IgG antibodies against phospholipase A2 from Crotalus durissus terrificus: cross-reaction with venoms from Bothrops species from Argentina

We examined the ability of IgG anti-crotalic PLA2 to cross-react with Bothrops spp. venoms, from snakes found in the northeast of Argentina. Immunoblotting and ELISA tests showed that IgG anti-crotalic PLA2 recognize antigens of bothropic venoms. Indirect hemolytic activity tests showed that the quantity of antibodies that neutralized 50% of Crotalus durissus terrificus venom (ED50: 2.1 mg IgG anti-crotalic PLA2/100 µg of venom) were also able to neutralize venom from other snakes in the following proportion: 34% of B. alternatus, 18% of B. diporus and 12% of B. jararacussu. Likewise, direct PLA2 activity neutralization tests showed a similar cross-neutralization pattern including 56% of B. alternatus, 29% of B. diporus and 30% of B. jararacussu. In addition, in a myotoxic activity neutralization test, measured by plasma activity of creatine kinase, 35% of B. alternatus venom and 26% of B. diporus venom were neutralized, while no neutralization was detected with B. jararacussu venom. This study presents original data concerning cross-reactions between bothropic venoms from Argentina and IgG anti-crotalic PLA2. Our results suggest that anti-crotalic PLA2 antibodies should not be used to neutralize PLA2 activity of B. alternatus, B. diporus and especially B. jararacussu venoms; nor to enrich commercial antivenoms against these Bothrops species

Detecting functional magnetic resonance imaging activation in white matter: Interhemispheric transfer across the corpus callosum

<p>Abstract</p> <p>Background</p> <p>It is generally believed that activation in functional magnetic resonance imaging (fMRI) is restricted to gray matter. Despite this, a number of studies have reported white matter activation, particularly when the corpus callosum is targeted using interhemispheric transfer tasks. These findings suggest that fMRI signals may not be neatly confined to gray matter tissue. In the current experiment, 4 T fMRI was employed to evaluate whether it is possible to detect white matter activation. We used an interhemispheric transfer task modelled after neurological studies of callosal disconnection. It was hypothesized that white matter activation could be detected using fMRI.</p> <p>Results</p> <p>Both group and individual data were considered. At liberal statistical thresholds (p < 0.005, uncorrected), group level activation was detected in the isthmus of the corpus callosum. This region connects the superior parietal cortices, which have been implicated previously in interhemispheric transfer. At the individual level, five of the 24 subjects (21%) had activation clusters that were located primarily within the corpus callosum. Consistent with the group results, the clusters of all five subjects were located in posterior callosal regions. The signal time courses for these clusters were comparable to those observed for task related gray matter activation.</p> <p>Conclusion</p> <p>The findings support the idea that, despite the inherent challenges, fMRI activation can be detected in the corpus callosum at the individual level. Future work is needed to determine whether the detection of this activation can be improved by utilizing higher spatial resolution, optimizing acquisition parameters, and analyzing the data with tissue specific models of the hemodynamic response. The ability to detect white matter fMRI activation expands the scope of basic and clinical brain mapping research, and provides a new approach for understanding brain connectivity.</p

Association between TCF7L2 gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Transcription factor 7-like 2 (<it>TCF7L2</it>) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the <it>TCF7L2 </it>gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action.</p> <p>Methods</p> <p>Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (<it>OR</it>). Publication bias and study-between heterogeneity were also examined.</p> <p>Results</p> <p>The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian <it>OR </it>for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (<it>CrI</it>): 1.790, 2.157), 1.406 (95% <it>CrI</it>: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%<it>CrI</it>: 1.698, 2.088), 1.360 (95% <it>CrI</it>: 1.291, 1.433), respectively. Four <it>OR</it>s among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (<it>P </it>> 0.10). Pooled <it>OR</it>s fit a codominant, multiplicative genetic model for all the four polymorphisms of <it>TCF7L2 </it>gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism.</p> <p>Conclusion</p> <p>This meta-analysis demonstrates that four variants of <it>TCF7L2 </it>gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the <it>TCF7L2 </it>gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the <it>TCF7L2 </it>gene influence the risk of T2MD need further exploration.</p

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

Abstract: The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here, we report the molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for resistance to neutrophil killing. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins

Uptake and intracellular trafficking of superantigens in dendritic cells.

Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II) on the antigen-presenting cell (APC), thereby circumventing intracellular processing to trigger T cell activation. Dendritic cells (DCs) are professional APCs that coat nearly all body surfaces and are the most probable candidate to interact with SAgs. We demonstrate that SAgs are taken up by mouse DCs without triggering DC maturation. SAgs were found in intracellular acidic compartment of DCs as biologically active molecules. Moreover, SAgs co-localized with EEA1, RAB-7 and LAMP-2, at different times, and were then recycled to the cell membrane. DCs loaded with SAgs are capable of triggering in vitro lymphocyte proliferation and, injected into mice, stimulate T cells bearing the proper TCR in draining lymph nodes. Transportation and trafficking of SAgs in DCs might increase the local concentration of these exotoxins where they will produce the highest effect by promoting their encounter with both MHC-II and TCR in lymph nodes, and may explain how just a few SAg molecules can induce the severe pathology associated with TSS