UV degradation of deoxyribonucleic acid

The effects of UV synchrotron radiation on deoxyribonucleic acid (DNA) cast films have been systematically investigated by vacuum ultraviolet and infrared spectrophotometry as a function of irradiation time. Cast DNA films exposed at 140 nm (8.85 eV) for different irradiations times, revealed consistent changes in their VUV spectra which indicate a decrease of thymine groups and an increase of ? ? ?* transition spectral signature associated with the C=O group of the open sugar chain. This result was corroborated by a decrease in C-O stretching vibration at 1061 cm?1 observed in the infrared spectra. Both these results are consistent with the creation of single strand breaks in the deoxyribose component of DNA molecule and a decrease in the phosphate groups. It was also shown that UV radiation is effective in damaging the thymine groups involved in Hoogsteen base pairing with adenine. The analysis of the infrared data suggests that the usual spectroscopic fingerprints of DNA denaturation are not necessarily a reliable measure of DNA damage

New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.This work was supported as part of the PhD project of K.A.G funded by the European Research Council and AstraZeneca Early Oncology TD

Setting Research Priorities To Reduce Global Mortality from Childhood Diarrhoea by 2015

Olivier Fontaine and colleagues applied a priority-setting methodology to identify research priorities aimed at reducing global diarrhea mortality by 2015

Anthropometry measures and prevalence of obesity in the urban adult population of Cameroon: an update from the Cameroon Burden of Diabetes Baseline Survey

BACKGROUND: The objective of the study was to provide baseline and reference data on the prevalence and distribution of overweight and obesity, using different anthropometric measurements in adult urban populations in Cameroon. METHODS: The Cameroon Burden of Diabetes Baseline Survey was a cross-sectional study, conducted in 4 urban districts (Yaoundé, Douala, Garoua and Bamenda) of Cameroon, using the WHO Step approach for population-based assessment of cardiovascular risk factors. Body mass index, waist circumference and waist-to-hip ratio were measured using standardized methods. Overall, 10,011 individuals, 6,004 women and 4,007 men, from 4,189 households, aged 15 years and above participated. RESULTS: Based on body mass index, more than 25% of urban men and almost half of urban women were either overweight or obese with 6.5% of men and 19.5% of women being obese. The prevalence of obesity showed considerable variation with age in both genders. Using body mass index provided the highest prevalence of obesity in men (6.5%) and waist-to-hip ratio the lowest prevalence (3.2%). Among women, using waist-to-hip ratio and waist circumference yielded the highest prevalence of obesity (28%) and body mass index the lowest (19.5%). There was a trend towards an increase in age-adjusted odd ratios of being overweight or obese with duration of education in both sexes. CONCLUSION: The study provides current data on anthropometric measurements and obesity in urban Cameroonian populations, and found high prevalences of overweight and obesity particularly over 35 years of age, and among women. Prevalence varied according to the measure used. Our findings highlight the need to carry out further studies in Cameroonian and other Sub-Saharan African populations to provide appropriate cut-off points for the identification of people at risk of obesity-related disorders, and indicate the need to implement interventions to reverse increasing levels of obesity

Flavaglines Alleviate Doxorubicin Cardiotoxicity: Implication of Hsp27

Background: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicininduced cardiotoxicity. Methodology/Principal Findings: Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50 % decrease of mortality. Conclusions/Significance: These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induce

Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity

Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8(+) T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8(+) T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8(+) T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-beta. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8(+) T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity

Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events