The scientific community has responded to the coronavirus disease 2019 (COVID-19) pandemic by rapidly undertaking research to find effective strategies to reduce the burden of this disease. ...Encouragingly, researchers from a diverse array of fields are collectively working towards this goal. Research with infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undertaken in high-containment laboratories; however, it is often desirable to work with samples at lower-containment levels. To facilitate the transfer of infectious samples from high-containment laboratories, we have tested methods commonly used to inactivate virus and prepare the sample for additional experiments. Incubation at 80°C, a range of detergents, Trizol reagents, and UV energies were successful at inactivating a high titer of SARS-CoV-2. Methanol and paraformaldehyde incubation of infected cells also inactivated the virus. These protocols can provide a framework for in-house inactivation of SARS-CoV-2 in other laboratories, ensuring the safe use of samples in lower-containment levels.
Speleothem oxygen isotope records have revolutionized our understanding of the paleo East Asian monsoon, yet there is fundamental disagreement on what they represent in terms of the hydroclimate ...changes. We report a multiproxy speleothem record of monsoon evolution during the last deglaciation from the middle Yangtze region, which indicates a wetter central eastern China during North Atlantic cooling episodes, despite the oxygen isotopic record suggesting a weaker monsoon. We show that this apparent contradiction can be resolved if the changes are interpreted as a lengthening of the Meiyu rains and shortened post-Meiyu stage, in accordance with a recent hypothesis. Model simulations support this interpretation and further reveal the role of the westerlies in communicating the North Atlantic influence to the East Asian climate.
Encephalitis, brain inflammation and swelling, most often caused by an infection or the body's immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical ...predictors of different types of encephalitis to help clinicians consider earlier treatment. We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had HSV, 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1.sup.st dose of aciclovir for those with HSV was 14 hours (IQR 5-50); time to 1.sup.st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45-250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x10.sup.6 /L, but they were less likely to have a febrile illness. Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE OF REVIEWThe purpose of this review is to give an overview of viral meningitis and then focus in on some of the areas of uncertainty in diagnostics, treatment and outcome.
RECENT ...FINDINGSBacterial meningitis has been declining in incidence over recent years. Over a similar time period molecular diagnostics have increasingly been used. Because of both of these developments viral meningitis is becoming relatively more important. However, there are still many unanswered questions. Despite improvements in diagnostics many laboratories do not use molecular methods and even when they are used many cases still remain without a proven viral aetiology identified. There are also no established treatments for viral meningitis and the one potential treatment, aciclovir, which is effective in vitro for herpes simplex virus, has never been subjected to a clinical trial.
SUMMARYViruses are in increasingly important cause of meningitis in the era of declining bacterial disease. The exact viral aetiology varies according to age and country. Molecular diagnostics can not only improve the rate of pathogen detection but also reduce unnecessary antibiotics use and length of hospitalization. Further research is required into treatments for viral meningitis and the impact in terms of longer term sequelae.
Interdecadal modes of tropical Pacific ocean-atmosphere circulation have a strong influence on global temperature, yet the extent to which these phenomena influence global climate on multicentury ...timescales is still poorly known. Here we present a 2,000-year, multiproxy reconstruction of western Pacific hydroclimate from two speleothem records for southeastern Indonesia. The composite record shows pronounced shifts in monsoon rainfall that are antiphased with precipitation records for East Asia and the central-eastern equatorial Pacific. These meridional and zonal patterns are best explained by a poleward expansion of the Australasian Intertropical Convergence Zone and weakening of the Pacific Walker circulation (PWC) between B1000 and 1500 CE Conversely, an equatorward contraction of the Intertropical Convergence Zone and strengthened PWC occurred between B1500 and 1900 CE. Our findings, together with climate model simulations, highlight the likelihood that century-scale variations in tropical Pacific climate modes can significantly modulate radiatively forced shifts in global temperature.
Recent studies have proposed that millennial-scale reorganization of the ocean-atmosphere circulation drives increased upwelling in the Southern Ocean, leading to rising atmospheric carbon dioxide ...levels and ice age terminations. Southward migration of the global monsoon is thought to link the hemispheres during deglaciation, but vital evidence from the southern sector of the vast Australasian monsoon system is yet to emerge. Here we present a 230thorium-dated stalagmite oxygen isotope record of millennial-scale changes in Australian-Indonesian monsoon rainfall over the last 31,000 years. The record shows that abrupt southward shifts of the Australian-Indonesian monsoon were synchronous with North Atlantic cold intervals 17,600-11,500 years ago. The most prominent southward shift occurred in lock-step with Heinrich Stadial 1 (17,600-14,600 years ago), and rising atmospheric carbon dioxide. Our findings show that millennial-scale climate change was transmitted rapidly across Australasia and lend support to the idea that the 3,000-year-long Heinrich 1 interval could have been critical in driving the last deglaciation.
FLT3–internal tandem duplications (FLT3-ITDs) are prognostic driver mutations found in acute myeloid leukemia (AML). Although these short duplications occur in 25% of AML patients, little is known ...about the molecular mechanism underlying their formation. Understanding the origin of FLT3-ITDs would advance our understanding of the genesis of AML. We analyzed the sequence and molecular anatomy of 300 FLT3-ITDs to address this issue, including 114 ITDs with additional nucleotides of unknown origin located between the 2 copies of the repeat. We observed anatomy consistent with replication slippage, but could only identify the germline microhomology (1-6 bp) anticipated to prime such slippage in one-third of FLT3-ITDs. We explain the paradox of the “missing” microhomology in the majority of FLT3-ITDs through occult microhomology: specifically, by priming through use of nontemplated nucleotides (N-nucleotides) added by terminal deoxynucleotidyl transferase (TdT). We suggest that TdT-mediated nucleotide addition in excess of that required for priming creates N-regions at the duplication junctions, explaining the additional nucleotides observed at this position. FLT3-ITD N-regions have a G/C content (66.9%), dinucleotide composition (P < .001), and length characteristics consistent with synthesis by TdT. AML types with high TdT show an increased incidence of FLT3-ITDs (M0; P = .0017). These results point to an unexpected role for the lymphoid enzyme TdT in priming FLT3-ITDs. Although the physiological role of TdT is to increase antigenic diversity through N-nucleotide addition during V(D)J recombination of IG/TCR genes, here we propose that illegitimate TdT activity makes a significant contribution to the genesis of AML.
•FLT3-ITDs unexpectedly show junctional N-nucleotides with properties consistent with synthesis by TdT.•Off-target TdT activity in AML is proposed to promote FLT3-ITD formation by priming replication slippage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Management of acute meningitis Griffiths, Michael J; McGill, Fiona; Solomon, Tom
Clinical medicine (London, England),
04/2018, Volume:
18, Issue:
2
Journal Article
Peer reviewed
Open access
Acute meningitis remains a devastating disease. Clinicians need a low threshold for suspecting meningitis, to undertake appropriate investigations and provide treatment in a timely manner, to ...minimise the risk of poor outcome in bacterial disease, while limiting unnecessary treatment in viral meningitis.
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GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Investigators seeking to identify genetic prognostic markers in a clinical trial to treat acute myeloid leukemia found that minimal residual disease, detected by the presence of mutation in
NPM1,
...provided prognostic information independent of other risk factors.
Although acute myeloid leukemia (AML) is genetically less complex than many other tumors, the condition is molecularly heterogeneous.
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Despite improved understanding of the mutational landscape, treatment decisions, particularly regarding allogeneic stem-cell transplantation, remain guided by cytogenetic analysis, a limited panel of molecular genetic markers, and morphology-based assessment of remission.
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Currently, a predicted risk of relapse of more than 35% is widely considered to warrant stem-cell transplantation during the first remission.
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Patients with high-risk disease undergo stem-cell transplantation if feasible, whereas those with low-risk disease usually do not. However, there is uncertainty about the role of transplantation in patients . . .
Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML). AML with mutated NPM1 is recognized as a separate entity in the World Health Organization 2016 classification ...and carries a relatively favorable prognosis. NPM1 mutations are predominantly 4-bp duplications or insertions in the terminal exon that arise through an unknown mechanism. Here we analyze 2430 NPM1 mutations from 2329 adult and 101 pediatric patients to address their origin. We show that NPM1 mutations display the hallmarks of replication slippage, but lack suitable germline microhomology available for priming. Insertion mutations display G/C-rich N-nucleotide tracts, with a significant bias toward polypurine and polypyrimidine stacking (P < .001). These features suggest terminal deoxynucleotidyl transferase (TdT) primes replication slippage through N-nucleotide addition, with longer syntheses manifesting as N-regions. The recurrent type A, type D, and type B mutations require 1, 2, and 3 N-nucleotide extensions of T, CC, and CAT, respectively, with the last nucleotide used as occult microhomology. This TdT-mutator model successfully predicts the relative incidence of the 256 potential 4-bp insertion/duplication mutations at position c.863_864 over 4 orders of magnitude (ρ = 0.484, P < .0001). Children have a different NPM1 mutation spectrum to adults, including a shift away from type A mutations and toward longer N-regions, consistent with higher TdT activity in pediatric myeloid stem cells. These findings complement our FLT3-ITD data, suggesting illegitimate TdT activity contributes to around one-half of AMLs. AML may therefore reflect the price for adaptive immunity.
•NPM1 mutations in AML arise from replication errors primed by illegitimate TdT activity.•The involvement of TdT in both NPM1 and FLT3-ITD mutagenesis suggests a significant proportion of AML is a by-product of adaptive immunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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