Letter from J. P. Fanning

Letter concerning recommendation for Albert W. Casey

p38 δ

p38δ mitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38δ MAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38δ MAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38δ MAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38δ MAPK activity. We outline a role for p38δ MAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38δ MAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38δ MAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38δ MAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts

Loss of p38δ mitogen-activated protein kinase expression promotes oesophageal squamous cell carcinoma proliferation, migration and anchorage-independent growth.

Oesophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Thus, a greater understanding of the biology of oesophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. The physiological functions of p38α and -β are now well documented in contrast to -γ and -δ which are comparatively under-studied and ill-defined. A major obstacle to deciphering the role(s) of the latter two p38 isoforms is the lack of specific chemical activators and inhibitors. In this study, we analysed p38 MAPK isoform expression in oesophageal cancer cell lines as well as human normal and tumour tissue. We observed specifically differential p38δ expression. The role(s) of p38δ and active (phosphorylated) p38δ (p-p38δ) in oesophageal squamous cell carcinoma (OESCC) was delineated using wild-type p38δ as well as active p-p38δ, generated by fusing p38δ to its upstream activator MKK6b(E) via a decapeptide (Gly-Glu)5 linker. OESCC cell lines which are p38δ-negative (KE-3 and -8) grew more quickly than cell lines (KE-6 and -10) which express endogenous p38δ. Re-introduction of p38δ resulted in a time-dependent decrease in OESCC cell proliferation which was exacerbated with p-p38δ. In addition, we observed that p38δ and p-p38δ negatively regulated OESCC cell migration in vitro. Finally both p38δ and p-p38δ altered OESCC anchorage-independent growth. Our results suggest that p38δ and p-p38δ have a role in the suppression of OESCC. Our research may provide a new potential target for the treatment of oesophageal cancer

Does microbicide use in consumer products promote antimicrobial resistance? A critical review and recommendations for a cohesive approach to risk assessment

The increasing use of microbicides in consumer products is raising concerns related to enhanced microbicide resistance in bacteria and potential cross resistance to antibiotics. The recently published documents on this topic from the European Commission have spawned much interest to better understand the true extent of the putative links for the benefit of the manufacturers, regulators, and consumers alike. This white paper is based on a 2-day workshop (SEAC-Unilever, Bedford, United Kingdom; June 2012) in the fields of microbicide usage and resistance. It identifies gaps in our knowledge and also makes specific recommendations for harmonization of key terms and refinement/standardization of methods for testing microbicide resistance to better assess the impact and possible links with cross resistance to antibiotics. It also calls for a better cohesion in research in this field. Such information is crucial to developing any risk assessment framework on microbicide use notably in consumer products. The article also identifies key research questions where there are inadequate data, which, if addressed, could promote improved knowledge and understanding to assess any related risks for consumer and environmental safety

Burdigalian deposits of the Santa Cruz Formation in the Sierra Baguales, Austral (Magallanes) Basin: Age, depositional environment and vertebrate fossils

Indexación: Web of Science; Scielo.ABSTRACT. A succession of marine and continental strata on the southern flank of Cerro Cono in the Sierra Baguales, northeast of Torres del Paine, can be correlated with stratigraphic units exposed along the southern border of the Lago Argentino region in Santa Cruz Province, Argentina. These include the Estancia 25 de Mayo Formation and the basal part of the Santa Cruz Formation. The lithological correlation is also confirmed by detrital zircon ages (maximum age of 18.23±0.26 Ma) and a rich assemblage of terrestrial vertebrate fossils, biostratigraphically equivalent to a postColhuehuapian, pre-Santacrucian South American Land Mammal Age (SALMA) fauna, suggesting a range of 19 to 17.8 Ma. Similar ages have been obtained from the basal part of the Santa Cruz Formation at Estancia Quién Sabe in southwestern Argentina, supporting the assumption of a regional continuity between these deposits. A measured lithostratigraphic column is presented and the depositional environment is interpreted as a coastal plain with small, meandering rivers and ephemeral floodplain lakes. The sedimentation coincides with intensified uplift of the Patagonian Andes during the ‘Quechua Phase’ of Andean tectonism, which is reflected by a change in paleocurrent directions from northwest to east-northeast. Keywords: Burdigalian, Santa Cruz Formation, Santacrucian SALMA, ‘Notohippidian’ fauna, Meandering rivers.RESUMEN. Una sucesión de estratos marinos y continentales en el flanco meridional del cerro Cono, en la sierra Baguales, al noreste de Torres del Paine, se correlaciona con estratos al sur de la región de lago Argentino en la Provincia de Santa Cruz, República Argentina. Estas unidades incluyen la Formación Estancia 25 de Mayo y la parte basal de la Formación Santa Cruz. La correlación litológica es, además, confirmada por datación de circones detríticos (edad máxima de 18,23±0,26 Ma) y un variado ensamble de vertebrados fósiles terrestres de edad post-Colhuehuapense a pre-Santacrucense en la escala de Edades Mamífero Sudamericanas (EMAS), con un rango temporal de entre 19 a 17,8 Ma. Edades similares han sido reportadas para la parte basal de la Formación Santa Cruz, en estancia Quién Sabe, en el suroeste de Argentina, ratificando la continuidad regional entre estos depósitos. Se presenta una columna estratigráfica y se interpreta el ambiente de depositación como una llanura costera con pequeños ríos sinuosos y lagos efímeros. La edad de sedimentación coincide con el solevantamiento de los Andes Patagónicos durante la 'Fase Quechua', lo que se ve reflejado por un cambio en la dirección de las paleocorrientes desde el noroeste hacia el este-noreste.http://ref.scielo.org/csxwd

Incorporation of commercially-derived antimicrobials into gelatin-based films and assessment of their antimicrobial activity and impact on physical film properties

Four antimicrobials, namely; Articoat DLP 02 (AR), Artemix Consa 152/NL (AX), Auranta FV (AFV) and sodium octanoate (SO) were examined for their effectiveness, both before and after heat treatments, against bacterial strains Bacillus cereus, Pseudomonas fluorescens, Escherichia coli, Staphylococcus aureus and the microflora obtained from commercial beef steaks. Minimum inhibitory concentrations (MIC) using AR, AX, AFV and SO against these microbes were then obtained using the 96-well plate method. SO was the most effective against all bacterial strains, demonstrating the lowest MIC compared to the other antimicrobials. These antimicrobials were then successively incorporated into beef-derived gelatine films and these films were subsequently tested for structural, mechanical and barrier properties. Significantly (p < 0.05) enhanced water vapour barrier properties were determined only for antimicrobial films containing AX or SO when compared to control films. On the basis of FTIR spectra, significant changes in the structure of SO-containing films were determined when compared with control gelatin films. It was shown that active antimicrobial agents could potentially serve as commercial antimicrobial coatings for application onto conventional plastic-based food packaging

Safety and Effectiveness of Direct Oral Anticoagulants Versus Warfarin in People with Atrial Fibrillation and Dementia

Objective: To determine risks of embolic events, bleeding, and mortality with direct oral anticoagulants (DOACs) vs warfarin in people with atrial fibrillation (AF) and dementia. / Design: New-user retrospective cohort study using The Health Improvement Network database. / Setting and Participants: A population-based sample comprising people with AF and dementia prescribed DOACs or warfarin from August 2011 to September 2017. / Methods: Risk of ischemic stroke (IS), ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE), all-cause mortality, intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and other bleeding were compared for DOACs vs warfarin using propensity score–adjusted Poisson regression. Incidence rate ratios (IRRs) and absolute risk differences (ARDs) were calculated. / Results: Overall, 2399 people with AF and dementia initiated DOACs (42%) or warfarin (58%). Before propensity score adjustment, patients who initiated DOACs were older and had more comorbidities. After adjustment, DOAC initiators demonstrated similar risks of IS, TIA, or SE; IS alone; and other bleeding but reduced ICB risk (IRR 0.27, 95% CI 0.08, 0.86; ARD −5.2, 95% CI –6.5, −1.0, per 1000 person-years) compared with warfarin. Increased risk of GIB (IRR 2.11, 95% CI 1.30, 3.42; ARD 14.8, 95% CI 4.0, 32.4, per 1000 person-years) and all-cause mortality (IRR 2.06, 95% CI 1.60, 2.65; ARD 53.0, 95% CI 30.2, 82.8, per 1000 person-years) were observed in DOAC initiators compared with warfarin. / Conclusions and Implications: Among people with AF and dementia, initiating treatment with DOACs compared with warfarin was associated with similar risks of IS, TIA, or SE and IS alone. DOAC-treated patients demonstrated reduced ICB risk but increased GIB and all-cause mortality risks. We cannot exclude the possible impact of residual confounding from channeling of DOACs toward older and sicker people, particularly for the outcome of all-cause mortality. Further safety data are urgently needed to confirm findings

Integronlike Structures in Campylobacter spp. of Human and Animal Origin

Resistance to antimicrobial agents used to treat severe Campylobacter spp. gastroenteritis is increasing worldwide. We assessed the antimicrobial resistance patterns of Campylobacter spp. isolates of human and animal origin. More than half (n = 32) were resistant to sulphonamide, a feature known to be associated with the presence of integrons. Analysis of these integrons will further our understanding of Campylobacter spp. epidemiology

Gastrointestinal bleeding risk with rivaroxaban vs aspirin in atrial fibrillation: a multinational study

Purpose: Comparative gastrointestinal bleeding (GIB) risk between rivaroxaban and low‐dose aspirin is unknown in patients with atrial fibrillation (AF). This study investigated GIB risk with rivaroxaban vs aspirin among two separate AF cohorts in Hong Kong and the United Kingdom, using a common protocol approach. Methods: This was a population‐based cohort study using separate data from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority (2010‐2018) and The Health Improvement Network (THIN) database in the United Kingdom (2011‐2017). Patients with AF newly prescribed aspirin or rivaroxaban were included. Cox proportional hazards regression was used to compare GIB risks for rivaroxaban vs aspirin, accounting for confounders using propensity score fine stratification approach. Results: In CDARS, 29 213 patients were included; n = 1052 (rivaroxaban), n = 28 161 (aspirin). Crude GIB event rates per 100 patient‐years in CDARS were 3.0 (aspirin) and 2.6 (rivaroxaban). No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.04, 95%CI = 0.76‐1.42), and in dose‐stratified analyses (HR = 1.21, 95%CI = 0.84‐1.74 [20 mg/day]; HR = 0.80, 95%CI = 0.44‐1.45 [≤15 mg/day]). In THIN, 11 549 patients were included, n = 3496 (rivaroxaban) and n = 8053 (aspirin). Crude GIB event rates were 1.3 (aspirin) and 2.4 (rivaroxaban) per 100 patient‐years. No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.40, 95%CI = 1.00‐1.98) and low‐dose rivaroxaban (≤15 mg/day) (HR = 1.00, 95%CI = 0.56‐1.30), but increased GIB risk was observed for rivaroxaban 20 mg/day vs aspirin (HR = 1.57, 95%CI = 1.08‐2.29). Conclusion: In patients with AF, GIB risk was comparable between aspirin and rivaroxaban ≤15 mg/day. GIB risk for rivaroxaban 20 mg/day vs aspirin remains uncertain and warrants further investigation