The plasma derived exosomal miRNA-483-5p/502-5p serve as potential MCI biomarkers in aging.

Alzheimer's disease (AD) is the leading cause of dementia and is rapidly becoming one of the most costly, fatal diseases, which is typically discovered in the late stage of molecular pathology, at which point medication intervention is irreversible. As a result, there is an urgent need for a low-cost, least-invasive way of screening cognitive impairment, with the goal of identifying persons at risk of AD. Mild cognitive impairment (MCI) has been described as a transitional state between normal cognitive aging and AD. Early detection and timely tracking of MCI can to some extent prevent the progression towards AD. We found a population in Northwestern China has a comparatively high prevalence of MCI. Continued education, consistent exercise, and a secure financial situation can all help older people maintain cognitive function. Due to the critical role of circulating microRNAs in intercellular signaling and the perturbations thereof, their investigation has assumed paramount significance in elucidating various pathological conditions. Numerous investigations have substantiated the significance of circulating miRNAs specifically in MCI. Here, we evaluated miR-483-5p (Area Under the Curve (AUC) is 0.901, sensitivity 79.2 % and specificity 100 %) and miR-502-5p (AUC is 0.872, sensitivity 79.2 % and specificity 83.3 %), which were derived from plasma exosomes and maintained at high levels in elderly people with MCI, could be employed as promising noninvasive biomarkers.

Severe acute respiratory syndrome coronavirus 2 virus-like particles induce dendritic cell maturation and modulate T cell immunity.

Dendritic cells (DCs) are professional antigen-presenting cells that play an important role in both innate and acquired immune responses against pathogens. However, the role of DCs in coronavirus disease 2019 (COVID-19) is unclear. Virus-like particles (VLPs) that structurally mimic the original virus are one of the candidates COVID-19 vaccines. In the present study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VLPs were used as an alternative to live virus to evaluate the interaction of the virus with DCs. The results revealed that SARS-CoV-2 VLPs induced DC maturation by augmenting cell surface molecule expression (CD80, CD86, and major histocompatibility complex class II (MHC-II)) and inflammatory cytokine production (tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-12p70) in DCs via the mitogen-activated protein kinase and nuclear factor-κB signaling pathways. In addition, mature DCs induced by SARS-CoV-2 VLPs promoted T cell proliferation, which was dependent on VLPs concentration. Our results suggest that SARS-CoV-2 VLPs regulate the immune response by interacting with DCs. These findings will improve the understanding of SARS-CoV-2 pathogenesis and SARS-CoV-2 vaccine development.

A new poly(I:C)-decorated PLGA-PEG nanoparticle promotes Mycobacterium tuberculosis fusion protein to induce comprehensive immune responses in mice intranasally.

Protein-based subunit vaccine against tuberculosis (TB) is regarded as safer but with lower immunogenicity. To investigate effective adjuvant to improve the immunogenicity of TB subunit vaccine, we modified ploy(I:C) onto PLGA-PEG copolymer nanoparticle with polydopamine to produce a new nanoparticle adjuvant named "PLGA-PEG-poly(I:C)" (NP). M. tuberculosis fusion proteins Mtb10.4-HspX and ESAT-6-Rv2626c (M4) were encapsulated in the nanoparticles to produce the NP/M4 subunit vaccine. The PLGA-PEG/M4 nanoparticle was 200.21 ± 1.07 nm in diameter, and the polydispersity index (PDI) was 0.127 ± 0.02. Following modification with poly(I:C) by polydopamine, the NP/M4 was administered to C57BL/6 female mice intranasally and the immune responses were evaluated. The NP/M4 significantly induced antigen-specific CD4+ T cells proliferation, IL-2 and IFN-γ production. In addition, the NP/M4 could promote the production of antigen-specific IgG, IgG1, IgG2c in serum, and sIgA in lung washings. Overall, our results indicated that the NP would be a potential TB subunit vaccine adjuvant with the ability to induce strong Th1-type cell-mediated immunity and humoral immune responses.

Production of SARS-CoV-2 Virus-Like Particles in Insect Cells.

Coronavirus disease (COVID-19) causes a serious threat to human health. Virus-like particles (VLPs) constitute a promising platform in SARS-CoV-2 vaccine development. In this study, the E, M, and S genes were cloned into multiple cloning sites of a new triple expression plasmid with one p10 promoter, two pPH promoters, and three multiple cloning sites. The plasmid was transformed into DH10 BacTMEscherichia coli competent cells to obtain recombinant bacmid. Then the recombinant bacmid was transfected in ExpiSf9TM insect cells to generate recombinant baculovirus. After ExpiSf9TM cells infection with the recombinant baculovirus, the E, M, and S proteins were expressed in insect cells. Finally, SARS-CoV-2 VLPs were self-assembled in insect cells after infection. The morphology and the size of SARS-CoV-2 VLPs are similar to the native virions.

Characterization and Recombinant Genotypes of HIV-1 in Gansu Province, China.

It is important to monitor the diversity and evolution of HIV-1 genotypes, especially in some remote and undeveloped regions in China where the diversity and distribution of HIV-1 genotypes are not fully clear. To investigate the genotypes and distribution of HIV-1 in far Northwestern Gansu Province of China, we selected 220 HIV-1-positive plasma samples from the Center for Disease Control and Prevention (CDC) in Gansu from January 2016 to December 2018. The viral load of inclusion samples were over 1,000 copies per milliliter. The gag, pol, and env gene of HIV-1 were amplified by nested reverse transcription-polymerase chain reaction kit, sequenced, and then identified genotypes using HIV-BLAST tool and the neighbor-joining method. One hundred fifty of 220 inclusion samples were successfully determined HIV-1 genotypes. Our results show that circulating recombinant forms (CRF) 07_BC and CRF01_AE are predominant and accounted for 46.7% and 28.0%, respectively. Other HIV-1 subtypes and genotypes included B/B' (6.0%), CRF08_BC (4.0%), and C (1.3%). In addition, we reported CRF65_cpx and CRF55_01B subtypes in Gansu for the first time. Phylogenetic tree analysis showed that the sequences of different samples are scattered in different genotype groups, and no obvious aggregation occurs. Our results indicate the genetic variety and complexity of HIV-1 and provide critical information for HIV/AIDS control and prevention in Gansu Province.

Nutrition and exercise interventions could ameliorate age-related cognitive decline: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effect of nutrition combined physical exercise interventions on age-related cognitive decline by a systematic review and meta-analysis. METHODS: We searched 9 databases, including PubMed, EMbase, The Cochrane Library, Web of Science, Science Direct, China National Knowledge Infrastructure (CNKI), VIP Information, China Biological Medical Database (CBM) and Wanfang for studies published until the end of December 2019. The selected trials should meet the following criteria, study objects: healthy adults aged 65 and over with cognitive dysfunction or diagnosed as MCI, but not meet the diagnostic criteria for dementia as well as no restriction on follow-up time, race or gender. Study interventions: multiple interventions including nutrition and exercise. EXCLUSION CRITERIA: (1) studies included elderly people with any type of dementia or patients with cognitive impairment induced by secondary causes, including drug, alcohol, severe organic brain diseases, mental disorders. (2) Republished literature. (3) Studies with significant differences in baseline data between groups. (4) The data in the study cannot be converted into the required data format. We reviewed and extracted information and assessed the risk of bias of recruited studies independently. Meta-analysis was performed using STATA v.15.1 software. The bias of publication was estimated by Egger test. RESULTS: A total of six RCTs representing 1039 participates were included in our meta-analysis. In terms of global cognitive function that has been assessed by neuropsychological test in different combinations, the result showed that the beneficial effect of nutrition combined exercise interventions was statistically significant [SMD = 0.23, 95% CI (0.1, 0.36), P = 0.0004]. There were no statistical differences from assays on MMSE scores, Memory, Executive Function, Attention, and Information Processing Speed across groups. CONCLUSIONS: The current study shows that nutrition combined exercise interventions can improve global cognitive function in the aged with cognitive decline. Further researches emphasizing on longer follow-up time, experimental randomness, credibility and scale would better elucidate the effect of nutrition combined exercise interventions on cognitive function, particularly in older adults. (registration number: CRD42020159291, date of registration: 28/04/2020).

Prevalence of Different Genotypes of HIV-1 in Injection Drug Users in China: A Systematic Review and Meta-Analysis.

BACKGROUND: Since 1981, an increasing trend in HIV has been observed for transmission via injection drug users (IDUs), sexual transmission and mother-to-child transmission. The IDUs are blamed for early increases in HIV-positive cases in China. OBJECTIVE: HIV genotypes of IDUs were comprehensively analysed to trace the source and relationships of the AIDS epidemic in China. METHODS: Relevant databases written in English and Chinese were searched. Overall, 7,149 publications were identified in six databases. After screening 7,104 articles according to the inclusion and exclusion criteria, 45 studies consisting of 2,765 cases were finally identified. A meta-analysis was conducted using R MATLAB software, RevMan and SPSS. Subgroup analyses focused on time frame, region, and location of different genotypes of IDUs in China. RESULTS: There were five dominant HIV-1 genotypes among the 2,765 IDU cases. The proportions of CRF07_BC, CRF01_AE, CRF08_BC, subtype B/B', and subtype C were 45.18% (95% CI: 33.55-57.08%), 16.00% (95% CI: 9.39-23.82%), 13.43% (95% CI: 7.32-20.84%), 3.58% (95% CI: 1.52-6.24%), and 0.90% (95% CI: 0.04-2.43%), respectively. HIV genotypes transmitted among IDUs in China are primarily CRF07-BC, followed by CRF01-AE and CRF08-BC. Across the different time frames and regions, CRF07_BC was the most prevalent HIV-1 genotype among IDUs, while CRF08_BC was the most prevalent genotype in the southwest region. CONCLUSION: Our study reveals that CRF07-BC was the dominant prevalent strain among IDUs from 1991 to 2015 in China, while CRF08-BC was the dominant prevalent strain among IDUs in southwestern China. This systematic review and meta-analysis shows evidence of the comprehensive prevalence of different genotypes, data and characteristics of HIV among IDUs in China.

Immunogenicity and protective efficacy of multistage vaccine candidates (Mtb8.4-HspX and HspX-Mtb8.4) against Mycobacterium tuberculosis infection in mice.

In this study, Mtb8.4 and HspX, which are expressed at proliferating and dormant stages of Mycobacterium tuberculosis (M. tuberculosis), respectively, were chosen to construct two fusion proteins, Mtb8.4-HspX (8.4H) and HspX-Mtb8.4 (H8.4), and we investigated whether the antigen dose and protein sequential order could impact the immunogenicity and protective efficacy of these fusion protein vaccines against M. tuberculosis. C57BL/6 mice were vaccinated with new constructions containing a fusion protein with adjuvant of N, N'-dimethyl-N, N'-dioctadecylammonium bromide (DDA) or a mixed adjuvant composed of DDA, polyribocytidylic acid and gelatin (DPG), and the antigen specific immune responses and protective efficacy against M. tuberculosis H37Rv were evaluated. The results showed that both antigens, Mtb8.4-HspX and HspX-Mtb8.4, could elicit strong human T cell responses. With the existing of DDA adjuvant, HspX-Mtb8.4 induced significantly higher secretion level of IFN-γ and TNF-α in spleen cells than Mtb8.4-HspX (p<0.05). In its protective efficacy study, the isolated bacterial Colony Form Unit (CFU) in H8.4-DPG group was significantly reduced compared to 8.4H-DPG group (p<0.05). Furthermore, with the stimulation of Mtb8.4 in vitro, the secretion of IFN-γ and TNF-α from mice immunized with 20µg of H8.4 exhibited relative higher level than the group immunized by 7µg of H8.4 (p<0.05), whereas, IL-2 secreting showed contrary result. The data suggest that the antigen sequential order and dose selection should be considered when a tuberculosis protein vaccine is to be constructed and its immune strategy is to be planned.

Sensitive Detection and Simultaneous Discrimination of Influenza A and B Viruses in Nasopharyngeal Swabs in a Single Assay Using Next-Generation Sequencing-Based Diagnostics.

Reassortment of 2009 (H1N1) pandemic influenza virus (pdH1N1) with other strains may produce more virulent and pathogenic forms, detection and their rapid characterization is critical. In this study, we reported a "one-size-fits-all" approach using a next-generation sequencing (NGS) detection platform to extensively identify influenza viral genomes for diagnosis and determination of novel virulence and drug resistance markers. A de novo module and other bioinformatics tools were used to generate contiguous sequence and identify influenza types/subtypes. Of 162 archived influenza-positive patient specimens, 161(99.4%) were positive for either influenza A or B viruses determined using the NGS assay. Among these, 135(83.3%) were A(H3N2), 14(8.6%) were A(pdH1N1), 2(1.2%) were A(H3N2) and A(pdH1N1) virus co-infections and 10(6.2%) were influenza B viruses. Of the influenza A viruses, 66.7% of A(H3N2) viruses tested had a E627K mutation in the PB2 protein, and 87.8% of the influenza A viruses contained the S31N mutation in the M2 protein. Further studies demonstrated that the NGS assay could achieve a high level of sensitivity and reveal adequate genetic information for final laboratory confirmation. The current diagnostic platform allows for simultaneous identification of a broad range of influenza viruses, monitoring emerging influenza strains with pandemic potential that facilitating diagnostics and antiviral treatment in the clinical setting and protection of the public health.

Pandemic Influenza A (H1N1) Virus Infection Increases Apoptosis and HIV-1 Replication in HIV-1 Infected Jurkat Cells.

Influenza virus infection has a significant impact on public health, since it is a major cause of morbidity and mortality. It is not well-known whether influenza virus infection affects cell death and human immunodeficiency virus (HIV)-1 replication in HIV-1-infected patients. Using a lymphoma cell line, Jurkat, we examined the in vitro effects of pandemic influenza A (H1N1) virus (pH1N1) infection on cell death and HIV-1 RNA production in infected cells. We found that pH1N1 infection increased apoptotic cell death through Fas and Bax-mediated pathways in HIV-1-infected Jurkat cells. Infection with pH1N1 virus could promote HIV-1 RNA production by activating host transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), nuclear factor of activated T-cells (NFAT) and activator protein 1 (AP-1) through mitogen-activated protein kinases (MAPK) pathways and T-cell antigen receptor (TCR)-related pathways. The replication of HIV-1 latent infection could be reactivated by pH1N1 infection through TCR and apoptotic pathways. These data indicate that HIV-1 replication can be activated by pH1N1 virus in HIV-1-infected cells resulting in induction of cell death through apoptotic pathways.

Bicarbonate- versus lactate-buffered solutions for acute continuous haemodiafiltration or haemofiltration.

BACKGROUND: Acute kidney injury (AKI) is a severe loss of kidney function that results in patients' inability to appropriately excrete nitrogenous wastes and creatinine. Continuous haemodiafiltration (HDF) or haemofiltration (HF) are commonly used renal replacement therapies for people with AKI. Buffered dialysates and solutions used in HDF or HF have varying effects on acid-base physiology and several electrolytes. The benefits and harms of bicarbonate- versus lactate-buffered HDF or HF solutions for treating patients with AKI remain unclear. OBJECTIVES: To assess the benefits and harms of bicarbonate- versus lactate-buffered solutions for HDF or HF for treating people with AKI. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 6 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched the Chinese Biomedical Literature Database. SELECTION CRITERIA: All randomised controlled trials (RCT) and quasi-RCTs that reported comparisons of bicarbonate-buffered solutions with lactate-buffered solutions for AKI were selected for inclusion irrespective of publication status or language. DATA COLLECTION AND ANALYSIS: Two authors independently assessed titles and abstracts, and where necessary the full text of studies, to determine which satisfied our inclusion criteria. Data were extracted by two authors who independently assessed studies for eligibility and quality using a standardised data extraction form. Methodological quality was assessed using the Cochrane risk of bias tool. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified four studies (171 patients) that met our inclusion criteria. Overall, study quality was suboptimal. There were significant reporting omissions related to methodological issues and potential harms. Outcome measures were not defined or reported adequately. The studies were small and lacked follow-up phases.Serum lactate levels were significantly lower in patients treated with bicarbonate-buffered solutions (4 studies, 171 participants: MD -1.09 mmol/L, 95% CI -1.30 to -0.87; I(2) = 0%). There were no differences in mortality (3 studies, 163 participants: RR 0.76, 95% CI 0.50 to 1.15; I(2) = 0%); serum bicarbonate levels (3 studies, 163 participants: MD 0.27 mmol/L, 95% CI -1.45 to 1.99; I(2) = 78%), serum creatinine (2 studies, 137 participants: MD -22.81 µmol/L, 95% CI -129.61 to 83.99; I(2) = 73%), serum base excess (3 studies, 145 participants: MD 0.80, 95% CI -0.91 to 2.50; I(2) = 38%), serum pH (4 studies, 171 participants: MD 0.01, 95% CI -0.02 to 0.03; I(2) = 70%) or carbon dioxide partial pressure (3 studies, 151 participants: MD -1.04, 95% CI -3.84 to 1.76; I(2) = 83%). A single study reported fewer cardiovascular events (RR 0.39, 95% CI 0.20 to 0.79), higher mean arterial pressure (10.25 mm Hg, 95% CI 6.68 to 13.82) and less hypotensive events (RR 0.44, 95% CI 0.26 to 0.75) in patients receiving bicarbonate-buffered solutions. One study reported no significant difference in central venous pressure (MD 2.00 cm H2O, 95% CI -0.7 to, 4.77). Total length of hospital and ICU stay and relapse were not reported by any of the included studies. AUTHORS' CONCLUSIONS: There were no significant different between bicarbonate- and lactate-buffered solutions for mortality, serum bicarbonate levels, serum creatinine, serum base excess, serum pH, carbon dioxide partial pressure, central venous pressure and serum electrolytes. Patients treated with bicarbonate-buffered solutions may experience fewer cardiovascular events, lower serum lactate levels, higher mean arterial pressure and less hypotensive events. With the exception of mortality, we were not able to assess the main primary outcomes of this review - length of time in ICU, total length of hospital stay and relapse.

Bicarbonate versus lactate solutions for acute peritoneal dialysis.

BACKGROUND: The high mortality rate among critically ill patients with acute kidney injury (AKI) remains an unsolved problem in intensive care medicine, despite the use of renal replacement therapy (RRT). Increasing evidence from clinical studies in adults and children suggests that the new peritoneal dialysis (PD) fluids may allow for better long-term preservation of peritoneal morphology and function. Formation of glucose degradation products (GDPs) can be reduced and even avoided with the use of newer "biocompatible" solutions. However, it is still unclear if there are any differences in using conventional (lactate) solutions compared with low GDP (bicarbonate) solutions for acute PD. OBJECTIVES: To look at the benefits and harms of bicarbonate versus lactate solutions in acute PD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966), EMBASE (from 1980), Latin American and Caribbean Health Sciences Literature Database LILACS (from 1982), and reference lists of articles.Date of last search: 6 May 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bicarbonate to lactate solution for acute PD. DATA COLLECTION AND ANALYSIS: Two authors independently assess the methodological quality of studies. One author abstracted data onto a standard form, and a second author checked data extraction. We used the random-effects model and expressed the results as relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included one study (20 patients) in this review. In shock patients, bicarbonate did not differ from lactate with respect to mortality (RR 0.50, 95% CI 0.06 to 3.91); however there were significant differences in blood lactate (MD -1.60 mmol/L, 95% CI -2.04 to -1.16), serum bicarbonate (MD 5.00 mmol/L, 95% CI 3.26 to 6.74) and blood pH (MD 0.12, 95% CI 0.06 to 0.18). In non-shock patients there was a significance difference in blood lactate (MD -0.60 mmol/L, 95% CI -0.85 to -0.35) but not in serum bicarbonate (MD 1.10 mmol/L, 95% CI -0.27 to 2.47) or blood pH (MD -0.02, 95% CI -0.02 to -0.06). Other outcomes could not be analysed because of the limited data available. AUTHORS' CONCLUSIONS: There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).

Some findings of FADD knockdown in inhibition of HIV-1 replication in Jurkat cells and PBMCs.

Fas-associated protein with death domain (FADD) is a key adaptor molecule transmitting the death signal mediated by death receptors, and it is also required for T cell proliferation. A recent study indicated that FADD is able to affect HIV-1 production, but the mechanism is not known. Using the susceptible Jurkat cell line and peripheral blood mononuclear cells, we studied the effects of FADD on HIV-1 production. TaqMan RT-PCR was used to quantify HIV-1 viral RNA copies, and Western blot analysis was used to detect protein expression. FADD knockdown decreased HIV-1 replication and inactivated caspase-3 activity in the cells and blocked CD4 translocation to the lipid rafts of the plasma membrane. Reduced expression of FADD suppressed TCR signaling through downregulation of TCR, CD3, and Zap-70 in response to HIV-1 infection and blocked the trafficking of TCR, CD3, CD28, and Zap-70 to lipid rafts, leading to reduced activation of NF-κB and NFAT, which are required for HIV-1 replication. FADD knockdown diminished caspase-8 migration to lipid rafts and its expression in response to HIV-1 infection. These results indicate that FADD, as a host pro-apoptotic protein, plays important roles in regulating HIV-1 replication and production in several ways, and apoptotic pathway inhibition is able to decrease HIV-1 replication and production.

Highly pathogenic avian influenza A virus (H5N1) can be transmitted in ferrets by transfusion.

BACKGROUND: Highly pathogenic avian influenza A virus has been shown to infect organs other than the lung, and this is likely to be mediated by systemic spread resulting from viremia which has been detected in blood in severe cases of infection with avian H5N1 viruses. The infectivity of virus in blood and the potential for virus transmission by transfusion has not been investigated. METHODS: Using a susceptible ferret animal model, we evaluated viremia and transmission by blood transfusion. Blood was collected on day 2, 4, 6, and 10 post-infection (or before death) from donor ferrets infected with either low dose (1.0 × 10(2.6) EID50/ml) or high dose (1.0 × 10(3.6) EID50/ml) of H5N1 virus, A/VN/1203/04 and transfused to recipient animals. RESULTS: Viremia was observed in 2/12 (16.67%) recipients that received blood from donor ferrets infected with low dose and 7/12 (58.33%) recipients who received blood from high dose infected donors. 1/12 (8.3%) low dose recipients and 6/12 (50%) high dose recipients died within 11 days after transfusion. Increased changes in body weight and temperatures were observed in high dose recipients, and high levels of viral RNA were detected in recipient ferrets after transfusion of blood from the early viremic phase, which also correlated with adverse impact on their survival. CONCLUSION: These data suggest that highly pathogenic avian influenza A virus, H5N1, is transmissible by blood transfusion in ferrets. Low levels of viremia were detected around the time of onset of symptoms and later in ferrets infected with highly pathogenic H5N1 virus. These findings may have implication for pathogenesis and transmissibility of H5N1.

Novel pandemic influenza A (H1N1) virus infection modulates apoptotic pathways that impact its replication in A549 cells.

It is not well-known whether apoptosis signaling affects influenza virus infection and reproduction in human lung epithelial cells. Using A549 cell line, we studied the relationship of some apoptosis-associated molecules with novel pandemic influenza A (H1N1) virus, A/California/04/2009. Infected cells displayed upregulated Fas ligand, activated FADD and caspase-8, and downregulated FLIP in the extrinsic apoptotic pathway. p53 expression increased and Bcl-XL expression decreased in the intrinsic pathway. Expression of pre-apoptotic molecules (FasL, FADD, and p53) increased virus replication, while inhibition of activity of FADD, caspase-8 and caspase-3, and expression of anti-apoptotic proteins (FLIP and Bcl-XL) decreased virus replication. p38, ERK and JNK from MAPK pathways were activated in infected cells, and inhibition with their inhibitors diminished virus replication. In the p38 superfamily, p38α expression increased viral RNA production, while expression of p38ß and p38γ decreased. These data indicated that influenza virus induces apoptotic signaling pathways, which benefit virus replication.

Some mechanisms of FLIP expression in inhibition of HIV-1 replication in Jurkat cells, CD4+ T cells and PBMCs.

HIV-1 infection and replication are affected by host factors. Recent studies demonstrate that molecules from apoptotic pathways regulate HIV-1 replication. Therefore, studies on effects of host factors that maintain host cell survival and influence HIV-1 replication are critical to understanding the mechanisms of HIV-1 replicative cycle. Using the susceptible Jurkat cell line, CD4(+) T cells, and peripheral blood mononuclear cells (PBMCs), we studied the role of FLIP, an inhibitor of caspase-8, in HIV-1 production. Full length cellular FLIP (cFLIP) inhibited HIV-1 replication in these cells. cFLIP upregulated the expression of viral restriction factors, such as TRIM5, Apobec3G, and Bst2/tetherin, decreased nuclear factor 1C expression and inactivated ERK and p38 induced by HIV-1 in Jurkat cells. cFLIP blocked the trafficking of gp120 and Gag p24 capsid protein into lipid rafts with inhibition of Tsg101 and Alix in ESCRT signaling pathway. cFLIP also promoted Bst2/tetherin trafficking into lipid rafts. These results indicate that cFLIP may inhibit the HIV-1 replication cycle at multiple steps, including viral RNA release, transcription, traffic and assembly. We also found that cFLIP expression downregulated Fas expression and inactivated FADD in the Fas-mediated apoptotic pathway. The inactivated FADD also inhibited HIV-1 replication.

HIV-1 and HIV-2 infections induce autophagy in Jurkat and CD4+ T cells.

Autophagy plays important roles during innate and adaptive immune responses to pathogens, including virus infection. Viruses develop ways to subvert the pathway for their own benefit in order to escape restriction by autophagy, leading to increased viral replication and/or control over apoptosis of their host cells. The effects of HIV infection on the autophagic pathway in host cells have been little documented. Using the susceptible Jurkat cell line and CD4(+) T cells, we studied the relationship of HIV-1 and -2 infections with autophagy. We found that HIV infections significantly increase transcription of ULK1, a member of the autophagy-initiated complex. Two ubiquitin-like conjugation systems, the Atg12 conjugation system and the microtubule-associated protein L chain 3 (LC3) conjugation system that control the elongation of the autophore to form the autophagosome, were activated after HIV infection, with upregulation of Atg12-Atg5 complex and increased transcription of LC3, and formed more autophagosome in infected cells detected using an EM assay. We also found that HIV-1 induced more autophagic death in Jurkat cells relative to HIV-2, and the inhibition of autophagy with 3MA and Beclin-1 knockdown decreased HIV-1 replication significantly. The results indicate that HIV is able to induce the autophagic signaling pathway in HIV-infected host cells, which may be required for HIV infection-mediated apoptotic cell death.

Bicarbonate versus lactate solutions for acute peritoneal dialysis.

BACKGROUND: The high mortality rate among critically ill patients with acute kidney injury (AKI) remains an unsolved problem in intensive care medicine, despite the use of renal replacement therapy (RRT). Increasing evidence from clinical studies in adults and children suggests that the new peritoneal dialysis (PD) fluids may allow for better long-term preservation of peritoneal morphology and function. Formation of glucose degradation products (GDPs) can be reduced and even avoided with the use of newer "biocompatible" solutions. However, it is still unclear if there are any differences in using conventional (lactate) solutions compared with low GDP (bicarbonate) solutions for acute PD. OBJECTIVES: To look at the benefits and harms of bicarbonate versus lactate solutions in acute PD. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966), EMBASE (from 1980), Latin American and Caribbean Health Sciences Literature Database LILACS (from 1982), and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bicarbonate to lactate solution for acute PD. DATA COLLECTION AND ANALYSIS: Two authors independently assess the methodological quality of studies. One author abstracted data onto a standard form, and a second author checked data extraction. We used the random-effects model and expressed the results as relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included one study (20 patients) in this review. In shock patients, bicarbonate did not differ from lactate with respect to mortality (RR 0.50, 95% CI 0.06 to 3.91); however there were significant differences in blood lactate (MD -1.60 mmol/L, 95% CI -2.04 to -1.16), serum bicarbonate (MD 5.00 mmol/L, 95% CI 3.26 to 6.74) and blood pH (MD 0.12, 95% CI 0.06 to 0.18). In non-shock patients there was a significance difference in blood lactate (MD -0.60 mmol/L, 95% CI -0.85 to -0.35) but not in serum bicarbonate (MD 1.10 mmol/L, 95% CI -0.27 to 2.47) or blood pH (MD -0.02, 95% CI -0.02 to -0.06). Other outcomes could not be analysed because of the limited data available. AUTHORS' CONCLUSIONS: There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).

Azithromycin vs. benzathine penicillin G for early syphilis: a meta-analysis of randomized clinical trials.

The World Health Organization estimates that at least 12 million people are infected with syphilis in the world. Southeast Asia accounts for 5.8 million; Africa accounts for 3.5 million. There has been controversy in using the two kinds of antibiotics for early syphilis. A systematic review comparing these antibiotics could affect treatment guidelines. The aim of this study was to evaluate the efficacy and safety of azithromycin vs. penicillin G benzathine for early syphilis and a meta-analysis to compare these two kinds of antibiotics for early syphilis. Four randomized controlled trials met the inclusion criteria; 476 patients were evaluated for their cure rate. Cure rates were 95.0% (227/239) for azithromycin and 84.0% (199/237) for penicillin G benzathine. After pooling the data, the difference in efficacy was computed. Cure rate (OR=1.37), 95% CI (1.05, 1.77) and the risk difference for cure rate between the two drugs were statistically significant. Although the gastrointestinal adverse effect of azithromycin is five times more than the adverse effect of penicillin G benzathine, the differences are not significant. Azithromycin achieved a higher cure rate than penicillin G benzathine in a long follow-up.

[A Meta-analysis of high-dose epinephrine in children with cardiopulmonary arrest].

OBJECTIVE: Epinephrine has a place in the treatment of pediatric cardiopulmonary arrest but has been controversy concerning its optimal dose. This meta-analysis aimed to seek for evidences of the effectiveness of different doses of epinephrine in children with cardiac arrest and to evaluate the effectiveness of high-dose versus standard-dose epinephrine in children with cardiac arrest. METHOD: Published papers on randomized controlled trials (RCTs) and prospective clinical controlled trials (CCTs) were electronically searched from MEDLINE (1966 to September 2006), EMBASE (1974 to June 2006), the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2006), CBM (1998 to 2006) and CNKI (1994 to 2006). We also had searched the related references and manual retrieval 10 professional academic journals about epinephrine treatment of pediatric cardiopulmonary arrest (1998 to 2006). The search strategy was made according to the collaborative review group search strategy. At first, we found 546 articles. Second, we excluded 474 of them through reading the title, abstract, excluding non-randomized, non-controlled trials and non-clinical studies. Finally, we identified 4 papers through searching for original articles and telephone contact with some of the authors after excluding 68 papers. Then we performed the meta-analysis by RevMan 4.2.7. For homogenous dichotomous data (P > or = 0.1, I(2) < or = 50%) we calculated fixed effects model, relative risk (RR), 95% confidence intervals (CI), For heterogeneity Dichotomous data (P < 0.1, I(2)>50%) we calculated random effects model, relative risk (RR) and 95% confidence intervals (CI). RESULT: Four trials involving 360 cases were included. The results of meta-analysis indicated that there were no statistical difference in recovery of spontaneous circulation [RR = 1.28, 95% CI (0.93, 1.77)]. Perondi, Patterson and Cheng xiuyong's study compared the rate of survival at 24 hours and showed statistical heterogeneity (P = 0.01, I(2) = 0.77). The random effects model indicated that there were no significant difference [RR = 1.40, 95% CI (0.43, 4.55)]. The sensitivity analysis showed that after deleting Perondi's group there were no statistical heterogeneity. Fixed effects model indicated that there were significant difference [RR = 2.50, 95% CI (1.52, 4.11)]. T When the rates of survival to hospital discharge were compared among the 4 studies, there was statistical heterogeneity (P = 0.07, I(2) = 0.58), the random effects model indicated that there were no statistical difference [RR = 1.78, 95% CI (0.42, 7.50)], There were no heterogeneity after Cheng Xiu-yong group was deleted. CONCLUSION: Higher doses of epinephrine in children with cardiopulmonary arrest may not increase the rate of recovery of spontaneous circulation, the rate of survival at 24 hours, the rate of survival to hospital discharge and worsen the neurological outcomes. Adverse reactions is difficult to monitor and evaluate because of the current restrictions on medical technology.