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BackgroundPreventive care is important for managing inflammatory bowel disease (IBD), yet primary care providers (PCPs) often face challenges in delivering such care due to discomfort and unfamiliarity with IBD-specific guidelines. This study aims to assess PCPs' attitudes towards, and practices in, providing preventive screenings for IBD patients, highlighting areas for improvement in guideline dissemination and education.MethodsUsing a web-based opt-in panel of PCPs (DocStyles survey, spring 2022), we assessed PCPs' comfort level with providing/recommending screenings and the reasons PCPs felt uncomfortable (n = 1,503). Being likely to provide/recommend screenings for depression/anxiety, skin cancer, osteoporosis, and cervical cancer were compared by PCPs' comfort level and frequency of seeing patients with IBD. We estimated adjusted odd ratios (AORs) of being likely to recommend screenings and selecting responses aligned with IBD-specific guidelines by use of clinical practice methods.ResultsAbout 72% of PCPs reported being comfortable recommending screenings to patients with IBD. The top reason identified for not feeling comfortable was unfamiliarity with IBD-specific screening guidelines (55%). Being comfortable was significantly associated with being likely to provide/recommend depression/anxiety (AOR = 3.99) and skin cancer screenings (AOR = 3.19) compared to being uncomfortable or unsure. Percentages of responses aligned with IBD-specific guidelines were lower than those aligned with general population guidelines for osteoporosis (21.7% vs. 27.8%) and cervical cancer screenings (34.9% vs. 43.9%), and responses aligned with IBD-specific guidelines did not differ by comfort level for both screenings. Timely review of guidelines specific to immunosuppressed patients was associated with being likely to provide/recommend screenings and selecting responses aligned with IBD-specific guidelines.ConclusionsDespite a general comfort among PCPs in recommending preventive screenings for IBD patients, gaps in knowledge regarding IBD-specific screening guidelines persist. Enhancing awareness and understanding of these guidelines through targeted education and resource provision may bridge this gap.

BackgroundOsteoarthritis (OA) is featured as cartilage loss, joint pain and loss of labor, which the inflammatory reaction may play critical roles. Ononin is an isoflavone isolating from medicinal plants and has anti-inflammatory effects. Our study investigated the anti-inflammation response of ononin on OA.MethodsAnterior cruciate ligament transection (ACLT)-induced OA operation was used to establish research model, then treated with ononin for 8 weeks. The condition of joint injury was assessed using pathological staining. The concentration of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum were measured by Elisa kit. The expression of collagen II and matrix metalloproteinase 13 (MMP-13) proteins to assess cartilage metabolism level by immunohistochemistry and Western blot. We detected the expression of proteins involved in the MAPK and NF-κB signaling pathways. Finally, we used molecular docking to assess the affinity of ononin for the target proteins ERK1/2, JNK1/2, p38 and p65.ResultsOur results confirmed that ononin ameliorated cartilage impairment through histopathological analysis by improving the morphological structures and cartilage tidal lines and decreasing Osteoarthritis Research Society International (OARSI) scores in OA rats. Moreover, ononin inhibited the secretion of above factors in OA rats. Furthermore, ononin has been shown to improve cartilage content levels in OA rats. In addition, ononin inhibited the reactivity of MAPK and NF-κB pathways in OA rats. And molecular docking indicated the ligand molecules could stably bind to the proteins of above receptors.ConclusionOur results demonstrated that ononin may ameliorate cartilage damage and inflammatory response in OA rats by downgrading MAPK and NF-κB pathways, thus identifying ononin as a potential novel drug to treat OA.

Background Patients with inflammatory bowel disease (IBD) have higher health services use than those without IBD. We investigated patient and hospital characteristics of major ambulatory surgery encounters for Crohn’s disease (CD) or ulcerative colitis (UC) vs non-IBD patients. Methods We conducted a cross-sectional study using 2017 Nationwide Ambulatory Surgery Sample. Major ambulatory surgery encounters among patients aged ≥18 years with CD (n = 20,635) or UC (n = 9,894) were compared to 9.4 million encounters among non-IBD patients. Weighted percentages of patient characteristics (age, sex, median household income, primary payers, patient location, selected comorbidities, discharge destination, type of surgeries) and hospital-related characteristics (hospital size, ownership, location and teaching status, region) were compared by IBD status (CD, UC, and no IBD). Linear regression was used to estimate mean total charges, controlling for these characteristics. Results Compared with non-IBD patients, IBD patients were more likely to have private insurance, reside in urban areas and higher income zip codes, and undergo surgeries in hospitals that were private not-for-profit, urban teaching, and in the Northeast. Gastrointestinal surgeries were more common among IBD patients. Some comorbidities associated with increased risk of surgical complications were more prevalent among IBD patients. Total charges were 9% lower for CD patients aged Conclusions Differences in characteristics of major ambulatory surgery encounters by IBD status may identify opportunities for efficient resource allocation and positive surgical outcomes among IBD patients.

ObjectiveThis study assessed the major nutrients and antioxidant properties of Berberis heteropoda Schrenk fruits collected from the Nanshan Mountain area of Urumqi City, Xinjiang Uygur Autonomous Region, China.Methods and materialsWe assessed the basic nutrients, including amino acids, minerals, and fatty acids, and determined the total phenol, flavonoid, and anthocyanin contents of the extracts.ResultsThe analytical results revealed the average water (75.22 g/100 g), total fat (0.506 g/100 g), total protein (2.55 g/100 g), ash (1.31 g/100 g), and carbohydrate (17.72 g/100 g) contents in fresh B. heteropoda fruit, with total phenol, flavonoid, and anthocyanin contents of B. heteropoda fruits at 68.55 mg gallic acid equivalents/g, 108.42 mg quercetin equivalents/g, and 19.83 mg cyanidin-3-glucoside equivalent/g, respectively. Additionally, UPLC-Q-TOF-MSE analysis of polyphenols in B. heteropoda fruit revealed 32 compounds.ConclusionB. heteropoda fruits may have potential nutraceutical value and represent a potential source of nutrition and antioxidant phytochemicals in the human diet.

Bovine tuberculosis (bTB) caused by Mycobacterium bovis (M. bovis) represents one of major zoonotic diseases among cattle, it also affects the health of human, other domestic animals and wild life populations. Inhalation of infected aerosol droplets is considered as the most frequent route of the infection. This study aims to investigate the current forms of tuberculosis in cattle and identify the possible transmission modes in dairy farms of China. 13,345 cows from eight dairy farms in three provinces were comprehensively diagnosed by a multitude of assays, including SIT, CIT, IFN-γ assay and ELISA. It has been indicated that advanced infection of bTB was found in 752 (5.64%) cattle, suggesting a high prevalence of tuberculosis in these dairy farms. In the necropsy examination of 151 positive cattle, typical bTB lesions were observed in 131 cattle (86.75%), of which, notably, 90.84% lesions appeared in liver, spleen, mesenteric lymph nodes, mammary lymph nodes and other organs, taking up a large proportion among cattle with advanced bTB infection. 71.26% extrapulmonary tuberculosis (EPTB) was related to gastrointestinal system. M. bovis nucleic acid was further found in milk and feces samples and M. bovis was even isolated from milk samples. Phylogenetic analysis based on whole genome sequencing unraveled that six isolates were closely related to M. bovis AF2122/97 originated from UK, whereas four isolates shared close relation to M. bovis 30 from China, respectively. Our data demonstrate that the increase of EPTB transmitted by digestive tract is implicated in the current high prevalence rate of bTB in China, which also provides leads for bTB control in other countries with high prevalence of bTB in the future.

BackgroundDietary behavior and nutrient intake patterns among U.S. men and women with inflammatory bowel disease (IBD) are unclear at the population level.MethodsThis cross-sectional study compared dietary intake patterns among U.S. adults (aged ≥18 years) with and without IBD in the 2015 National Health Interview Survey (N = 33,626). Age-standardized weighted prevalences for intake of fruits, vegetables, dairy, whole grain bread, dietary fiber, calcium, total added sugars, sugar-sweetened beverages (SSBs), processed meat, and supplement use were compared between adults with and without IBD by sex.ResultsIn 2015, an estimated 3 million adults (1.3%) reported IBD. Compared with adults without IBD, adults with IBD were more likely to be older, non-Hispanic white, not currently working, former smokers, and former alcohol drinkers. Overall, dietary behaviors were similar among adults with and without IBD. However, adults with IBD were more likely to take vitamin D supplements (31.5% vs 18.8%) and consume dietary fiber ConclusionsAdopting a healthy diet, especially limiting added sugars intake among women with IBD, might be important for the overall health.

BackgroundIt is unclear whether there are individual differences in the long-term efficacy of computer-assisted and traditional total knee arthroplasty. The purpose of this study was to perform a meta-analysis comparing the same individuals undergoing computer-assisted and traditional total knee arthroplasty separately to determine whether computer-assisted total knee arthroplasty can provide better lower extremity radiographic results and clinical outcomes.MethodsWe searched literatures to identify relevant randomized controlled trials comparing the effects of computer-assisted and traditional methods in bilateral total knee arthroplasty. After screening, quality evaluation and data extraction according to inclusion and exclusion criteria, the quality and bias risks of the included studies were evaluated. The meta-analysis compared the radiographic results, functional outcomes and complications of the two techniques.ResultsSix clinical controlled trials were included, with total of 1098 patients. The meta-analysis showed that the accuracy in terms of the mechanical axis of the lower extremity, the sagittal alignment of the femoral component and the coronal alignment of the tibial component in computer-assisted total knee arthroplasty was significantly better than those in traditional total knee arthroplasty. There were no differences in the functional results, revision rates or aseptic loosening rates between the two techniques.ConclusionAfter excluding individual differences such as bone development and bone quality, although computer-assisted techniques can better accurately correct the mechanical axis of the lower extremity and the position of prosthesis implantation than traditional techniques, there is no significant difference in the functional results and revision rate of bilateral total knee arthroplasty in the same individual.

Construction of a reliable stock portfolio remains an open issue in quantitative investment. Multiple machine learning models have been trained for stock portfolio selection, but their practical applicability remains limited due to the challenges posed by the characteristic of a low signal-to-noise ratio (SNR), the nature of time-series data, and non-independent identical distribution in financial data. Here, we transformed the stock selection task into a matching problem between a group of stocks and a stock selection target. We proposed a novel representation algorithm of stock selection target and a novel deep matching algorithm (TS-Deep-LtM). Then we proposed a deep stock profiling method to extract the optimal feature combination and trained a deep matching model based on TS-Deep-LtM algorithm for stock portfolio selection. Especially, TS-Deep-LtM algorithm was obtained by setting statistical indicators to filter and integrate three deep text matching algorithms. This parallel framework design made it good at capturing signals from time-series data and adapting to non-independent identically distributed data. Finally, we applied the proposed model to stock selection and tested long-only portfolio strategies from 2010 to 2017. We demonstrated that the risk-adjusted returns obtained by our portfolio strategies outperformed those obtained by the CSI300 index and learning-to-rank approaches during the same period.

Hepatitis E virus (HEV) infection is relatively high in the southern regions of China. Yunnan, located in southwestern China, has the highest number of ethnic groups. However, HEV infection in the ethnic population is largely unknown. Therefore, we aimed to investigate the seropositive rate, risk factor, and clinical impact of HEV infection in the ethnic groups of Yunnan. We recruited 1912 individuals from four minority groups in three prefectures of Yunnan province. Epidemiological records on potential risk factors for exposure to HEV and blood biochemical index were analyzed. All the serum samples were tested for anti-HEV IgM/IgG by enzyme-linked immunosorbent assay, and the IgM-positive samples were subjected to nested reverse transcription-PCR to detect HEV RNA. Overall, 1273 individuals (66.58%) were positive for anti-HEV IgG, 16 (0.84%) for anti-HEV IgM, and 64 (3.35%) for anti-HEV IgG and IgM both; none of them had detectable HEV RNA. Multivariate analysis revealed a strong statistical association between ethnic origin and HEV IgG seroprevalence. Anti-HEV IgG reactivity in the Hani ethnic (82.3%; 401/487) population was higher than that in the Naxi (71.9%, 340/473), Bulang (65.1%; 302/464), and Wa (60.2%; 294/488) ethnic populations (p < 0.0001). Older age and male sex were independently associated with the risk of past HEV infection. Moreover, anti-HEV IgG-positive individuals showed significantly higher levels of total and direct bilirubin and alanine amino transferase but significantly lower levels of globulin and low-density lipoprotein, than the respective levels in anti-HEV IgG-negative individuals. Thus, the seroprevalence of HEV infection is high in the ethnic populations of Yunnan, China. It is therefore necessary to increase the surveillance of specific risk groups and raise awareness about the possible infectious diseases to help limit the HEV transmission here.

Bone tissue engineering shows good prospects for mandibular reconstruction. In recent studies, prefabricated tissue-engineered bone (PTEB) by recombinant human bone morphogenetic proteins (rhBMPs) applied in vivo has found to be an effective alternative for autologous bone grafts. However, the optimal time to transfer PTEB for mandibular reconstruction is still not elucidated. Thus, here in an animal experiment of rhesus monkey, the suitable transferring time for PTEB to reconstruct mandibular defects was evaluated by 99mTc-MDP SPECT/CT, and its value in monitoring orthotopic rhBMP-2 implants for mandibular reconstruction was also evaluated. The result of SPECT/CT showed higher 99mTc-MDP uptake, indicating osteoinductivity, in rhBMP-2 incorporated demineralized freeze-dried bone allograft (DFDBA) and coralline hydroxyapatite (CHA) implants than those without BMP stimulation. 99mTc-MDP uptake of rhBMP-2 implant peaked at 8 weeks following implantation while CT showed the density of these implants increased after 13 weeks' prefabrication. Histology confirmed that mandibular defects were repaired successfully with PTEB or orthotopically rhBMP-2 incorporated CHA implants, in accordance with SPECT/CT findings. Collectively, data shows 99mTc-MDP SPECT/CT is a sensitive and noninvasive tool to monitor osteoinductivity and bone regeneration of PTEB and orthotopic implants. The PTEB achieved peak osteoinductivity and bone density at 8 to 13 weeks following ectopic implantation, which would serve as a recommendable time frame for its transfer to mandibular reconstruction.

Interferon Gamma Release Assays (IGRAs) were developed for the indirect or immunologic diagnosis of tuberculosis infection; however, they have also been used to assist in difficult to diagnose cases of tuberculosis disease in adults, and to a lesser extent, in children, especially in those under 5 years old. We evaluated the utility of using an IGRA in pediatric tuberculosis in younger children in a hospital setting. The diagnostic accuracy of T-SPOT.TB and TST was assessed in 117 children with active tuberculosis and 413 children with respiratory tract infection. Sensitivity and specificity were calculated for the tests used individually and together. Concordance was also calculated. Sensitivity of T-SPOT.TB (82.9%) was higher than TST (78.6% using a 5mm cut-off), especially in children confirmed to have TB. T-SPOT.TB was more specific than TST using a 5mm cut-off (96.1% vs. 70.9%). Combining T-SPOT.TB and TST results improved the sensitivity to 96.6%. In conclusion, the results of the current study indicate that T-SPOT.TB has good sensitivity and specificity, supporting its use among patients of this age. A combination of IGRA and TST would be useful additions to assist in the diagnosis of childhood TB.

Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.

Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease in which the pathogenic mechanism is complicated and not completely understood. Reports on the role of regulated cells in AD have recently evolved to regulate B cells, which may play a role in allergic inflammation as well. In the present study, we examined the frequency and regulatory function of CD5+CD19+CD1dhi B10 cells in an AD-like mouse model. Our results showed that the percentage of CD5+CD19+CD1dhi B10 cells increased while the frequency of IL-10-producing B cells in CD19+B cells decreased in the mice of AD group. Moreover, no difference in the percentage of B10pro + B10 cells was observed between the AD and control groups. Strikingly, B10 cells from control mice effectively inhibited IgE secretion, whereas the suppressive function of B10 cells from the AD mice was significantly decreased, which was similar to that observed in the group without B10. Altogether, these results suggest that the number of IL-10-producing B cells decreased in the AD group and these cells showed a defective regulatory function on IgE secretion.

BackgroundDelayed chemotherapy is associated with inferior survival in stage III colon and stage II/III rectal cancer patients, but similar studies have not been performed in stage II colon cancer patients. We investigate the association between delayed and incomplete chemotherapy, and the association of delayed chemotherapy with survival in stage II colon cancer patients.Patients and methodsPatients (age ≥ 66) diagnosed as stage II colon cancer and received chemotherapy from 1992 to 2005 were identified from the linked SEER-Medicare database. The association between delayed and incomplete chemotherapy was assessed using unconditional and conditional logistic regressions. Survival outcomes were assessed using stratified Cox regression based on propensity score matched samples.Results4,209 stage II colon cancer patients were included, of whom 73.0% had chemotherapy initiated timely (≤ 2 months after surgery), 14.7% had chemotherapy initiated with moderate delay (2-3 months), and 12.3% had delayed chemotherapy (≥ 3 months). Delayed chemotherapy was associated with not completing chemotherapy (adjusted odds ratio (OR): 1.33 (95% confidence interval: 1.11, 1.59) for moderately delayed group, adjusted OR: 2.60 (2.09, 3.24) for delayed group). Delayed chemotherapy was associated with worse survival outcomes (hazard ratio (HR): 1.75 (1.29, 2.37) for overall survival; HR: 4.23 (2.19, 8.20) for cancer-specific survival).ConclusionAlthough the benefit of chemotherapy is unclear in stage II colon cancer patients, delay in initiation of chemotherapy is associated with an incomplete chemotherapy course and poorer survival, especially cancer-specific survival. Causal inference in the association between delayed initiation of chemotherapy and inferior survival requires further investigation.

Cryptochromes are photolyase-like blue/UV-A light receptors that evolved from photolyases. In plants, cryptochromes regulate various aspects of plant growth and development. Despite of their involvement in the control of important plant traits, however, most studies on cryptochromes have focused on lower plants and herbaceous crops, and no data on cryptochrome function are available for forest trees. In this study, we isolated a cryptochrome gene, PeCRY1, from Euphrates poplar (Populus euphratica), and analyzed its structure and function in detail. The deduced PeCRY1 amino acid sequence contained a conserved N-terminal photolyase-homologous region (PHR) domain as well as a C-terminal DQXVP-acidic-STAES (DAS) domain. Secondary and tertiary structure analysis showed that PeCRY1 shares high similarity with AtCRY1 from Arabidopsis thaliana. PeCRY1 expression was upregulated at the mRNA level by light. Using heterologous expression in Arabidopsis, we showed that PeCRY1 overexpression rescued the cry1 mutant phenotype. In addition, PeCRY1 overexpression inhibited hypocotyl elongation, promoted root growth, and enhanced anthocyanin accumulation in wild-type background seedlings grown under blue light. Furthermore, we examined the interaction between PeCRY1 and AtCOP1 using a bimolecular fluorescence complementation (BiFc) assay. Our data provide evidence for the involvement of PeCRY1 in the control of photomorphogenesis in poplar.

BACKGROUND: China has made remarkable progress in schistosomiasis control over the past decades. Transmission control has replaced morbidity control as the country moves towards the goal of elimination and the current challenge is to find a sensitive measure capable of gauging transmission risk in low-prevalence areas. The study aims to develop a Schistosomiasis Early Warning Index (SEWI) and demonstrate its use in Jiangsu Province along the lower Yangtze River. METHODOLOGY/PRINCIPAL FINDINGS: The Delphi approach, a structured communication technique, was used to develop the SEWI. Two rounds of interviews with 30 public health experts specialized in schistosomiasis control were conducted using 40 indicators that reflected different aspects of schistosomiasis transmission and control. The necessity, feasibility, and sensitivity of each indicator were assessed and the weight value of each indicator determined based on these experts' judgment. The system included 3 first-order indicators, 7 second-order indicators, and 30 third-order indicators. The 3 first-order indicators were endemic status, control measures, social and environmental factors, with the weight values 0.366, 0.343 and 0.291, respectively. For the 7 second-order indicators, the highest weight value was for control measures for snails (0.175) and the lowest for transmission route (0.110). We estimated and mapped the SEWI for endemic areas at the county scale in Jiangsu Province finding that the majority of the endemic areas were characterized as medium transmission risk (SEWI risk values between 0.3 and 0.6), while areas where transmission interruption had been officially declared showed SEWI values 0.60. These estimates are largely in agreement with the endemicity levels based on recent epidemiological surveys. CONCLUSIONS/SIGNIFICANCE: The SEWI should be useful for estimation of schistosomiasis transmission surveillance, particularly with reference to the elimination of the disease in China.

Knowledge of drug safety in the pediatric population of China is limited. This study was designed to evaluate ADRs in children reported to the spontaneous reporting system (SRS) of Shanghai in 2009.Crude ADR reports submitted to Shanghai SRS in 2009 for individuals aged from birth to 17 years (including 17 years) were included. Data were analyzed with respect to age, gender, category of ADR (System Organ Class [SOC]), the severity of reports and type of reporter.A male overrepresentation was observed regarding the total number of reports. The most frequently reported group of drugs were vaccines (42.15%). Skin rash and fever were the commonest symptoms reported in the total pediatric dataset. The proportion of children that suffered from a serious ADR was 2.16% and that for drug related deaths was 0.34%. And we found that the multiple drug exposure experienced a high proportion of serious ADRs compared with the single drug use (χ² = 15.99, P

BackgroundMicrosatellite markers or Simple Sequence Repeats (SSRs) are the most popular markers in population/conservation genetics. However, the development of novel microsatellite markers has been impeded by high costs, a lack of available sequence data and technical difficulties. New species-specific microsatellite markers were required to investigate the evolutionary history of the Euphratica tree, Populus euphratica, the only tree species found in the desert regions of Western China and adjacent Central Asian countries.Methodology/principal findingsA total of 94,090 non-redundant Expressed Sequence Tags (ESTs) from P. euphratica comprising around 63 Mb of sequence data were searched for SSRs. 4,202 SSRs were found in 3,839 ESTs, with 311 ESTs containing multiple SSRs. The most common motif types were trinucleotides (37%) and hexanucleotides (33%) repeats. We developed primer pairs for all of the identified EST-SSRs (eSSRs) and selected 673 of these pairs at random for further validation. 575 pairs (85%) gave successful amplification, of which, 464 (80.7%) were polymorphic in six to 24 individuals from natural populations across Northern China. We also tested the transferability of the polymorphic eSSRs to nine other Populus species. In addition, to facilitate the use of these new eSSR markers by other researchers, we mapped them onto Populus trichocarpa scaffolds in silico and compiled our data into a web-based database (http://202.205.131.253:8080/poplar/resources/static_page/index.html).ConclusionsThe large set of validated eSSRs identified in this work will have many potential applications in studies on P. euphratica and other poplar species, in fields such as population genetics, comparative genomics, linkage mapping, QTL, and marker-assisted breeding. Their use will be facilitated by their incorporation into a user-friendly web-based database.

Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

The key components of insight include breaking mental sets and forming the novel, task-related associations. The majority of researchers have agreed that the anterior cingulate cortex may mediate processes of breaking one's mental set, while the exact neural correlates of forming novel associations are still debatable. In the present study, we used a paradigm of answer selection to explore brain activations of insight by using event-related functional magnetic resonance imaging during solving Chinese 'chengyu' (in Chinese pinyin) riddles. Based on the participant's choice, the trials were classified into the insight and non-insight conditions. Both stimulus-locked and response-locked analyses are conducted to detect the neural activity corresponding to the early and late periods of insight solution, respectively. Our data indicate that the early period of insight solution shows more activation in the middle temporal gyrus, the middle frontal gyrus and the anterior cingulate cortex. These activities might be associated to the extensive semantic processing, as well as detecting and resolving cognitive conflicts. In contrast, the late period of insight solution produced increased activities in the hippocampus and the amygdala, possibly reflecting the forming of novel association and the concomitant "Aha" feeling. Our study supports the key role of hippocampus in forming novel associations, and indicates a dynamic neural network during insight solution.

Since the antiretroviral therapy (ART) was introduced to patients infected by human immunodeficiency virus (HIV), the HIV related mortality and morbidity have been significantly reduced. The major obstacle for long-term successful anti-HIV treatment is the emergence of drug resistant mutants. Current data of drug resistance was mainly obtained on HIV-1 subtype B but rarely on non-B virus, even more rare with newly emerged circulating recombinant forms (CRFs). The lack of such data limits the rational management of ART for the increasing number of patients infected by non-subtype B virus. In this study, a HIV-1 CRF07_BC strain CNGZD was isolated from a HIV patient and its genome was sequenced and deposited in GenBank (JQ423923). Potential drug resistant mutants of this CRF07_BC virus strain were selected in PBMCs cultures in the presence of Nevirapine (NVP), which is the most frequently used antiretroviral drug in China. Four combination profiles of mutations were identified in the NVP-selected mutants, which were initiated with A98G, V108I, Y181C and I135T/I382L and followed by more than two other mutations at the end of the selections, respectively. A total of seven previously reported mutations (A98G, V106M, V108I, I135T, Y181C, V189I, K238N) and seven novel mutations (P4H, T48I, I178M, V314A, I382L/V, T386A) in the reverse transcriptase gene were found in these NVP-selected mutants. Phenotypic analysis in the NVP-selected mutants showed that all the mutations, except P4H, contribute to NVP resistance. Among them, V106M and Y181C reduce NVP susceptibility for more than 20-fold, while the other mutations cause less than 20 folds drug resistance. Although the information obtained in this in vitro selection study may not fully cover resistant mutations which will actually occur in patients, it has still provided useful information for rational management of ART in patients infected with HIV CRF_BC subtype.

A reliable disease model mimicking Enterovirus 71 (EV71) infection in humans is essential for understanding pathogenesis and for developing a safe and effective vaccine. Commonly used rodent models including mouse or rat models are not suitable for vaccine evaluation because the rodents are resistant to EV71 infection after they reach the age of 6 days. In this study, 21-day-old gerbils inoculated intraperitoneally (IP) with a non mouse-adapted EV71 strain developed neurological lesion-related signs including hind limb paralysis, slowness, ataxia and lethargy similar to those of central nervous system (CNS) infection of EV71 in humans. The infected gerbils eventually died of the neurological lesions and EV71 could be isolated from lung, liver, spleen, kidney, heart, spinal cord, brain cortex, brainstem and skeletal muscle. Significantly high virus replication was detected in spinal cord, brainstem and skeletal muscle by cellular analysis, real-time quantitative PCR (RT-PCR) and immunohistochemical staining. Histopathologic changes such as neuronal degeneration, neuronal loss and neuronophagia were observed in spinal cord, brain cortex, brainstem, and skeletal muscle along with necrotizing myositis and splenic atrophy. Gerbils that received two doses of inactive whole-virus vaccine showed no EV71-specific symptoms after challenged with EV71. In contrast, gerbils that received mock vaccination died of EV71-induced neuropathology after challenged with EV71. The result indicates that gerbils can serve as a reliable disease model for evaluating safety and efficacy of EV71 vaccine.

BACKGROUND: Aspirin and clopidogrel monotherapies are effective treatments for preventing vascular disease. However, new evidence has emerged regarding the use of combined aspirin and clopidogrel therapy to prevent cardiovascular events. We therefore performed a comprehensive systematic review and meta-analysis to evaluate the benefits and harms of combined aspirin and clopidogrel therapy on major cardiovascular outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies to fit our analysis. Eligible studies were randomized controlled trials assessing the effect of combined aspirin and clopidogrel therapy compared with aspirin or clopidogrel monotherapy. We identified 7 trials providing data with a total of 48248 patients. These studies reported 5134 major cardiovascular events, 1626 myocardial infarctions, 1927 strokes, and 1147 major bleeding events. Overall, the addition of aspirin to clopidogrel therapy as compared to single drug therapy resulted in a 9% RR reduction (95%CI, 2 to 17) in major cardiovascular events, 14% RR reduction (95%CI, 3 to 24) in myocardial infarction, 16% RR reduction (95%CI, 1 to 28) in stroke, and 62% RR increase (95%CI, 26 to 108) in major bleeding events. We also present the data as ARR to explore net value as the reduction in cardiovascular events. Overall, we observed that combined therapy yielded 1.06% decrease (95%CI, 0.23% to 1.99%) in major cardiovascular events and 1.23% increase (95%CI, 0.52% to 2.14%) in major bleeding events. CONCLUSION/SIGNIFICANCE: Although the addition of aspirin to clopidogrel resulted in small relative reductions in major cardiovascular events, myocardial infarction, and stroke, it also resulted in a relative increase in major bleeding events. In absolute terms the benefits of combined therapy, a 1.06% reduction in major cardiovascular events, does not outweigh the harms, a 1.23% increase in major bleeding events.

BACKGROUND: Anti-obesity drugs are widely used to prevent the complications of obesity, however, the effects of anti-obesity drugs on cardiovascular risk factors are unclear at the present time. We carried out a comprehensively systematic review and meta-analysis to assess the effects of anti-obesity drugs on cardiovascular risk factors. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures. We included randomized placebo-controlled trials that reported the effects of anti-obesity drugs on cardiovascular risk factors compared to placebo. Overall, orlistat produced a reduction of 2.39 kg (95%CI-3.34 to -1.45) for weight, a reduction of 0.27 mmol/L (95%CI: -0.36 to -0.17) for total cholesterol, a reduction of 0.21 mmol/L (95%CI: -0.30 to -0.12) for LDL, a reduction of 0.12 mmol/L (95%CI: -0.20 to -0.04) for fasting glucose, 1.85 mmHg reduction (95%CI: -3.30 to -0.40) for SBP, and a reduction of 1.49 mmHg (95%CI: -2.39 to -0.58) for DBP. Sibutramine only showed effects on weight loss and triglycerides reduction with statistical significances. Rimonabant was associated with statistically significant effects on weight loss, SBP reduction and DBP reduction. No other significantly different effects were identified between anti-obesity therapy and placebo. CONCLUSION/SIGNIFICANCE: We identified that anti-obesity therapy was associated with a decrease of weight regardless of the type of the drug. Orlistat and rimonabant could lead to an improvement on cardiovascular risk factors. However, Sibutramine may have a direct effect on cardiovascular risk factors.

BACKGROUND: Critically ill patients with 2009 H1N1 influenza are often treated in intensive care units (ICUs), representing significant risk of nosocomial transmission to critical care clinicians and other patients. Despite a large body of literature and guidelines recommending infection control practices, numerous barriers have been identified in ICUs, leading to poor compliance to the use of personal protective equipment (PPE). The use of PPE among critical care clinicians has not been extensively evaluated, especially during the pandemic influenza. This study examined the knowledge, attitudes, and self-reported behaviors, and barriers to compliance with the use of PPE among ICU healthcare workers (HCWs) during the pandemic influenza. METHODOLOGY/PRINCIPAL FINDINGS: A survey instrument consisting of 36 questions was developed and mailed to all HCWs in 21 ICUs in 17 provinces in China. A total of 733 physicians, nurses, and other professionals were surveyed, and 650 (88.7%) were included in the analysis. Fifty-six percent of respondents reported having received training program of pandemic influenza before they cared for H1N1 patients, while 77% reported to have adequate knowledge of self and patient protection. Only 18% of respondents were able to correctly identify all components of PPE, and 55% reported high compliance (>80%) with PPE use during patient care. In multivariate analysis, vaccination for 2009 H1N1 influenza, positive attitudes towards PPE use, organizational factors such as availability of PPE in ICU, and patient information of influenza precautions, as well as reprimand for noncompliance by the supervisors were associated with high compliance, whereas negative attitudes towards PPE use and violation of PPE use were independent predictors of low compliance. CONCLUSION/SIGNIFICANCE: Knowledge and self-reported compliance to recommended PPE use among Chinese critical care clinicians is suboptimal. The perceived barriers should be addressed in order to close the significant gap between perception and knowledge or behavior.

BACKGROUND: The detection of signals of adverse drug events (ADEs) has increased because of the use of data mining algorithms in spontaneous reporting systems (SRSs). However, different data mining algorithms have different traits and conditions for application. The objective of our study was to explore the application of association rule (AR) mining in ADE signal detection and to compare its performance with that of other algorithms. METHODOLOGY/PRINCIPAL FINDINGS: Monte Carlo simulation was applied to generate drug-ADE reports randomly according to the characteristics of SRS datasets. Thousand simulated datasets were mined by AR and other algorithms. On average, 108,337 reports were generated by the Monte Carlo simulation. Based on the predefined criterion that 10% of the drug-ADE combinations were true signals, with RR equaling to 10, 4.9, 1.5, and 1.2, AR detected, on average, 284 suspected associations with a minimum support of 3 and a minimum lift of 1.2. The area under the receiver operating characteristic (ROC) curve of the AR was 0.788, which was equivalent to that shown for other algorithms. Additionally, AR was applied to reports submitted to the Shanghai SRS in 2009. Five hundred seventy combinations were detected using AR from 24,297 SRS reports, and they were compared with recognized ADEs identified by clinical experts and various other sources. CONCLUSIONS/SIGNIFICANCE: AR appears to be an effective method for ADE signal detection, both in simulated and real SRS datasets. The limitations of this method exposed in our study, i.e., a non-uniform thresholds setting and redundant rules, require further research.

BackgroundFolic acid is widely used to lower homocysteine concentrations and prevent adverse cardiovascular outcomes. However, the effect of folic acid on cardiovascular events is not clear at the present time. We carried out a comprehensive systematic review and meta-analysis to assess the effects of folic acid supplementation on cardiovascular outcomes.Methodology and principal findingsWe systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings for relevant literature. We included randomized placebo-controlled trials that reported on the effects of folic acid on cardiovascular events compared to placebo. Of 1594 identified studies, we included 16 trials reporting data on 44841 patients. These studies reported 8238 major cardiovascular events, 2001 strokes, 2917 myocardial infarctions, and 6314 deaths. Folic acid supplementation as compared to placebo had no effect on major cardiovascular events (RR, 0.98; 95% CI, 0.93-1.04), stroke (RR, 0.89; 95% CI,0.78-1.01), myocardial infarction (RR, 1.00; 95% CI, 0.93-1.07), or deaths from any cause (RR, 1.00;95% CI, 0.96-1.05). Moreover, folic acid as compared to placebo also had no effect on the following secondary outcomes: risk of revascularization (RR, 1.05; 95%CI, 0.95-1.16), acute coronary syndrome (RR, 1.06; 95%CI, 0.97-1.15), cancer (RR, 1.08; 95%CI, 0.98-1.21), vascular death (RR, 0.94; 95%CI,0.88-1.02), or non-vascular death (RR, 1.06; 95%CI, 0.97-1.15).Conclusion/significanceFolic acid supplementation does not effect on the incidence of major cardiovascular events, stroke, myocardial infarction or all cause mortality.

BACKGROUND: Studies have shown that steroids can improve kidney survival and decrease the risk of proteinuria in patients with Immunoglobulin A nephropathy, but the overall benefit of steroids in the treatment of Immunoglobulin A nephropathy remains controversial. The aim of this study was to evaluate the benefits and risks of steroids for renal survival in adults with Immunoglobulin A nephropathy. METHODOLOGY AND PRINCIPAL FINDINGS: We searched the Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE and EMBASE databases. All eligible studies were measuring at least one of the following outcomes: end-stage renal failure, doubling of serum creatinine and urinary protein excretion. Fifteen relevant trials (n = 1542) that met our inclusion criteria were identified. In a pooled analysis, steroid therapy was associated with statistically significant reduction of the risk in end-stage renal failure (RR: 0.46, 95% CI: 0.27 to 0.79), doubling of serum creatinine (RR = 0.34, 95%CI = 0.15 to 0.77) and reduced urinary protein excretion (MD = -0.47 g/day, 95%CI = -0.64 to -0.31). CONCLUSIONS/SIGNIFICANCE: We identified that steroid therapy was associated with a decrease of proteinuria and with a statistically significant reduction of the risk in end-stage renal failure. Moreover, subgroup analysis also suggested that long-term steroid therapy had a higher efficiency than standard and short term therapy.

Oxidation of cysteine residues of proteins is emerging as an important means of regulation of signal transduction, particularly of protein kinase function. Tools to detect and quantify cysteine oxidation of proteins have been a limiting factor in understanding the role of cysteine oxidation in signal transduction. As an example, the p38 MAP kinase is activated by several stress-related stimuli that are often accompanied by in vitro generation of hydrogen peroxide. We noted that hydrogen peroxide inhibited p38 activity despite paradoxically increasing the activating phosphorylation of p38. To address the possibility that cysteine oxidation may provide a negative regulatory effect on p38 activity, we developed a biochemical assay to detect reversible cysteine oxidation in intact cells. This procedure, PROP, demonstrated in vivo oxidation of p38 in response to hydrogen peroxide and also to the natural inflammatory lipid prostaglandin J2. Mutagenesis of the potential target cysteines showed that oxidation occurred preferentially on residues near the surface of the p38 molecule. Cysteine oxidation thus controls a functional redox switch regulating the intensity or duration of p38 activity that would not be revealed by immunodetection of phosphoprotein commonly interpreted as reflective of p38 activity.

BackgroundSoil fungi face a variety of environmental stresses such as UV light, high temperature, and heavy metals. Adaptation of gene expression through transcriptional regulation is a key mechanism in fungal response to environmental stress. In Saccharomyces cerevisiae, the transcription factors Msn2/4 induce stress-mediated gene expression by binding to the stress response element. Previous studies have demonstrated that the expression of extracellular proteases is up-regulated in response to heat shock in fungi. However, the physiological significance of regulation of these extracellular proteases by heat shock remains unclear. The nematophagous fungus Clonostachys rosea can secret an extracellular serine protease PrC during the infection of nematodes. Since the promoter of prC has three copies of the stress response element, we investigated the effect of environmental stress on the expression of prC.Methodology/principal findingsOur results demonstrated that the expression of prC was up-regulated by oxidants (H(2)O(2) or menadione) and heat shock, most likely through the stress response element. After oxidant treatment or heat shock, the germination of conidia in the wild type strain was significantly higher than that in the prC mutant strain in the presence of nematode cuticle. Interestingly, the addition of nematode cuticle significantly attenuated the production of reactive oxygen species (ROS) induced by oxidants and heat shock in the wild type strain, but not in prC mutant strain. Moreover, low molecule weight (Conclusions/significanceThese results indicate that PrC plays a protective role in oxidative stress in C. rosea. PrC degrades the nematode cuticle to produce degradation products, which in turn offer a protective effect against oxidative stress by scavenging ROS. Our study reveals a novel strategy for fungi to adapt to environmental stress.

BACKGROUND:ATP-binding cassette transporter A1 mediates apolipoprotein AI-dependent efflux of cholesterol and thereby removes cholesterol from peripheral tissues. ABCA1 expression is tightly regulated and deficiency of this cholesterol transporter results in cholesterol accumulation within cells. Low-density lipoprotein receptor-related protein 1 (LRP1) participates in lipid metabolism and energy homeostasis by endocytosis of apolipoprotein E-containing lipoproteins and modulation of cellular proliferation signals. METHODS AND PRINCIPAL FINDINGS:In the present study, we demonstrate a new role for LRP1 in reverse cholesterol transport. Absence of LRP1 expression results in increased PDGFRbeta signaling and sequential activation of the mitogen-activated protein kinase signaling pathway, which increases phosphorylation of cytosolic phospholipase A(2) (cPLA(2)). Phosphorylated and activated cPLA(2) releases arachidonic acid from the phospholipid pool. Overproduction of arachidonic acid suppresses the activation of LXR/RXR heterodimers bound to the promoter of LXR regulated genes such as ABCA1, resulting in greatly reduced ABCA1 expression. CONCLUSIONS AND SIGNIFICANCE:LRP1 regulates LXR-mediated gene transcription and participates in reverse cholesterol transport by controlling cPLA(2) activation and ABCA1 expression. LRP1 thus functions as a physiological integrator of cellular lipid homeostasis with signals that regulate cellular proliferation and vascular wall integrity.

The mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways conserved in essentially all eukaryotes, but haven't been subjected to functional studies in the most important cellulase-producing filamentous fungus Trichoderma reesei. Previous reports suggested the presence of three MAPKs in T. reesei: Tmk1, Tmk2, and Tmk3. By exploring the phenotypic features of T. reesei Δtmk3, we first showed elevated NaCl sensitivity and repressed transcription of genes involved in glycerol/trehalose biosynthesis under higher osmolarity, suggesting Tmk3 participates in high osmolarity resistance via derepression of genes involved in osmotic stabilizer biosynthesis. We also showed significant downregulation of genes encoding chitin synthases and a β-1,3-glucan synthase, decreased chitin content, ‘budded’ hyphal appearance typical to cell wall defective strains, and increased sensitivity to calcofluor white/Congo red in the tmk3 deficient strain, suggesting Tmk3 is involved in cell wall integrity maintenance in T. reesei. We further observed the decrease of cellulase transcription and production in T. reesei Δtmk3 during submerged cultivation, as well as the presence of MAPK phosphorylation sites on known transcription factors involved in cellulase regulation, suggesting Tmk3 is also involved in the regulation of cellulase production. Finally, the expression of cell wall integrity related genes, the expression of cellulase coding genes, cellulase production and biomass accumulation were compared between T. reesei Δtmk3 grown in solid state media and submerged media, showing a strong restoration effect in solid state media from defects resulted from tmk3 deletion. These results showed novel physiological processes that fungal Hog1-type MAPKs are involved in, and present the first experimental investigation of MAPK signaling pathways in T. reesei. Our observations on the restoration effect during solid state cultivation suggest that T. reesei is evolved to favor solid state growth, bringing up the proposal that the submerged condition normally used during investigations on fungal physiology might be misleading. [ABSTRACT FROM AUTHOR]

Oxidation of cysteine residues of proteins is emerging as an important means of regulation of signal transduction, particularly of protein kinase function. Tools to detect and quantify cysteine oxidation of proteins have been a limiting factor in understanding the role of cysteine oxidation in signal transduction. As an example, the p38 MAP kinase is activated by several stress-related stimuli that are often accompanied by in vitro generation of hydrogen peroxide. We noted that hydrogen peroxide inhibited p38 activity despite paradoxically increasing the activating phosphorylation of p38. To address the possibility that cysteine oxidation may provide a negative regulatory effect on p38 activity, we developed a biochemical assay to detect reversible cysteine oxidation in intact cells. This procedure, PROP, demonstrated in vivo oxidation of p38 in response to hydrogen peroxide and also to the natural inflammatory lipid prostaglandin J2. Mutagenesis of the potential target cysteines showed that oxidation occurred preferentially on residues near the surface of the p38 molecule. Cysteine oxidation thus controls a functional redox switch regulating the intensity or duration of p38 activity that would not be revealed by immunodetection of phosphoprotein commonly interpreted as reflective of p38 activity. [ABSTRACT FROM AUTHOR]