randomly selected from five schools in Wuhan, China, including 1101 boys and 912 girls with the age ranging between 10 and 24 years. NSSI, suicidal ideation, suicide attempts and depressive symptoms were measured by self-rated questionnaires. Self-reported suicide attempts were regressed on suicidal ideation and NSSI, controlling for participants' depressive symptoms, and demographic characteristics.

Results

The self-reported prevalence rates of NSSI, suicidal ideation, suicide attempts were 15.5%, 8.8%, and 3.5%, respectively. Logistic regression analyses indicated that NSSI was significantly associated with self-reported suicide attempts. Analyses examining the conditional association of NSSI and suicidal ideation with self-reported suicide attempts revealed that NSSI was significantly associated with greater risk of suicide attempts in those not reporting suicidal ideation than those reporting suicidal ideation in the past year.

Conclusions

These findings highlight the importance of NSSI as a potentially independent risk factor for suicide attempts among Chinese/Han adolescents and college students.

The overwhelming amount of available scholarly literature in the life sciences poses significant challenges to scientists wishing to keep up with important developments related to their research, but also provides a useful resource for the discovery of recent information concerning genes, diseases, compounds and the interactions between them. In this paper, we describe an algorithm called Bio-LDA that uses extracted biological terminology to automatically identify latent topics, and provides a variety of measures to uncover putative relations among topics and bio-terms. Relationships identified using those approaches are combined with existing data in life science datasets to provide additional insight. Three case studies demonstrate the utility of the Bio-LDA model, including association predication, association search and connectivity map generation. This combined approach offers new opportunities for knowledge discovery in many areas of biology including target identification, lead hopping and drug repurposing.

Although carpal tunnel release is one of the most commonly performed procedures in the USA, the morphology of the carpal tunnel as determined previously in the literature has been questioned. Previous methodology has been questioned for accuracy by recent studies. The purpose of this study was to perform a morphological analysis of the carpal tunnel and correlate carpal tunnel and hand dimensions. The carpal tunnels of ten cadaveric specimens were emptied of their contents and a silicone cast of the carpal tunnel was then created. This cast was then digitized, and the dimensions of the carpal tunnel were calculated. These dimensions were compared with the measured hand dimensions of the specimens. The width, depth, tilt angle, length, cross-sectional area, and volume of the carpal tunnel were 19.2 ± 1.7 mm, 8.3 ± 0.9 mm, 14.8 ± 7.8°, 12.7 ± 2.5 mm, 134.9 ± 23.6 mm2, and 1,737 ± 542 mm3, respectively. Width, depth, and cross-sectional area did not change significantly along the length of the carpal tunnel, but tilt angle did. The width of the palm strongly correlates with the width of the carpal tunnel. Other dimensional correlations did not reach statistical significance. The carpal tunnel is of uniform dimension along its length. The long axis of the carpal tunnel in cross-section rotates volarly from the radial side of the hand increasingly with distal progression along the carpal tunnel. Based on our analysis of ten cadaveric specimens, the width of the carpal tunnel may be estimated by the width of the palm using the equation: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {\text{Widt}}{{\text{h}}_{\text{CT}}} = 1.285 + 0.236 \times {\text{Widt}}{{\text{h}}_{\text{palm}}} $$\end{document}.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, regulating inflammatory and immune responses. MIF binds to cell surface receptor CD74, resulting in both rapid and sustained ERK activation. It was reported that MIF-induced rapid ERK activation requires its co-receptor CD44. But the exact mechanism underlying sustained ERK activation is not well understood. In the current study, we described a detailed mechanism of MIF mediated sustained ERK activation. We found that β-arrestin1, a scaffold protein involved in the activation of the MAPK cascade, interacts with CD74 upon MIF stimulation, resulting in CD74-mediated MIF endocytosis in a chlorpromazine (CPZ)-sensitive manner. β-arrestin1 is also involved in endocytotic MIF signaling, leading to sustained ERK activation. Therefore β-arrestin1 plays a central role in coupling MIF endocytosis to sustained ERK activation.

Purpose

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous complications of diabetes. We assessed the effect of a novel RAGE fusion protein inhibitor on retinal histopathology and nerve function, and on retinal inflammation and oxidative stress.

Methods

C57BL/6J mice were made diabetic with streptozotocin, and some were given a RAGE fusion protein (10, 100, or 300 µg per mouse 3 times per week). Mice were sacrificed at 2 months and 10 months into the study to assess retinal vascular histopathology, accumulation of albumin in the neural retina, cell loss in the ganglion cell layer, and biochemical and physiologic abnormalities in the retina. Tactile allodynia (light touch) was measured on a paw of each animal at 2 months.

Results

Leukostasis, expression of the intercellular adhesion molecule-1 (ICAM-1), accumulation of albumin in the neural retina, and nitration of retinal proteins were significantly increased in the retinas of mice diabetic for 2 months. The number of degenerate retinal capillaries was significantly increased in mice diabetic for 10 months, compared to the nondiabetic controls. Diabetes also enhanced sensitivity of peripheral nerves to tactile allodynia. All three doses of the RAGE fusion protein inhibited capillary degeneration, accumulation of albumin in the neural retina, nitration of retinal proteins, and tactile allodynia, demonstrating that biologically meaningful levels of the drug reached the retina. RAGE inhibition did tend to inhibit diabetes-induced retinal leukostasis and ICAM-1 expression (previously postulated to be important in the pathogenesis of retinopathy), but these effects were not statistically significant for the use of the lower doses of the drug that normalized the vascular histopathology.

Conclusions

Inhibition of RAGE blocked the development of important lesions of diabetic retinopathy, but these beneficial effects seemed not to be mediated via leukostasis. RAGE inhibition also blocked the development of sensory allodynia in diabetes. RAGE is an important therapeutic target to inhibit the development of vascular and neural complications of diabetes.

The Adenoma Prevention with Celecoxib (APC) Trial examined the efficacy and safety of the Cox-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer (CRC). The trial randomized 2035 subjects to receive either placebo, celecoxib 200mg twice daily, or celecoxib 400mg twice daily. The primary study safety and efficacy analyses involved three years of treatment. The results showed significant anti-tumor effect, but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared to placebo. A total of 933 patients participated in an extension of the APC Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (p<0.0001) for those receiving low dose celecoxib, and 60.1% (p<0.0001) for those receiving high dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (p<0.0001) of those taking low dose celecoxib and 15.8% (p<0.0001) of those taking high dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95%CI 1.0, 2.5) for those using 200mg BID celecoxib and 1.9 (95%CI 1.2, 3.1) for those using 400mg BID celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (p=0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with pre-existing atherosclerotic heart disease.

Backgroud

The purpose of this study was to describe actual measured weight and perceived weight and to explore associations with depressive, anxiety symptoms in school adolescents in China.

Methods

A sample of 1144 Chinese adolescents was randomly selected from four schools in Wuhan, China, including 665 boys and 479 girls with ages ranging between 10 and 17 years. Actual measured weight and height and perceived weight status were compared to anxiety and depressive symptoms measured using the revised Self-Rating Anxiety Scale and Children's Depression Inventory. A general linear model was used to compare differences in psychological symptoms among the teenagers with different measured and perceived weights.

Results

When compared with standardized weight tables (WHO age- and gender-specific body mass index (BMI) cutoffs (2007 reference)), girls were more likely to misperceive themselves as overweight, whereas more boys misclassified their weight status as underweight. The adolescents who perceived themselves as overweight were more likely to experience depressive and anxiety symptoms (except girls) than those who perceived themselves as normal and/or underweight. However, no significant association was found between depressive and anxiety symptoms actual measured weight status.

Conclusions

Perceived weight status, but not the actual weight status, was associated with psychological symptoms.