Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

The doctrine of the 'responsibility to protect' as a practice of political exceptionalism

The consensus on the doctrine of the ‘responsibility to protect’ has replaced ideas of humanitarian intervention with a new vision of the responsibilities that states have to protect their peoples from the most egregious suffering. The contention of this article is that this is a politics of exceptionalism, whereby power is legitimated by reference to its effectiveness in responding to emergency or crisis. By analysing the doctrine in this way, new light is shed on the debate surrounding the responsibility to protect. First, understanding the doctrine in terms of exceptionalism helps explain the paradox of how the doctrine has been assimilated so readily into institutional and state practice without manifesting any greater commitment to international intervention. Second, understanding these new security practices in terms of exceptionalism allows us to move beyond questions of imperialism. Once understood in terms of exceptionalism, it can be shown that the stakes in the debate on the responsibility to protect are restricted not only to relations between states, but also to relations within them: principles of representative government are to be substituted with paternalist and authoritarian visions of state power

Circumstellar discs: What will be next?

This prospective chapter gives our view on the evolution of the study of circumstellar discs within the next 20 years from both observational and theoretical sides. We first present the expected improvements in our knowledge of protoplanetary discs as for their masses, sizes, chemistry, the presence of planets as well as the evolutionary processes shaping these discs. We then explore the older debris disc stage and explain what will be learnt concerning their birth, the intrinsic links between these discs and planets, the hot dust and the gas detected around main sequence stars as well as discs around white dwarfs.Comment: invited review; comments welcome (32 pages

Hepatitis B virus infection among different sex and age groups in Pakistani Punjab

<p>Abstract</p> <p>Background</p> <p>Hepatitis B virus (HBV) infection is a serious health problem in the developing countries including Pakistan. Various risk factors are responsible for the spread of this infectious disease. Prevalence of HBV infection in apparently suspected individual of Punjab province of Pakistan was analyzed during January 2008 to December 2010. Current study was aimed to investigate the epidemiology and risk factors of HBV infection.</p> <p>Methodology</p> <p>Four thousand eight hundred and ninety patients suffering from chronic liver disease were screened for the presence of HBV DNA using qualitative Real Time PCR methodology to confirm their status of infection. A predesigned standard questionnaire was filled for all the patients that included information about the possible risk factors.</p> <p>Results</p> <p>A total of 4890 ELISA positive patients were screened for Hepatitis B virus infection. Of these 3143 were positive for HBV, includes 68.15% males and 31.85% females. Male were observed to be more frequently infected as compared to the female with a positivity ratio of 2.14: 1. The rate of infection increases with the passage of time in the course of three years. Highest frequency of infection was found in the age of 21-30 was 34.93% followed by 23.83% in 31-40. Only (13.39%) were belonging to the age group 11-20 year. The rate of infection declines with increasing age as shown by age groups 41-50 (16.13%) and 51-60 (7.09%). While children aged 0-10 and very old >60 age groups were very less frequently 1.49% and 1.65% infected respectively. Important risk factors contributing to HBV spread include barber risk (23.60%), blood transfusion (4.04%), History of injection 26.19%, Reuse of syringes 26.60%, dental risk (11.20%) and surgical procedure (4.26%). Among the entire respondents trend sharing personal items was very common. History of injection, barber risk, surgery and dental procedure and reuse of syringes appear as major risk factors for the transmission.</p> <p>Conclusion</p> <p>Male were more frequently exposed to the risk factors as compared to female. Similarly the younger age group had high rate of infection as compared to the children's and the older age groups. Reuse of syringes', barber risk and History of injection were main risk identified during the present study. To lower HBV transmission rate Government should take aggressive steps towards massive awareness and vaccination programs to decrease the burden of HBV from the Punjab province of Pakistan.</p

GB virus-C – a virus without a disease: We cannot give it chronic fatigue syndrome

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness in search of an infectious etiology. GB virus-C (GBV-C) virus is a flavivirus with cell tropism and host defense induction qualities compatible with a role in producing the syndrome. The GBV-C genome is detectable in 4% of the population and 12% of the population is seropositive. The present study evaluated the association between infection with GBV and CFS. METHODS: We used a commercial EIA to detect antibodies against the GBV-C E2 protein and a quantitative real-time RT-PCR assay to detect active GBV-C infection. Sera were from a case control study of CFS in Atlanta, Georgia. The Fisher's exact two-tailed test was used for statistical analysis. RESULTS: Two of 12 CFS patients and one of 21 controls were seropositive for prior GBV-C infection and one control had viral RNA detected, indicating active infection. The results are not statistically different. CONCLUSION: We found no evidence that active or past infection with GBV is associated with CFS

Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients

Viral Hepatitis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65791/1/j.1365-4362.1981.tb00836.x.pd

Predictors of tuberculosis (TB) and antiretroviral (ARV) medication non-adherence in public primary care patients in South Africa: A cross sectional study

Background: Despite the downward trend in the absolute number of tuberculosis (TB) cases since 2006 and the fall in the incidence rates since 2001, the burden of disease caused by TB remains a global health challenge. The co-infection between TB and HIV adds to this disease burden. TB is completely curable through the intake of a strict anti-TB drug treatment regimen which requires an extremely high and consistent level of adherence.The aim of this study was to investigate factors associated with adherence to anti-TB and HIV treatment drugs. Methods: A cross-sectional survey method was used. Three study districts (14 primary health care facilities in each) were selected on the basis of the highest TB caseload per clinic. All new TB and new TB retreatment patients were consecutively screened within one month of anti-tuberculosis treatment. The sample comprised of 3107 TB patients who had been on treatment for at least three weeks and a sub-sample of the total sample were on both anti-TB treatment and anti-retro-viral therapy(ART) (N = 757). Data collection tools included: a Socio-Demographic Questionnaire; a Post-Traumatic-Stress-Disorder (PTSD) Screen; a Psychological Distress Scale; the Alcohol Use Disorder Identification Test (AUDIT); and self-report measures of tobacco use, perceived health status and adherence to anti-TB drugs and ART. Results: The majority of the participants (N = 3107) were new TB cases with a 55.9% HIV co-infection rate in this adult male and female sample 18 years and older. Significant predictors of non-adherence common to both anti-TB drugs and to dual therapy (ART and anti-TB drugs) included poverty, having one or more co-morbid health condition, being a high risk for alcohol mis-use and a partner who is HIV positive. An additional predictor for non-adherence to anti-TB drugs was tobacco use. Conclusions: A comprehensive treatment programme addressing poverty, alcohol mis-use, tobacco use and psycho-social counseling is indicated for TB patients (with and without HIV). The treatment care package needs to involve not only the health sector but other relevant government sectors, such as social development.IS